Although after adjustment for sex, GA, birth weight, and growth restriction, GA  and writhing GMs  were not significant, a strong trend still persisted. The HNNE scores significantly correlated with both the HINE evaluation  and fidgety GMs . Linear regression confirmed the HNNE was highly predictive of the HINE . Writhing GMs did not significantly correlate with either fidgety GMs  or the HINE . Conclusions: Abnormal writhing GMs in the neonatal period were non-significantly associated with early CP/high-risk diagnoses in extremely preterm infants in a multivariate analysis. Additionally, the HNNE significantly correlated with both fidgety GMs and the HINE.Background: Early diagnosis of cerebral palsy (CP) in high-risk infants is possible at 3–4 months’ corrected age (CA) using standardised assessments. Aim: To assess the utility of neonatal screening assessments—writhing general movements (GMs) and the Hammersmith Neonatal Neurological Examination (HNNE)—to predict CP/high-risk status at 3–4 months’ CA in extremely preterm infants. Methods: Retrospective cohort study of high-risk preterm infants (born < 29 weeks’ gestation and/or birth weight < 1000 g) attending an Early Neurodevelopment Clinic. Data from neonatal assessments were compared with CP/high-risk diagnosis at 3–4 months’ CA, fidgety GMs, and Hammersmith Infant Neurological Examinations (HINE) using logistic regression, linear regression, and Spearman rank correlation. Results: Two hundred and two preterm infants (median gestation age at birth 27.3 (IQR 25.4–28.3) weeks, mean birth weight 870.3 (SD 248.4) grams) were included. A total of 26 (12.8%) infants received early CP/high-risk diagnoses at 3–4 months’ CA. A lower gestational age (GA) (OR = 0.78;  Cerebral palsy (CP) is the most common physical disability diagnosed in children, with an overall prevalence of approximately 2.0–2.11/1000 live births internationally and 1.4/1000 live births in Australia . The early diagnosis of CP is now possible in high-risk infants at 3–4 months’ corrected age (CA). Early intervention may promote positive cognitive and motor developmental outcomes amongst high-risk infants, and thus the early diagnosis or early identification of infants at high risk of CP is a critical step towards enabling this .There is a range of assessment tools currently utilised to detect movement difficulties and predict CP in infants. Prechtl’s general movement assessments (GMA), Hammersmith Infant Neurological Examinations (HINE), and MRI brain scans have the highest predictive validity before 5 months’ corrected age and are recommended to be used to predict CP with high sensitivity before 5 months’ corrected age ,7,8. NotThe Prechtl GMA is an observational tool used to assess the spontaneous movements of an infant, known as general movements (GMs). GMs arise during early foetal life and persist until 4–5 months’ CA. GMs can be recorded after a preterm birth until 6 weeks’ CA. Known as “writhing movements”, these are characterised by variable movements through the whole body, including arm, leg, neck, and trunk movements. Normal writhing movements appear smooth and unpredictable and show variability in the intensity, range, direction, and complexity of movement ,10. AbnoThe Hammersmith Infant Neurological Examination (HINE) is a validated scored assessment of 26 items, each scored from 0 to 3, used to evaluate infants between 2 and 24 months’ CA to inform a diagnosis of CP. It functions as both a quantitative and qualitative assessment, evaluating movement, cranial nerves, tone, reflexes, and posture . A globaCurrently, a combination of GMA, the HINE, and neonatal MRI is the gold standard for the diagnosis of CP in high-risk infants and can be used to accurately predict CP before 5 months’ CA ,7,8,14.The Hammersmith Neonatal Neurological Examination (HNNE) is a scored neurological assessment presently limited to use as a screening tool in term and preterm infants, though it has not been validated for use in infants <34 weeks’ GA. It consists of 34 items across six domains: tone (10 items), tone patterns (5 items), reflexes (6 items), spontaneous movements (3 items), abnormal signs (3 items), and behaviour (7 items), with a maximum global optimality score of 34 ,20. In aSeveral studies have identified a relationship between GMs and CP diagnosis amongst very preterm infants assessed at preterm or term-equivalent age ,23,24. HPresently, no studies have analysed the utility of early neonatal assessments in the preterm period for predicting the later diagnoses made based on fidgety age assessments in very preterm (<29 weeks) or extremely low birth weight (1000 g) infants at 3–4 months of corrected age. There are also no studies tracking the correlation between the HNNE and HINE scores.We conducted an exploratory study to assess how early neonatal screening assessments correlate with 3–4-months’ CA assessments of high-risk infants in the setting of a clinical surveillance clinic (Early Neurodevelopment Clinic (ENC)), in order to answer the question: can early neonatal screening assessments accurately predict early diagnoses of CP/high-risk status in high-risk infants at 3–4 months’ corrected age in a real-world setting? The answer to this question may be useful in guiding the approach to high-risk infants and maximising early intervention at term age to improve outcomes amongst the high-risk preterm cohort, or in guiding further research that needs to be undertaken. This retrospective cohort study analysed the data of high-risk preterm infants (born < 29 weeks’ gestation and/or birth weight < 1000 g) attending the Early Neurodevelopment Clinic at Monash Children’s Hospital, Melbourne, Australia. This clinic was established in 2018 to facilitate the early diagnosis of CP in line with current recommendations .Data were collected from electronic records of clinic notes between May 2019 and November 2021. The records of 393 patients attending ENC were reviewed; 190 did not fit the inclusion criteria (<29 weeks/<1000 g) and were excluded. One further patient was excluded due to non-attendance at their ENC appointment. Early neonatal assessment results and demographic information were obtained from the electronic patient records of the remaining 202 infants who attended the clinic. Assessments were performed and videos were scored in practice by experienced clinicians at Monash Newborn and ENC, and videos were not re-reviewed during the study. Where practicable, infants had multiple writhing GM videos captured and assessed during their neonatal admission between 32 and 46 weeks’ GA. Thirty infants had only one writhing GM video recorded during their admission. Factors preventing multiple recordings included short admission duration, inter-hospital transfer, and patient behaviour unsuitable for assessment. The HNNE was performed between 35 and 45 weeks’ GA. Participants were divided into two cohorts based on their diagnosis at 3–4 months’ CA:CP or high-risk for developing CP, and normal development or developmental delay other than CP. Diagnoses were made based on fidgety GMA and the HINE in combination with neuroimaging findings, such as cranial ultrasounds or MRI brain scans, where available. CP and high-risk status were distinguished as some infants meeting criteria for CP  did not receive a definitive diagnosis at 3–4 months’ CA but were still referred for close follow-up to monitor progression. Neonatal neuroimaging findings were included in the 3–4-month assessment for CP, and thus cannot be included in the comparison between these two time points. Therefore, this paper focuses on clinical assessments.Normal = 0;PR = 1;PR/CS = 2;CS on one occasion = 3;CS on two or more occasions = 4.All available writhing GM scores from the neonatal period were reviewed, and patients were categorised according to the worst recorded score, as follows: The group for which CS > 2 was distinguished from the CS group to illustrate the difference between a one-off CS GM and a trajectory of persistent CS GMs. Of the 27 infants who received a score of 3, only 1 did not have multiple writhing GM assessments performed. Present = 0;Sporadic = 1;Abnormal = 2;Absent = 3.Fidgety GMs were categorised as follows:Global cut-off scores of 27 and 57 were used for the HNNE and the HINE, respectively.This study was exempt from review by Monash Health Human Research Ethics Committee and received ethics approval by Monash Health as a quality assurance project (ERM Reference No. 81908). It followed NHMRC Ethical Considerations in Quality Assurance and Evaluation Activities (2014) guidelines.Statistical analyses were performed using Stata Version 16 . Additional analyses were performed in GraphPad Prism Version 9.0 . The Wilk–Shapiro test was performed to determine the normality of numerical data. The mean and standard deviation were calculated for normally distributed data, while the median and inter-quartile range were calculated for non-normally distributed data. Data from neonatal assessments (writhing GMs and HNNE scores) were correlated against results of 3–4-months’ CA assessments (fidgety GMs and HINE scores) using Spearman’s Rho correlation. Linear regression was performed to directly compare the HNNE with subsequent HINE scores. Neonatal assessment scores (writhing GMs and HNNE) were studied for association with the 3–4-months’ CA diagnosis using a parsimonious model univariate logistic regression and then adjusted for demographic characteristics  with the results expressed as odds ratios, with 95% confidence intervals and significance set at <0.05. Two hundred and two preterm infants were included in the study. The median gestational age of participants was 27 + 3 weeks (IQR 25 + 4–28 + 3), and the mean birth weight was 870.3 g (SD 248.4 g). Twenty-six infants (12.8%) received a CP or high-risk clinic diagnosis—eight (4.0%) infants were diagnosed with CP, and eighteen (8.9%) were considered at high-risk. Eighty-two (40.6%) infants were deemed developmentally normal at ENC, and ninety-four (46.5%) were deemed delayed in specific parts of development but not high-risk for CP. Additional demographic characteristics of the participants are outlined in One infant did not receive a diagnosis at ENC. Eight did not receive HINE scores, and three did not receive fidgety GM scores. Thirty-three infants did not have available HNNE scores, and three did not have available writhing GMs. All infants attending the clinic were within the fidgety period (between 10 and 20 weeks’ CA) .p = 0.029, 95% CI ) and all abnormal writhing GMs  were significantly predictive of CP/high-risk diagnosis at 3–4 months’ CA. The relationship between writhing GMs and 3–4-month diagnosis is represented in Parsimonious model univariate logistic regression  determinp = 0.068, 95% CI ) or writhing GMs .This trend persisted in multivariate analyses , though s) of 0.43 for the HINE  and −0.18 for fidgety GMs , indicating a significant correlation between the HNNE and both the HINE and fidgety GM scores. Linear regression .Correlation analysis  showed tgression  confirmep = 0.723, 95% CI ) and −0.10 for the HINE . The writhing GMs had a non-significant Spearman’s Rho coefficient of 0.03 for fidgety GMs . However, once the data were adjusted for birth weight, sex, GA, and SGA/IUGR, this correlation was not statistically significant . Abnormal writhing GMs were also found to be weakly correlated with abnormal fidgety GMs   and abnormal HINE scores . Both writhing and fidgety GMs were scored with normal being 0 and increasing scores indicating worsening performance, which is reflected