The growth parameters at 60 months of age showed a significant correlation with those at 6 months of age especially in extremely low birth weight infants. The incidence of suspected developmental delay was significantly higher in infants with growth below the 10th percentiles than in those with growth above the 10th percentiles. Among 4571 (1.6%) infants with suspected developmental delay results at 60 months of age, birth weight, sex, and poor growth parameters were confirmed as associated factors. This nationwide Korean study shows that poor growth and neurodevelopment outcomes persisted among low-birth-weight infants at 60 months of age. Our findings provide guidance for developing a nationwide follow-up program for infants with perinatal risk factors in Korea.This study aimed to investigate the nationwide growth pattern of infants in Korea according to the birth-weight group and to analyze the effect of growth on development. A total of 430,541 infants, born in 2013 and who received the infant health check-up regularly from 6 months to 60 months of age, were included. The weight, height, head circumferences percentiles, and neurodevelopment using screening tests results were compared among the birth-weight groups. Using longitudinal analysis, the study found a significant difference in height, weight, and head circumference, respectively, according to age at health check-up, birth weight group, and combination of age and birth weight ( Due to the improvement in perinatal care, the survival and major morbidity free survival of preterm infants have improved dramatically. The focus of neonatology has shifted towards improving nutrition and anthropometry . Growth A significant number of infants are discharged with their growth parameters still well below the normal range. In particular, very low birth weight (VLBW) infants and small for gestational age (SGA) preterm infants have a higher risk of growth deviations . SeveralThe catch-up growth patterns of preterm infants have been a matter of debate. Approximately 80% of preterm infants after initial postnatal growth failure show catch-up growth in weight, length, and head circumference (HC), generally starting early in the first months of life and often achieving targets within the first two years of life . HoweverIn Korea, the total number of births in 2013 was 436,455, including 5.5% of which were low birth weight (LBW) infants and 0.7% of which were VLBW infants. The national health screening program in Korea checks anthropometric measurement and developmental progress serially until 6 years of age. However, little is known about the postnatal growth patterns of infants in Korea. Thus, it is important to use population-based nationwide data to understand of the early growth patterns of preterm infants. This study aimed to estimate the nationwide growth patterns according to the birth-weight group and to analyze the relationship between growth