in the negative coefficients with both the HINE and HNNE. A review of the literature found fidgety GMs had sensitivity between 95 and 100% with a specificity of 89–98% for predicting CP diagnosis at 2 years of age ,13,14,26p = 0.05, 95% CI ). This is consistent with current evidence, which suggests that the HNNE performed at two weeks post-term in term infants, or at term-corrected age in preterm infants, is highly predictive of a neurodevelopmental deficit [Our study also found the HNNE scores to be somewhat predictive of early CP diagnosis at 3–4 months (OR= 0.88). Because the HNNE scores increase with improving performance, an odds ratio <1 indicates that an increasing HNNE score is associated with a decreased likelihood of early CP diagnosis. However, this association was not statistically significant  for early CP diagnosis at ENC. As with the HNNE, the risk of CP decreases with increasing gestational age. It is known that reduced gestational age at birth is a risk factor for CP [Our study also identified gestational age at birth as a significant predictive factor in the development of CP. Reduced gestational age had an odds ratio of 0.78  hospitals. Three patients (1.5%) did not have scores for writhing GMs; thirty-three (16.3%) did not have scores for the HNNE. A small number of infants attending the ENC had incomplete 3–4-month assessments; three (1.5%) did not have recorded results for fidgety GMs, and eight (4.0%) did not have HINE scores. The reasons cited included telehealth appointments limiting the ability to perform assessments, infant irritability impeding the assessment, and parental reluctance. Additionally, whilst all participants attending ENC appointments were within the 10–20-week fidgety period, there was some variation in the age at the time of appointment, which may have impacted the data. This is due in part to the COVID-19 pandemic, which resulted in some patient clinic appointments needing to be rescheduled due to lockdown requirements or moved to telehealth, which also impacted the examination accuracy. However, it is reflective of the real-world setting in which these assessments are conducted, and thus still provides valuable insight into their utility.The findings of this study suggest that early neonatal assessments, in particular writhing GMs, are non-significantly associated with the early diagnosis of CP at 3–4 months’ CA. Writhing GMs and the HNNE may have combined value as supportive assessments for infants at risk of poorer outcomes at 3–4 months. This information may be utilised to identify infants who are likely to be diagnosed with CP or high-risk status from a high-risk population and ensure that long-term follow-up is planned from inpatient discharge. Additionally, it may be beneficial in organising access to early intervention and support services for high-risk infants.


The relationship between maternal folic acid supplementation and the birth weights of offspring remains inconclusive.To examine the associations between maternal supplementation with folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) and newborn birth weights, as well as the risk of small for gestational week age (SGA) and large for gestational week age (LGA) newborns.Data on 31,107 births from 2015 to 2018 were extracted from the population-based prenatal health care system in a district of Beijing. Generalized linear and logistic regression models were used to evaluate the association between maternal periconceptional folic acid supplementation and birth weights or with risk of small for gestational week age (SGA) and large for gestational week age (LGA).aOR) = 0.81 (95% CI: 0.68–0.97)], however newborns born to mothers who took multiple micronutrients with folic acid (MMFA) with high compliance had a 25.59 g (95% CI: 6.49–44.69) higher median birth weight. Periconceptional women took folic acid only (FAO)  or MMFA  with high compliance decreased the risk of SGA, but has no impact on the risk of LGA.Compared with newborns whose mothers did not use any folic acid supplements, the newborns with maternal periconceptional folic acid supplementation had similar median birth weight but had a lower risk of SGA [adjusted odds ratio (Periconceptional FAO supplementation has no impact on the median birth weight of offspring and the risk of LGA. Compared with FAO, MMFA supplementation may increase the average birth weight, and a high compliance of supplementation with FAO or MMFA may reduce the risk of SGA, with MMFA having ad stronger effect than FAO. Periconceptional FAO supplementation has no impact on the median birth weight of offspring and the risk of LGA.; Compared with FAO, MMFA supplementation increases the average birth weight, and a high compliance of supplementation with FAO or MMFA reduces the risk of SGA, with MMFA having ad stronger effect than FAO.Periconceptional folic acid only supplementation may have no impact on the average birth weight and the risk of LGA of offspring.Periconceptional multiple micronutrients supplementation may increases the average birth weight compared with folic acid only.A high compliance of supplementation with multiple micronutrients may reduce the risk of SGA.Birth weight has long been used as an indicator for the healthy status of newborns and it is widely accepted that an abnormal birth weight, such as SGA or LGA, can have either short or long-term effects on an offspring's health –7. PreseFolate is a water-soluble member of the vitamin B complex family. It acts as a substrate and cofactor in many cellular metabolic pathways and biochemical reactions, such as DNA and RNA synthesis, intracellular signal transduction and methylation –13. In tEvidence that FAO or MMFA can prevent neural tube defects has also stimulated research on the relationship between maternal folic acid supplementation and other pregnancy outcomes. Among these studies, the subject of most concern is the effect of folic acid supplementation on birth weights. However, the evidence on the effect of folic acid supplementation on the birth weights of newborns is not consistent in the literature –21. RetrFolate metabolism is particularly active during cell division, and embryo tissues are very sensitive to folate deficiency or metabolic changes , 23. TheThe study aimed to understand the use of folic acid supplements in Beijing women during the periconceptional period, and to evaluate its impact on birth weights and the risk for SGA and LGA for their offspring, to further understand the safety and necessity of maternal periconceptional folic acid supplementation.The data was drawn from the Prenatal Health Care System (PHCS) at the Tongzhou Maternal and Child Health Care Hospital in Beijing from 2015 to 2018. The PHCS is a networked system in Beijing City, and it covers all the community hospitals and hospitals with obstetrics and gynecology. Each woman who is diagnosed as pregnant in a hospital needs to register with the PHCS before 13 weeks of pregnancy at the community hospital closest to their place of residence. A prenatal health care booklet with a barcode containing a unique 14-digit number is given to the women, which is her pregnancy identification number in the system. She can be identified by scanning the barcode when she goes to a delivery hospital in Beijing to have her prenatal health care examinations, and then her clinical medical information will be recorded in the system.Uniformly trained doctors or nurses from the community hospital collected the demographic information, medical history, obstetrics and gynecology history, disease history, and information on folic acid supplementation during the periconceptional period using face-to-face interviews at the time of registration. The information includes maternal nationality, age, education level, occupation, pre-pregnancy body mass index (BMI), compliance with supplementation, delivery year, household registration, and information on folic acid supplementation.The information on the gestational week of delivery, birth weight, gender, and other delivery information for the baby was entered in the PHCS by the doctors and nurses at the delivery hospital. The birth weight was measured by the obstetrician or midwife of the delivery hospital using an electronic weighing scale with an accuracy of 10 g <30 min after the baby was delivered.From October to November every year, 200 women were selected monthly by the doctors at the District Maternal and Child Health Hospital, and the data in the pregnancy health database was verified by a telephone survey. The qualifying rate for the information from the annual information verification was more than 96.5%. The information on the newborns included birthweight, gender, and other parameters, as well as information on gestational complications, including gestational diabetes, hypertensive disorders of pregnancy, and anemia, among others. This information was then checked with the clinical medical records information obtained from the Maternal and Child Health Hospital's clinic information system in this study.n = 429), multiple pregnancies (n = 356), stillbirths (n = 438), those with missing data on gestational weeks (n = 113), with gestational weeks >43 (n = 269), and with a birthweight lower than half of the weight of neonates with the same gender and gestational age (n = 2), or missing information on formula of folic acid supplementation (n = 29). As a result, 31,136 records for mother and newborn pairs were left for analysis in the study .Information maternal on the use of periconceptional folic acid supplements was collected with four questions: Did you take folic acid supplements during periconceptional period? (Yes/No); Which kind of formula supplements did you take? [Pills containing folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA)]; What time did you initiate the supplementation? ; What was the frequency of your supplementation? (8 days or more out of 10 days or <8 days out of 10 days). The last menstrual period was used to determine the timing of conception, pre-conception was indicated by “before the last menstrual period” and post-conception was indicated by “after the last menstrual period.” The periconceptional period was defined as the period from 12 weeks before the last menstrual period to 12 weeks after the last menstrual period. Taking folic acid supplements with high compliance was defined as supplementation for 8 days or more out of 10 days, whereas low compliance was defined as supplementation for <8 days out of 10 days.The outcome variables in this study are birth weight, SGA, and LGA, which are defined as follows: SGA: according to the Chinese male and female birth weight percentile in 2015 , SGA is P < 0.001), the median and interquartile range  were selected to describe the average and deviation in birth weight. The descriptive statistics for the categorical variables were reported as frequencies and percentages. The chi-square test was used to compare the general characteristics of women among the groups of women with using folic acid supplements. The Wilcoxon rank-sum test was used to compare the differences in average birth weight of different genders. Spearman's rank correlation was used to analyze birth weight change by years.Since birth weight did not conform to the normal distribution .Wilcoxon rank-sum test, Kruskal–Wallis P < 0.05).The maternal mean (SD) age was 29.16 (±4.06) years, the mean (SD) pre-pregnancy BMI was 22.21 (±3.43) kg/m  birth weight was 3,390 g , among which the median (P25-P75) birth weight for females was 3,330 g  and 3,440 g  for males. According to the Wilcoxon rank-sum test analysis, the differences in the average birth weight of male and female newborns was statistically significant (P < 0.001). In addition, according to the Spearman's rank correlation analysis, the median birth weight increased from 2015 to 2018 (Ptrendtest = 0.001).As can be seen in P = 0.002) and the prevalence of LGA increased from 2015 to 2018 (Ptrendtest = 0.014).The overall prevalence of SGA and LGA were 5.5 and 11.6%, respectively. The differences in prevalence for SGA among newborns by gender or delivery year were not statistically significant. The differences in prevalence for LGA was not statistically significant for gender, but the difference was statistically significant for different delivery years .The results of a univariate analysis on the relationship between folic acid supplementation and newborn birth weight are shown in (P < 0.01) and multivariate analysis β = 15.09 (95% CI: 4.92–24.73).The results of multivariate generalized linear models on the relationship between periconceptional folic acid supplementation and newborn birth weight are shown in aOR) = 0.81 (95% CI: 0.68–0.97)]. Babies born to mothers who took MMFA with high compliance had a 25.59 g (95% CI: 6.49–44.69) higher median birth weight than those whose mothers did not take any supplements. After adjusting for confounding factors, the risk of SGA among newborns whose mothers took FAO or MMFA during the periconceptional period with high compliance was lower than those whose mothers did not take any folic acid supplements, with aOR = 0.83 (95% CI: 0.67–1.01) and aOR = 0.74 (95% CI: 0.60–0.91) for FAO and MMFA, respectively.Compared with newborns whose mothers did not use any folic acid supplements, newborns with maternal periconceptional folic acid supplementation had a lower risk of SGA [. Finally, 94% of the participants were urban women of Han ethnicity having similar dietary patterns and lifestyles, which further reduced the remaining confounding factors.RR) for folic acid supplementation vs none supplementation was 0.72 in a birth cohort study in Lanzhou city in north of China . The research proposal was approved by the Institutional Review Board of Peking University, because as it was a retrospective study based on routine data, we need not to get informed consent from the participants. This manuscript reported adherence to Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.JL and CW: data curation, methodology, and writing—original draft. JZ, SL, and MT: data curation. LJ and WM: collected data and contributed to data cleaning and analysis. AR: critically reviewed the manuscript for important intellectual content. LJ and LC: conceptualization, funding acquisition, project administration, writing—review, and editing. All authors contributed to the article and approved the submitted version.This work was supported by Capital's Funds for Health Improvement and Research, CFH) in People's Republic of China (020-1-5112). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding 10 authors had full access to all the data in the study and had final responsibility 10 for the decision to submit for publication.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.


Communication and information are part of the Sexual and Reproductive Health and Rights (SRHR). Various studies show that successful communication between birthing person and health care professionals (HCP) has a positive impact on birth and lowers risk of traumatic birth experience for women. Since information and communication is a major challenge for both forced migrant women (FMW) and health workers during birth, we investigated experiences of both sides in qualitative study.Qualitative interviews were conducted with 7 maternal HCPs  and with 7 FMW 1-9 months after the birth of their child in 3 regions in Germany. The refugee sample included new mothers from 6 countries of origins, 14 languages, and an average of three years living in Germany. The interviews were analyzed via framework analysis.The majority of the interviewed FMW had no or little knowledge about SRHR. Good communication is one of the main factors allowing a safe and trustful environment with the birthing women. If verbal communication is not possible nonverbal communication helps to create and maintain a care relationship with the women is given. However, due to lack of staff, time and interpreters FMW with little German language proficiencies receive hardly any relevant information and had a poorer accompaniment during birth.To provide for equity and SRHRs in maternal health and care there is an urgent need for reliable professional interpretation and easily accessible information in relevant languages material about giving birth, medical possibilities, procedures and interventions. Additionally, further training on heterogeneous needs and life contexts is necessary, to improve professional care during birth in maternity wards. HCPs 1:1 support is strongly recommended.• Information on SRHR and communication are a fundamental part of birth work and should be made possible for all women including FMW to prevent discrimination and traumatic birth experiences.• If given, 1:1 support by HCPs during birth can comensate missing communication.


Several studies have linked longer legs with favorable adult metabolic health outcomes and greater offspring birth weight. A recent Mendelian randomization study suggested a causal link between height and cardiometabolic risk; however, the underlying reasons remain poorly understood.Using a cross-sectional design, we tested in a convenience sample of 70 healthy young women whether birth weight and tibia length as markers of early-life conditions associated more strongly with metabolically beneficial traits like organ size and skeletal muscle mass (SMM) than a statistically derived height-residual variable indexing later, more canalized growth.Consistent with the ‘developmental origins of health and disease’ hypothesis, we found relatively strong associations of tibia length—but not birth weight—with adult organ size, brain size, SMM and resting energy expenditure measured by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry and indirect calorimetry, respectively.Building on prior work, these results suggest that leg length is a sensitive marker of traits directly impacting metabolic and reproductive health. Alongside findings in the same sample relating tibia length and height-residual to MRI-measured pelvic dimensions, we suggest there may exist a degree of coordination in the development of long bone, lean mass and pelvic traits, possibly centered on early, pre-pubertal growth periods. Such phenotypic coordination has important implications for fitness, serving to benefit both adult health and the health of offspring in subsequent generations. Taller stature and longer leg length have been linked with a range of adult cardiometabolic health outcomes, such as lower blood pressure and insulin resistance, and reduced risk of ischemic heart disease and type 2 diabetes . Conversin utero results in ‘brain sparing’ at the expense of other organs, thereby increasing susceptibility to non-communicable disease in later life. Indeed, individuals of both high and low birth weight appear susceptible to later obesity, while low birth weight may predispose to increased visceral fat .In R2 for tibia, height residual and birth weight. The tibia made the greatest relative contribution in all but the FM model, while the contribution of height residual varied across models and that of birth weight was overall negligible.In contrast, controlling for tibia length and height residual, associations of birth weight with body composition and REE were weak, with all point estimates close to zero. We further tested associations of body composition and REE with relative leg length, which, as noted above, has been evidenced as a marker specifically of post-natal growth . PeThis study has documented associations of different growth markers with adult organ size, brain size, SMM and REE. For all organs and for muscle mass, the strongest associations were evident with tibia, whereas a contrasting pattern was evident for body fat, most strongly correlated with height residual. Organs and SMM are highly metabolically active and important for metabolic homeostasis , 33, thuHeight has for some time been recognized to correlate with organ size in both children and adults , 37, butOur results, coupled with those that previously identified leg length-cardiovascular disease links, are consistent with the capacity–load model; namely, crucial components of metabolic capacity  develop early in life and may later aid in mitigating the deleterious effects of metabolic load (i.e. high glycemic load diets and sedentariness) . EvidencAlthough perhaps less involved in mitigating metabolic risk than internal organs, SMM and REE, the implications of optimal brain development for health and fitness cannot be overstated. The relatively strong association we observed for tibia length versus height residual is consistent with what is known about the importance of early life growth for brain development, even as various aspects of brain phenotype continue to grow and develop across the life course . As enviWith respect to reproductive outcomes, our study sample included only nulliparous women; therefore, we were not able to directly test potential intergenerational associations of participants’ tibia length with the birth weight of their offspring. Our results, however, arguably aid in explaining previously identified positive associations of parental—in particular, maternal—leg length with offspring birth weight , and poiIn a prior analysis of this sample, we tested associations of similar growth markers—tibia length, a height-residual variable and birth weight—with MRI-measured adult pelvic dimensions and found stronger associations for tibia length and height-residual relative to birth weight . Taken tA strength of our study is the use of high-quality measurement techniques to obtain body composition, brain and REE outcomes, all of which were collected by a single observer. We made an effort to control for potentially confounding variables in our study design and there were few missing data. At the same time, birth weight may have suffered from recall bias, with additional noise in the data potentially impacting our findings. Our sample size was relatively small, and, as noted previously, a cross-sectional design and the use of growth proxy measures may be considered a limitation . For exaLongitudinal studies are needed to further elucidate how different growth periods shape aspects of adult phenotype, including organs, SMM and pelvis size. Although leg length–adult health associations have been similarly documented in differentially affluent populations , there hDespite limitations, we believe the results presented here are an important addition to the literature. These results are, to our knowledge, the first to demonstrate associations of tibia length—a sensitive component of the leg jointly indexing fetal life, infancy and early childhood—with adult organs, brain size, SMM and REE. Height residual as a marker of later growth, and birth weight, by contrast, demonstrated weaker associations. Our findings may aid in explaining previously observed associations of leg length with both adult metabolic health outcomes and offspring birth weight. They further support the importance of targeting interventions in early life , 50 so aeoac023_Supplementary_DataClick here for additional data file.


In 2020, over 6,500 newborn deaths occured every day, resulting in 2.4 million children dying in their 1st month of life. Ethiopia is one of the countries that will need to step up their efforts and expedite progress to meet the 2030 sustainable development goal. Developing prediction models to forecast the mortality of preterm neonates could be valuable in low-resource settings with limited amenities, such as Ethiopia. Therefore, the study aims to develop a nomogram for clinical risk prediction of preterm neonate death in Ethiopia in 2021.A prospective follow-up study design was employed. The data were used to analyze using R-programming version 4.0.3 software. The least absolute shrinkage and selection operator (LASSO) regression is used for variable selection to be retained in the multivariable model. The model discrimination probability was checked using the ROC (AUROC) curve area. The model’s clinical and public health impact was assessed using decision curve analysis (DCA). A nomogram graphical presentation created an individualized prediction of preterm neonate risk of mortality.The area under the receiver operating curve (AUROC) discerning power for five sets of prognostic determinants  is 92.7% (95% CI: 89.9–95.4%). This prediction model was particular (specificity = 95%) in predicting preterm death, with a true positive rate (sensitivity) of 77%. The best cut point value for predicting a high or low risk of preterm death (Youden index) was 0.3 (30%). Positive and negative predictive values at the Youden index threshold value were 85.4 percent and 93.3 percent, respectively.This risk prediction model provides a straightforward nomogram tool for predicting the death of preterm newborns. Following the preterm neonates critically based on the model has the highest cost-benefit ratio. Preterm birth is defined by the World Health Organization as any birth occurring before 37 weeks of pregnancy or within 259 days of a woman’s last regular menstrual period (LMP) . An estiEvidence from different studies showed that birth weight, gestational age, marital status, required resuscitation after delivery, no antenatal care, plurality of pregnancy, sex of neonate, respiratory distress syndrome (RDS), hypothermia, not initiating exclusive breastfeeding, mode of delivery, non-cephalic presentation, fifth minute APGAR score < 7, did not receive kangaroo mother care (KMC) were risk factors in preterm mortality –9.In 2020, over 6,500 newborn deaths occured every day, resulting in 2.4 million children dying in their 1st month of life , 11. NeoPredictive models are used to help clinicians determine if a clinical disease exists (diagnostic models) or whether an event will occur within the time frame (prognostic models) to aid in decision-making . Risk asContinuous positive airway pressure (CPAP), surfactant administration for newborns with RDS, and phototherapy for jaundiced neonates are among the WHO recommendations from 2015 to increase the chances of survival and health outcomes for preterm infants. However, most of the above-mentioned preterm care facilities, such as radiant warmers, CPAP, surfactant, mechanical ventilators, and phototherapy, are sparse or non-existent in most of Ethiopia’s public hospitals. As a result, developing predicted probability models to forecast the mortality of preterm neonates could be beneficial, especially in low-resource settings with limited resources. Predictive models developed in developed countries might not be suitable for developing countries because they vary with the use of Biomarkers, sophisticated facilities, and devices that are not readily accessible due to resource or practical limitations in low-resource settings.A predictive model allows real-time preterm neonates risk stratification, which guides primary attention to care for the good health outcome of the neonates. There is no study on the risk prediction of preterm neonatal mortality in Ethiopia. Identifying prognostic predictors of preterm mortality in the setting would be vital to decrease deaths of preterm mortality and meet sustainable development goal (SDG) targets on time. According to the Lancet report, if all nations achieved the SDG newborn mortality target by 2030, more than 5 million deaths may be averted over the next 10 years . Two-thiA prospective institutional-based observational study design was employed in South Gondar zone public hospital, Northwest Ethiopia. Among eight public hospitals, this study was done in Addis- Zemen primary hospital, Wegeda primary hospital, Nefas Mewcha primary hospital, and Debretabor General Hospital. The study was conducted from December 2020 to May 2021.All preterm neonates delivered and admitted in South Gondar Zone Public Hospitals were a source population. Preterm neonates who were delivered in the labor ward and admitted to NICU within 72 h of life were included in the study. Pregnant women without reliable last menstrual period or pregnant women without an early ultrasound report (first tri -minister), incomplete prenatal, delivery, and neonatal chart, and preterm neonates without parents were excluded during the data collection period.Since there is no prior prediction study for preterm neonates’ death in a similar setting to calculate the sample size, as the rule of thumb, ten events/preterm neonate death/per covariates were considered. Thirteen covariates were recruited in the final model from a total of 36 prognostic maternal and neonatal determinants based on literature or clinical experience. From a total of 456 neonates prospectively followed, there were 132 preterm neonate deaths that occurred.Preterm neonates delivered from December 1, 2020 to May 30, 2021, delivered and admitted in a neonatal intensive care unit (NICU) in South Gondar zone public hospitals, were included. Eligible participants came up in the labor ward and admitted neonatal intensive care unit with consecutive sampling techniques. Proportional allocation based on the monthly average number of preterm delivered and admitted has been determined for each public hospital. We followed 204 preterm neonates at Debre Tabor Hospital, 76 preterm neonates at MekaneEyesus Hospital, 112 preterm neonates at Wegeda Hospital, and 28 preterm neonates at AdisZemen Hospital for 6 months during the data collection period.We have used a reliable last menstrual period or an early ultrasound (first trimester) to determine gestational age. Data were collected based on an adapted interview-administered questionnaire and reviewing medical records. The questionnaire was adapted by reviewing different pieces of literature, including maternal socio-demographic, maternal medical, obstetric, prenatal, and neonatal variables, including age of the mother, the residence of the mother , marital status (union/non-union), pre-pregnancy body mass index, mother occupation, mother education, gestational age , parity, current pregnancy complications , birth interval, antenatal care (ANC) follow-up, the plurality of the child , pregnancy intension (wanted/unwanted), mode of delivery, presentation, magnesium given for this pregnancy, antenatal steroids given or not, sex of the neonate, birth weight, age of the neonate, any resuscitation during delivery, sepsis, perinatal asphyxia (PNA), feeding status, APGAR score, kangaroo mother care (KMC) given or not, type of preterm (spontaneous or induced), respiratory distress syndrome (RDS), hypothermia, jaundice, congenital anomaly, and hypoglycemia.The data were collected by 12 BSc neonatal nurses and four assistant lecturers in nursing supervisors. Trained data collectors interviewed mothers who were at 28 to less than 37 weeks (36 + 6 days) gestation at the labor ward and were abstracted pregnancy, delivery, and infant data from the chart and followed during a 24-h period until discharge, transfer, death, or 42 postmenstrual ages after birth, and their outcome was recorded.Infant death between birth and 42 postmenstrual ages was declared dead. Neonates beyond 42 postmenstrual ages, referred to, and left with medical advice, were declared alive.Neonatal morbidity was immediate neonatal complications, including  regression. Two-sided Model calibration was assessed by plotting declines of the predicted probability of preterm death in each decline and fitting a smooth line. The model discrimination probability was checked by using the area under ROC (AUROC) curve. “givitiR” R-packages were used to check the calibration plot. Bi-normal smoothing bootstrapping technique was used to validate AUROC internally. After bootstrapping, the model’s predictive performance was considered the performance that can be expected when the model is applied to future similar populations. Decision curve analysis (DCA) was used to evaluate the model’s clinical and public health impact.The Youden index value, which classified high or low risk, was used to predict the likelihood of preterm death. Sensitivity, specificity, and the positive and negative predictive values were computed. The probability of preterm death for each neonate was predicted using the linear predictor of estimated risk of death, which is: P (Risk score for each patient) = risk score X prognostic determinant + … + N (risk score) X N (prognostic determinant). Additionally, a nomogram graphical presentation was prepared to construct an easily clinically applicable individualized prediction of preterm neonate risk of death.The study participants were informed about the purpose, risk, benefits, and confidentiality of the study, and informed and voluntarily signed written consent has been obtained during the interview previously. Ethical approval was obtained from Debre Tabor University, College of Health Sciences, and the Institutional Review Board (IRB).A total of 456 preterm neonates were involved in this study. The median age of the respondents was 26 years. Most of the respondents (95.6%) were married, followed by single status (3.5%). Thirty-eight percent of the respondents were unable to read and write. Regarding the occupation of the respondents, 364 (79.8%) of them were housewives, and 68 (14.9%) of them were employees. Three hundred (65.8%) of the respondents were rural residents .Of the total respondents, one hundred seventy-two (37.7%) were Para-one. Most of the mothers (97.4%) have ANC follow-up during this pregnancy. Four hundred sixteen (93.7%) have four times and above ANC follow-up among those with ANC follow-up. About the delivery route, the majority (91.2%) of mothers had vaginal route delivery. Seventy-six (16.2%) of the mothers encountered complications during this pregnancy. APH was the most common one 24 (31.6%) among those who had complications during this pregnancy. The median afterbirth interval of the respondents was 36 months for those gravid two and above .One hundred eighty-four (40.4%) of neonates were with gestational age between 32 and 34 weeks. Two hundred forty (52.6%) of the neonates were male .One-fourth of the neonates had RDS. The majority (89.9%) of preterm neonates were hypothermic during admission. Thirty-six percent of preterm neonates were diagnosed with sepsis. Forty-four (9.6%) preterm neonates had PNA. Seven percent  of the pThe maternal socio-demographic, obstetric, and neonatal-related prognostic determinants were considered to predict preterm mortality. In the final model, the plurality of the neonate (multiple) has no RDS, gestational age of less than 32 weeks, low birth weight, and KMC were the remaining significant predictors of preterm mortality .After the multivariable logistic model, a total of five prognostic determinants were left for the prediction of preterm mortality, and the relative contribution of each prognostic determinant to the probability of preterm mortality was calculated by dividing each beta coefficient by the lowest beta coefficient and rounding to the nearest integer (score chart rule formula) .linear prediction formula was:Therefore, the probability of preterm mortality among preterm neonates using the Linear predictor of the model (l p) = −1.54 + 2.66 * gestational age less than 32 weeks + 0.77 *multiple pregnancy- 4.4; *has no RDS, + 2.1; *has not gotten KMC, + 1.52; *low birth weight.The area under the receiver operating characteristics curve (AUROC) had a discrimination power of 92.7% (95% CI: 89.9–95.4) . The finThe cost-benefit analysis of the prediction model was compared between no follow-up for all the preterm neonates, followed by all the preterm neonates, and critically follow selectively based on these predictors. For example, if we critically follow all preterm neonates at a threshold risk of death probability of 30%, we will find 30% prevalence of preterm death. Whereas, if we follow the preterm neonates based on the prediction model, the preterm neonates need critical follow-up at the risk of preterm death threshold of more than 80%. Therefore, following the preterm neonates selected based on the model has the highest cost-benefit ratio .10.1. Therefore, the probability of preterm death with the corresponding total points in the nomogram was 0.2 (20%), indicating a low risk of preterm death. Whereas a preterm neonate had RDS and low birth weight, the total points were 10 + 4.8 = 14.8. Thus, the probability of preterm death, approximately 0.68 (68%), is declared a high risk of preterm death  results in the discernment power of area under the receiver operating curve (AUROC), 92.7% (95% CI: 89.9–95.4%). Having an e in the model’s AUROC of 0.93 indicates that it is 93 percent accurate incapable of distinguishing between preterm neonates who died and those who survived. The higher the AUC indicates, the better the model predicts dead preterm neonates’ classes as death and alive preterm neonates’ classes as alive The area under the ROC curve (AUC) results was reflected excellent for AUC values between 0.9 and 1 , 29. BecClinicians can determine the likelihood of preterm neonate risk of mortality by adding each value of the prognostic factors that the neonate possesses from the nomogram. This study’s nomogram graphical display offers a clinically useful customized prediction of preterm neonate death risk. The prognostic predictor of five factors was assessed in the probability of preterm death in the nomogram to predict preterm neonate death.In this study, the maximum sensitivity and specificity of the Youden index cut point value were 83.3 and 94.4%, respectively. It means that this tool has an 83% probability of correctly identifying all those who do, indeed, have died from among preterm neonates who have died and the probability of avoiding neonates who have not died when they have. Similarly, this model has a 94% probability of correctly identifying; from among preterm neonates who do not die, all those who do, indeed, have not died and not categorizing some neonates as died when, in fact, they do not die . These fAt the Youden index threshold value, the positive and negative predictive values were 85.4 and 93.3%, respectively. This indicates that this tool has an 85 percent chance of correctly identifying all newborns that have died from among preterm neonates who may or may not have died and not categorizing some neonates as dead while they are alive. Furthermore, this tool has a 93 percent chance of correctly identifying all neonates who do not die among preterm neonates who may or may not die while correctly categorizing some neonates as alive when they are not. It accurately predicted that the neonate perished and, if true, projected that the neonate was alive. It has good predicted the neonate died and if was died and predicted the neonate was alive if was alive. As a result, it can accurately predict preterm mortality.In this study, RDS is one prognostic determinant for preterm mortality. It is similar to different studies on neonatal mortality prediction , 32. TheGestational age less than 32 weeks was another prognostic determinant for preterm mortality. It is consistent with different studies on the prediction of neonatal mortality , 32. TheMultiple neonates are one prognostic determinant for preterm mortality. It is similar to a study done in Ohio that revealed that twin pregnancy was predicted risk of adverse pregnancy outcomes, including neonatal death . It mighLow birth weight is one prognostic determinant for preterm mortality. This might be lower birth weight  prone thKangaroo Mother Care is one prognostic determinant for preterm mortality. One reason is that KMC prevents hypothermia, which causes neonatal mortality , 32. KMCIn our study, a combination of five sets of prognostic determinants  was estimated in the probability of preterm death in the nomogram. This nomogram can be used to graphically predict the risk of death among preterm neonates. In settings with similar demographics, the risk prediction tool can assist clinicians and health care providers to predict preterm neonates’ death and target interventions. Following the preterm neonates based on the selectively using the model has the highest cost-benefit ratio.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Debre Tabor University, College of Health Sciences, and Institutional Review Board (IRB). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.HH was involved in conceptualization, methodology, data cleaning, data analysis, interpretation, drafting, reviewing, and revising of the manuscript. ST was involved in methodology, data cleaning, data analysis, interpretation, drafting, reviewing, and revising of the manuscript. Both authors read and approved the final manuscript.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.


Previous studies have consistently found that women living in low socioeconomic status (SES) neighbourhoods are at higher risk of experiencing adverse birth outcomes compared to women from high SES areas. However, the mechanisms through which neighbourhood SES might influence health at birth remain poorly understood. One of the proposed pathways is the exposure to higher crime rates. The aim of this study is to investigate whether neighbourhood crime mediates the relationship between neighbourhood SES and birth outcomes.A retrospective cohort study including over 1.3 million singleton births occurred in the Netherlands between 2010 and 2017. Individual-level data from the Dutch perinatal registry was linked to quintiles of neighbourhood SES scores and neighbourhood-level crime rates. Using the mediational g-formula, we estimated the total effect, natural direct effect, and natural indirect effect of neighbourhood SES on birth outcomes: small-for-gestational-age (SGA), low birth weight, and preterm birth. The neighbourhood SES intervention settings correspond with a hypothetical improvement in neighbourhood SES from the lowest to the highest quintile.The hypothetical improvement in neighbourhood SES resulted in a 6.6%  relative reduction in the proportion of SGA births, an 8.9%  reduction in the proportion of low birth weight, and a 5.1%  decrease of preterm birth. Neighbourhood crime accounted for 29.0%  of the total effect of neighbourhood SES on SGA, and for 8.6%  of the total effect on low birth weight. For preterm birth, we found no evidence of mediation by neighbourhood crime.Neighbourhood crime mediates the association between neighbourhood SES and key adverse birth outcomes. Interventions targeted at lowering neighbourhood crime rates could improve birth outcomes in disadvantaged areas.Neighbourhood crime mediates the association between neighbourhood SES and adverse birth outcomes in the Netherlands.Results from this study can provide guidance to neighbourhood-level strategies aiming at improving health at birth and reducing health inequalities.


Nature Biomedical Engineering [A universal and modular strategy for intratumoral delivery of cytokines was recently reported by Agarwal et al. in an article published in ineering .i.t.) administration of cytokines may be expected to improve the therapeutic effect and mitigate systemic toxicity. In addition, with the development of interventional techniques, researchers no longer have to concern about the feasibility of i.t. dosing in most locations of lesions, suggesting the broad prospect of i.t. cytokine-based therapy.Cytokines are messenger molecules that mediate intercellular communication, and play an important role in host antitumor immunity. Various categories of cytokines are implicated in tumor development, progression, and metastasis, mainly including interleukins (ILs), interferons (IFNs), chemotactic cytokines (chemokines), growth factors, and some members of the tumor necrosis factor (TNF) superfamily. Some cytokines can directly inhibit tumor growth, such as transforming growth factor-β (TGF-β) and IFN-α, while others  achieve the antitumor effect by enhancing the cytotoxic activity of lymphocytes . Therefoi.t. administration of the cytokines invariably leads to unsatisfactory therapeutic effect and systemic toxicity. Recently, Wittrup, Irvine, and coworkers developed a universal and modular strategy for the i.t. delivery of high-dose cytokines, realizing the long retention of cytokines within tumor sites for weeks after injection [Notwithstanding, the rapid escape of soluble cytokines from the tumor after njection  Fig. 1)i.t. admii.t. retention compared with free IL-12, with no observed systemic toxicity. Furthermore, a single dose of alum-tethered IL-12 induced a robust IFN-γ-mediated synergism between adaptive and innate immunocytes, as well as notable activation of antigen-presenting cells in draining lymph nodes, thereby producing strong systemic antitumor effects in poorly immunogenic tumor models when used in conjunction with checkpoint blockade therapy. The inhibition of distant untreated tumor growth and lung metastasis was also achieved.To produce the phosphorylated ABP-labeled cytokines, Fam20C, a kind of kinase in charge of the phosphorylation of most of the mammalian cell-secreted phosphoproteome, was engineered with a KDEL C-terminal sequence, which is an endoplasmic reticulum retention signal. Additionally, an initial set of ABPs with S-x-E motifs in which serines can be recognized and phosphorylated by Fam20C, was designed and fused to diverse therapeutic cytokines, including a single-chain form of IL-12, mouse serum albumin-fused IL-2, and an IL-15 superagonist complex with the IL-15α chain (IL-15sa). Thus, when coexpressed together with Fam20C-KDEL in cell expression platforms, cytokines modified with ABPs can be specifically phosphorylated by Fam20C during their secretion from mammalian cells. The resulting proteins were then subjected to immobilized metal affinity chromatography and subsequent anion exchange chromatography treatments for purification. The obtained ABP-fused cytokines exhibit stable alum binding potency while still maintaining activity. Specifically, alum-anchored IL-12 exhibited a remarkably increased i.t. injection [i.t. administration of alum-bound cytokines is a tumor-agnostic approach for realizing the concurrent enhancement of local and systemic antitumor responses. Furthermore, the site-specific binding of cytokines to the solid surface of alum may also enhance the stability and protect the cytokines from degradation by endogenous proteases. Additionally, by optimizing the sequence of the linker between target cytokine and ABP, the location of ABP in the protein, and the design of ABP, this delivery strategy can be widely applied to diverse cytokines, and has been successfully utilized to i.t. injection of IFNs as well [Actually, Wittrup’s group has previously reported an approach of anchoring cytokines to lumican (a collagen-binding protein) for enhancing local retention after njection . Althoug as well .i.t. consumption rate. Intratumorally administering cytokines in the alum-anchored format can obviate this issue. However, to fuse with ABPs, the single-chain forms of cytokines are generally used, which may lead to different degrees of activity loss of cytokines. Besides, the binding of cytokines to alum has an influence on the activity of some cytokines; for instance, phosphorylated IL-2–ABP and IL-12–ABP showed a 4-fold loss in activity when tethered to alum [i.t. administration of alum-anchored cytokines and a systemic therapeutic modality such as immune checkpoint blockade therapy or chimeric antigen receptor T (CAR T) cell therapy for achieving an improved therapeutic outcome. Overall, this modular method for safe i.t. delivery of cytokines introduced by Wittrup, Irvine, and coworkers may offer inspirations for the potential clinical applications of cytokines.Although the enclosure of cytokines within material depots  can prevent their rapid leakage, it is still challenging to tune the release rate of cytokines to coordinate with their


Objective: To assess the risk factors perceived as stressors by pregnant women in the work environment and the possible adverse consequences of such exposure for the normal development of pregnancy.Methods: Systematic review, guided by the PRISMA guidelines, and using Pubmed, Web of Science, Dialnet, SciELO, and REDIB databases. Methodological quality was assessed using the critical appraisal tools for non-randomised studies of the Joanna Briggs Institute.Results: A total of 38 studies were included. The main risk factors found in the work environment of pregnant women were chemical, psychosocial, physical-ergonomic-mechanical factors, and other work-related factors. The main adverse consequences of exposure to these factors include low birth weight, preterm birth, miscarriage, hypertension and pre-eclampsia, as well as various obstetric complications.Conclusion: During pregnancy, working conditions that are considered acceptable in normal situations may not be so during this stage due to the major changes that occur during pregnancy. Many obstetric effects may have an important impact in the mother’s psychological status; therefore, it is important to optimise working conditions during this stage and to reduce or eliminate possible risks. One of the most important structural changes in the labour market in recent years has been the incorporation of women into paid employment .Based on the information provided by the Spanish National Institute of Statistics through the Labour Force Survey, it is estimated that the active population of Spain in 2021 reached 23 million people, of which 19 million were employed and more than 9 million were women. Disaggregated data by age and sex shows that female participation in the labour market reached 34.28% among women aged 20 to 24, and 70.05% among women aged 25 to 54. In terms of male participation, 38.49% and 80.69% for the same age groups, respectively  guidelines . This reThe research question that marked the review was: What risk factors do working women perceive as stressors in their work environment and what are the consequences of possible exposure to them?For an adequate development of the research question and subsequent review of the literature, the PECOT strategy was used: 1) Population: working pregnant women or women who had worked during pregnancy; 2) Effect: work-related stress; 3) Comparator: exposure to existing risk factors in the work environment; 4) Outcomes/Results: consequences of possible exposure according to the type of agent  and; 5) Type of studies: cohort studies, case-control studies, and quantitative studies.This subdivision allowed selecting a combination of appropriate terms related to each of the components of the PECOT strategy so as to answer the research question posed. In this case, the descriptors used were Risk Factors, Occupational Stress, and Pregnancy, which were obtained from the MeSH  thesaurus. The Boolean operator used was the restricted AND combination. This was the connector that allowed the combination of the descriptors listed above to search for related literature.Red Iberoamericana de Innovación y Conocimiento Científico, i.e.: Ibero-American Network of Innovation and Scientific Knowledge), in which a double search was conducted by including the terms in both Spanish and English. The search in all databases was performed on 26 January 2023. In the advanced search generators of the said databases, “risk factors and occupational stress and pregnancy” was entered. The same search was performed for the Spanish terms.The databases used were Pubmed, Web of Science (WoS), Dialnet, SciELO (Scientific Electronic Library Online), and REDIB (The inclusion criteria for the selection of articles were: 1) articles published in English, Spanish, French, and Portuguese; 2) works with full texts accessible; 3) type of studies: cohort studies, case-control studies, and quantitative studies; 4) studies carried out in the period from 2000 to the date of the search and; 5) articles in which at least one risk factor of the physical-ergonomic-mechanical, biological, chemical, psychosocial, or environmental type could be identified. The exclusion criteria were: 1) not exceeding the scientific-technical quality criteria; 2) language reasons ; 3) non-pregnant working women or non-working pregnant women and; 4) non-peer-reviewed articles.For data collection and extraction, once the keywords were agreed, two researchers searched the stated databases individually. Subsequently, they retrieved the records and entered them into the Mendeley bibliographic manager, where duplicate studies were eliminated. Then, the articles that could be included after reading the title and abstract were selected according to the previously established criteria. The selected studies were then retrieved in full text and a selection report was made individually by both researchers compiling data on authorship, country, population, type of risk factor , main findings, and the result of the Joanna Briggs Institute (JBI) critical appraisal tool . At thisThe JBI critical appraisal tool for non-randomised studies was used to assess the methodological quality of the studies . ThroughThe flowchart in A total of 38 articles were finally selected and summarised in The selected studies suggest that the main adverse consequences derived from the work activity carried out during the gestational period are low birth weight, preterm births, miscarriages, hypertension/pre-eclampsia, and gestational complications of various kinds such as miscarriage, cervicovaginitis, and foetal distress, among others , 25. TheIn the case of the study by Ronda et al.  carried p = 0.001) and low demands and normal birth weight . Similarly, low control over the labour process is also a risk factor, while work stress and birth weight are not (p = 0.01) as did active work (high demands and high control)   . In line= 0.002)  found th= 0.002) , and in = 0.002) .On the other hand, Begtrup et al.  developeIn this sense, Pedersen et al.  stated tHaelterman et al.  conducteHigh levels of noise (>85 dBA) was found to be another factor possibly associated with an increased risk of the child being born small for gestational age, with OR 1.44 (95% CI 1.01–2.03), compared to noise exposure <75 dBA .The results proposed by Hansen et al.  showed tRonda et al.  conducteThere were a number of studies comparing different occupational groups. In a study, it was found that nurses had significantly higher risk of caesarean section  1.03–1.22]), tocolysis (OR 1.18 [95% CI 1.09–1.29]), and preterm labour (OR 1.46 [95% CI 1.28–1.67]) than non-nurses . In the Given that pregnancy implies important changes in the life of the pregnant woman that will affect, among other things, her work situation, the aim of this systematic review was to carry out a study on how work affects and what consequences it has for both the pregnant woman and the foetus. The results show that there are chemical, physical/ergonomic/mechanical, psychosocial, and other work-related factors at work that can affect the normal development of pregnancy and foetal growth.Based on the chemical factors evaluated in the articles included in the review, exposure to inorganic particles as iron, benzene or ethylene oxide can be associated with low birth weight, miscarriage, risk of preterm birth, and even pregnancy loss , 39. In In the case of occupational factors, there seems to be an association with the likelihood of hypertensive disorders, low birth weight, preterm birth, and miscarriage, among others. In this sense, belonging during pregnancy to certain occupational groups such as agricultural work, the service sector, domestic work, or manual labour in the industry and the construction sectors may have adverse effects . The triIn relation to physical/ergonomic/mechanical factors during pregnancy, possible negative consequences may be related to the occurrence of pre-eclampsia and hypertension, sick leaves, and preterm birth. In fact, physically demanding occupational conditions, lifting heavy loads during pregnancy and strenuous positions in early pregnancy increase the risk of pre-eclampsia, low birth weight babies, and preterm birth , 31, 50.The impact of psychosocial factors on the normal development of pregnancy analysed in the different articles included in the review have yielded contradictory data. Among the studies showing a significant association between psychosocial work-related stress and adverse pregnancy outcomes, the main findings are the triggering of preterm births and low birth weight babies , 15. StrThis phenomenon could be explained by the fact that, when faced with a high level of stress, the body activates the hypothalamic-pituitary-adrenal axis, causing a release of corticotropin-releasing hormone, which in turn increases glucocorticoid levels and releases the stimulation of oxytocin and prostaglandins, thus favouring the onset of preterm labour . In otheIn line with the above, it is observed that jobs involving higher risk factors , when comparing different occupational groups, have a higher risk of caesarean section, tocolysis, preterm labour , and risWhen work provides the opportunity to redesign jobs, to organise adjustments during pregnancy, to provide support, etc., the causal relationships found could diminish or even disappear, thus making work activity no longer an obstetric risk factor for employed women. Having knowledge of these data allows researchers to establish guidelines for future studies with the aim of clarifying the associations found. It is necessary to delve deeper through a much more complex evaluation of the subject and an evaluation that will allow institutions to determine, with these results, the intervention requirements in each case.With regard to the limitations found in the present systematic review, it could be highlighted that, as this is a study of the different risk factors present in the working environment of pregnant women, it has not been possible to cover all the works that has been found referring to each factor. Furthermore, this study is mainly descriptive and combines data from multiple sources, which could result in an inherent reporting bias. Similarly, the review does not include conference papers, dissertations, or grey literature. Also, the measurement instruments used were different and, in some cases, the sample was small.Based on the data obtained through this systematic review, it seems obvious that all the risk categories analysed have some negative effect on pregnancy, i.e., the presence to a greater or lesser extent of such factors can contribute to the appearance of risks that negatively affect the normal development of pregnancy.The main adverse effects of exposure to chemical factors such as chlorinated solvents, polycyclic aromatic hydrocarbons, iron, benzene or ethylene oxide may be risk of preterm birth, low birth weight, neural tube defects, conotruncal heart defects, and miscarriage. Physical-ergonomic-mechanical factors  may lead to pre-eclampsia and hypertension, sick leaves, lower growth rates for foetal head circumference, premature rupture of membranes, and preterm birth. Similarly, psychosocial factors (high work demands and reduced workplace support) can lead to low birth weight, preterm birth, gestational complications, antenatal depressive symptoms, having children with attention deficit hyperactivity disorder, and miscarriage. Finally, certain occupations such as agricultural work, the service sector, nurses, etc. have an increased risk of developing hypertensive disorders, low birth weight, preterm delivery, and even foetal distress.The results of the present review suggest that no special protection measures are being applied on a regular basis to pregnant women in the workplace, with the possibility of this being a shared responsibility between public administrations, the company, and the working women.


Neonates defined as LGA by the customized model (LGA-CUST) and AGA by the population-based model LGA-CUST ONLY had a significantly higher risk for morbidity compared to the reference  or the LGA POP group. Neonatal mortality only occurred in the SGA and AGA groups. Conclusions: The application of a parity-customized only birth weight chart in a population of singleton, term neonates is a simple platform to better identify birth weight related neonatal risk for morbidity and mortality.Objective: To investigate the impact of parity-customized versus population-based birth weight charts on the identification of neonatal risk for adverse outcomes in small (SGA) or large for gestational age (LGA) infants compared to appropriate for gestational age (AGA) infants. Study design: Observational, retrospective, cohort study based on electronic medical birth records at a single center between 2006 and 2017. Neonates were categorized by birth weight (BW) as SGA, LGA, or AGA, with the 10th and 90th centiles as boundaries for AGA in a standard population-based model adjusted for gestational age and gender only (POP) and a customized model adjusted for gestational age, gender, and parity (CUST). Neonates defined as SGA or LGA by one standard and not overlapping the other, are SGA/LGA CUST/POP ONLY. Analyses used a reference group of BW between the 25th and 75th centile for the population. Results: Overall 132,815 singleton, live, term neonates born to mothers with uncomplicated pregnancies were included. The customized model identified 53% more neonates as SGA-CUST ONLY who had significantly higher rates of morbidity and mortality compared to the reference group (OR = 1.33 95% CI [1.16–1.53];  Birth weight is a major predictor of neonatal morbidity and mortality and is used for tailoring the delivery decision-making process and future prenatal care. As a result, the definition of neonatal weight as appropriate or inappropriate for gestational age has major clinical and financial implications. Neonatal birth weight below the 10th percentile, the small for gestational age (SGA), and above the 90th percentile, the large for gestational age (LGA), being associated with increased perinatal morbidities and mortality ,3, even Previous studies have suggested that customized birthweight curves may provide a better predictive tool for the adverse neonatal outcome than the traditional population-based gender-adjusted curve ,14,15,16Among the many factors that influence neonatal birth weight, parity is a substantial determinant . The matData were retrieved from the electronic medical charts (EMC) of all women who gave birth at the Shaare Zedek Medical Center (SZMC) in 2006–2017. All mothers and neonates benefit from antenatal and birth health care coverage of the Israel National Health Insurance Plan. Similar to others, for the purpose of the present study in order to better isolate the effect of parity on BW curves, we included uncomplicated, singleton pregnancies resulting in term births, 37–42 weeks’ gestation. The exclusion criteria for the study were: any maternal record of background of chronic illness or pregnancy complications  ,23,24,25This is an observational, retrospective, cohort study. Each delivery was categorized into one of ten parity groups, from parity 1 to ≥10, and the mean birth weight was calculated for each parity group and gestational age.The cohort was used to generate new customized birth weight centiles, adjusted for fetal gender, week of gestation, and maternal parity. Each neonate was then classified as SGA, AGA, or LGA, using the 10th and 90th percentiles for BW as cutoffs, based on two models:The standard population-based growth chart was used in Israel, adjusted for gestational age and neonatal gender only  (POP).The new growth chart we generated was customized for gestational age, neonatal gender, and maternal parity (CUST).Data regarding adverse neonatal outcomes were extracted for the cohort population. Data regarding the following adverse outcomes were included: meconium aspiration (ICD9 770.12), hypoglycemia (ICD9 775.6), 5′ Apgar < 7, admission to the neonatal intensive care unit (NICU) for over 72 h, shoulder dystocia (ICD9 660.4), and neonatal death, defined as death within 28 days of birth.For further analysis, the study population was then reclassified to create the “groups of disagreement” between the two models.Finally, to investigate the risk associated with each of the “groups of disagreement”: SGA-CUSTONLY, SGA-POP ONLY, LGA-CUST ONLY, and LGA-POP ONLY, a multivariable model was generated for a composite adverse outcome and each adverse outcome individually. Neonates in the 25–75th centiles of weight served as a reference population for the analyses. All models in the study were adjusted for the following variables: parity, maternal age, conception by in vitro fertilization (IVF), and use of epidural or oxytocin during labor. Odds ratios (ORs) for composite adverse outcomes were calculated with 95% confidence intervals (CIs). A separate model, adjusted for the same variables and using the same reference population, was used to investigate the risk of shoulder dystocia among LGA neonates.Customized birth weight percentiles were calculated separately for each gender in all term singleton deliveries according to gestational age and parity. Mean birth weights of all parity groups were compared using one-way ANOVA. Comparisons between the distribution of national population percentiles and customized percentiles were performed using the Chi-square test.For the purpose of the study, we defined the following study groups: (1.1) SGA by population percentile only; (1.2) SGA by customized percentile only; (1.3) SGA by both percentiles; (2.1) LGA by population percentile only; (2.2) LGA by customized percentile only; (2.3) LGA by both percentiles and (3) non-SGA and non-LGA. Univariate analysis (Chi-square test) was used to compare the rates of any adverse neonatal outcome for (1.1), (1.2), and (1.3) vs. (3) and for (2.1), (2.2), and (2.3) vs. (3).Multivariable logistic models were used to assess the independent role of extreme neonatal birth weight according to all definitions of neonatal adverse outcomes, using neonates in the 25–75th birth weight percentiles as a reference group.p < 0.05 was considered statistically significant. Analyses were carried out using SPSS Statistics for Windows, Version 25.0. .All tests were two-sided. This study was approved by the SZMC research ethics review board (Helsinki committee authorization number 0154-17-s2).During the study period, 168,979 births were registered at SZMC, of which 165,633 (98%) were singleton and 157,969 (93.5%) were singleton term births (37–42 weeks’ gestation).We excluded 24,813 deliveries (14.7%) due to chronic background maternal medical conditions and pregnancy complications and 249 (0.001%) were excluded due to intrauterine fetal demise, yielding 132,907 deliveries, 92 were excluded from the analysis due to errors in the documentation of data. As a result, 132,815 deliveries  by 69,955 women met the study inclusion criteria . Overallp < 0.001, Calculation of mean birth weight for each maternal parity group demonstrated a progressive increase in birth weight from a mean of 3220 g ± 405 for primiparas up to a mean birth weight of 3498 ± 450 for parity group ≥ 10  defined as LGA using the population-based chart (LGA POP), while 13,155 (9.9%) were defined as LGA using the parity-adjusted model (LGA CUST). Within the LGA CUST group, 2068/13,155 (15.7%) neonates were defined as LGA CUST ONLY, while in the LGA POP group, 2261/13,348 (16.9%) neonates were defined as LGA POP ONLY. A total of 11,087/132,815 (8.3%) neonates were defined as LGA BOTH and 117,399/132,815 (88.3%) were defined as NON-LGA.n = 3640; 2.7%) and the least common was neonatal death . Notably, all cases of neonatal death occurred within the AGA and SGA groups. Detailed data regarding the distribution of outcomes among the birth weight groups are in the Overall, 5656 neonates (4.25%) experienced any of the previously defined adverse outcomes. The most common adverse outcome was hypoglycemia . The SGA-POP ONLY group experienced a slightly higher rate of adverse outcomes than the SGA-CUST ONLY group . The NON-SGA group had the lowest adverse outcome rate of 4.1% . SGA data are shown in LGA: Neonates in the LGA-BOTH group had the highest rate of adverse outcomes among the LGA groups, which were experienced by 7.7% . The LGA-POP ONLY group had a higher rate of adverse outcomes compared to the LGA-CUST ONLY group . The NON-LGA group had the lowest rate of adverse outcomes . The highest rate of shoulder dystocia among the LGA groups occurred in the LGA-BOTH group . The differences in the rate of meconium aspiration and NICU > 72 h did not reach statistical significance. LGA data are shown in p < 0.0001), but lower than the SGA-BOTH group. Confidence intervals overlapped between the SGA-POP ONLY and SGA-CUST ONLY groups , compared to the reference population. However, neonates defined as LGA-POP ONLY were not at significantly increased risk for the neonatal composite adverse outcome   . The ris= 0.092) .p < 0.0001) and was also elevated almost seven-fold in the LGA-CUST ONLY and LGA-POP ONLY groups  and customized (SGA-CUST) models, and risks were estimated and compared accordingly. The neonatal risks identified by this classification are mainly related to the SGA neonates, the most challenging neonatal population. Using the parity-customized definition, an additional 4742 neonates were defined as SGA, a 53% increase from the number characterized as SGA based on the population-based definition. This large difference can be explained by the higher parity of our study population relative to the general Israeli population used to generate the population-based charts. Neonates that were defined as SGA according to either definition had higher overall rates of adverse outcomes than non-SGA newborns. Notably, all cases of neonatal death occurred in the SGA and AGA groups, either population- or parity-adjusted. This may be due to exclusion of maternal morbidities, mainly diabetes, in our cohort. Of note, the overall mortality rate for our cohort was exceptionally low . The SGA-CUST ONLY group experienced a higher number of individual cases for each adverse neonatal outcome, but a lower adverse outcome rate hypothetically to be attributed to increased sensitivity at the expense of lower specificity resulting from the customized SGA definition. The higher morbidity in the SGA group is even more remarkable for a maternal study population with no chronic background disease or pregnancy complications; thus, SGA represents an intrinsic neonatal risk for this group .The SGA-CUST ONLY group showed a 33% increase in the risk for composite neonatal adverse outcomes compared to normal birth weight neonates. The SGA-POP ONLY group, which included neonates defined as SGA by the population-based chart but not by the customized model, also had increased risk of the composite adverse outcome, but included a relatively small group, with just 302 neonates experiencing 17 cases of adverse outcomes. In the present study we excluded maternal chronic background diseases or pregnancy complications, which are associated with SGA; thus, in a general population the increased risk for adverse outcomes seen for the SGA neonates, adjusted for parity, might become even more significant. These results, strengthen the notion that the use of the customized chart might be beneficial in the population of SGA neonates.Studies ,36 usingRegarding the LGA population, both models defined a comparable number of neonates, about 10% of the cohort, as LGA, with the population-based chart (LGA-POP) including just 1.5% more neonates in this group. About 15% of the members of each group did not overlap with the other. Unlike the large difference in SGA populations, this smaller difference in LGA populations might stem from the fact, that the most significant impact of parity on birth weight manifests in parity 1 to 2, a neonate population more prone to low birth weight. This diminishing impact of parity in the higher birth weights may lead to a less pronounced difference using the customized model. Importantly, the neonates in the LGA-CUST ONLY subgroup had a 36% higher risk of composite adverse outcomes compared to those in the reference population, while the difference in risk for LGA-POP ONLY neonates did not reach statistical significance. This may indicate the ability of the parity-customized model to separate between neonates who are constitutionally large and those with an underlying pathological condition, a possible advantage of the parity customized model in the LGA population.Indeed, the impact of customized charts for the term LGA is disputable. Chiossi et al. in a meta-analysis  concludeThe main strengths of this study include the large cohort of women with high parity and their equal access to health insurance and prenatal care. This large sample with well documented validated records allowed us to isolate the parity and uncomplicated pregnancies, thus eliminating additional risks associated with maternal or fetal compromise. These background maternal diseases challenge any systematic review and meta-analyses of customized growth curves . Other sIn conclusion, we have explored the impact of a customized birth weight chart based on parity alone, in a population of singleton, term neonates born to healthy mothers. We found that this simple customized definition especially for the SGA neonates, may enable a more precise identification of those at higher risk for adverse outcomes in parous mothers. These results support the importance of maternal parity as a meaningful variable for customization models, especially for future machine-learning algorithms.


Ectopia cordis is a rare type of malformation where the heart is not located normally. It may be partially or completely located outside the thoracic cavity and can be associated with other congenital abnormalities. It results from failure of maturation of midline mesoderm and ventral body formation during embryogenic formation. The exact etiology remains unknown. The literature review reveals the prognosis for infants with ectopia cordis is very poor. Here, we are reporting the first case of a fetus that was prenatally diagnosed with ectopia cordis that was associated with omphalocele documented in our country. Considering the poor prognosis for the fetus, conservative management during the prenatal period was chosen. Ectopia cordis is a rare congenital malformation with an estimated incidence of 5.5 to 7.9 per million live births . Haller This is a four-day-old male neonate of a 23-year-old gravida 4, para 1 plus 2 previous abortions. The mother of the patient had a healthy female full-term baby who was delivered by caesarian section for fetal distress.During pregnancy, the mother had a routine anomaly scan at 21 weeks and 6 days of gestation which showed ectopia cordis with a small chest and lung volume. The heart was lying completely outside of the chest cavity, with a normal four-chamber view and a regular heart rate and rhythm . The outDuring the pregnancy, there was no history of ingestion of unprescribed medications, use of illicit drugs, cigarette smoking, alcohol abuse, or history of chronic ill health. There was no relevant family history of congenital anomalies, genetic abnormalities, or history of an ectopia cordis in other family members. However, there was a history of first-degree consanguinity.Despite an unfavorable prognosis for the fetus that has been explained to the mother, a conservative management during the prenatal care was planned upon the parent's request.At 36 weeks of gestation, she presented with scar tenderness and had an emergency lower segment caesarian section with an outcome of alive male baby born with an Apgar score of 9 at 1 minute and 10 at 5 minutes. His birth weight was 2.200 kilograms. The physical examination revealed a responsive newborn with an externalized heart totally outside the chest, without pericardium protection. The dynamic movement of heart beats outside the chest cavity is shown in the supplementary files Video . The remEctopia cordis is a congenital heart exposure which means the heart outside the thoracic cavity could be partial or complete . The cauEctopia cordis can be associated with chromosomal abnormalities like turner syndrome (XO), trisomy 21, and Edward syndrome trisomy 18) . Intraca . IntracMoreover, noncardiac malformations can occur such as pentalogy of Cantrell, omphalocele, diagrammatic hernia, hypoplastic lung disease, skeletal dysplasia, and cleft palate , 3, 10.Despite that our patient had normal chromosomal study, an associated omphalocele was noted.Differential diagnosis of ectopia cordis includes pentalogy of Cantrell, Beckwith–Wiedemann syndrome, amniotic band syndrome, and limb-body-wall complex .Ectopia cordis is associated with the presence of amniotic band syndrome. Bands may be attached to the ectopic heart or a defect in the thorax and abdominal wall. Almost all cases of amniotic band syndrome are sporadic, and the risk of recurrence is low in subsequent pregnancy , 12.Prenatal diagnosis has an important role in identifying ectopia cordis and its associated abnormalities. It can be detected in the first trimester or the beginning of the second trimester . UnfortuFetal cardiac magnetic resonance imaging (MRI) is an alternative imaging option to echocardiography, where it was limited by maternal or fetal factors such as maternal obesity or abnormal fetal positions and placental calcifications , 16.Chromosomal analysis is highly recommended due to its association with chromosomal abnormalities , 16.Treatment of ectopia cordis requires a multidisciplinary approach consisting of a perinatologist, neonatologist, radiologist, pediatric, and pediatric cardiac surgeon. The multisurgical approach requires repair of omphalocele, sternal, diaphragmatic, pericardial defects, repair of intracardiac anomalies, and reducing the heart into the chest cavity. Since it is known that the thorax is small in ectopia cordis, the surgical approach is challenging and reducing the heart can cause kinking and compression of vessels . The firThe efficacy of surgery depends on the degree of ectopia cordis and other congenital heart defects. The main aim of the surgical treatment is to provide a soft tissue cover to the heart along with reduction of the heart to the thoracic cavity and reconstruction of the chest wall , 24.In the year of 2020 in Indonesia, Limanto and Soebroto did a palliative surgery on a five-day-old full-term newborn for a complete thoracic ectopia cordis with the aim of covering the exposed heart with the use of bovine pericardium material that is commonly used in reconstruction in cardiac surgery. Unfortunately, the patient expired on the third postoperative day due to heart failure . In the Unfortunately, no surgical intervention could be carried out in our case because the pediatric surgeon believed that the thoracic cavity volume was very small.The overall prognosis of ectopia cordis is poor as it is a lethal anomaly, and despite advances in neonatal cardiac surgery, this remains a surgical challenge with only a few long-term survivals.In conclusion, the management of ectopia cordis is a challenge for any obstetrician and pediatric surgeon due to its rarity. It causes mental agony and anxiety to the parents. With early diagnosis, termination of pregnancy can be one of the options. Once it is diagnosed late, it needs a multidisciplinary approach, and the services of a very experienced pediatric surgeon to improve the prognosis.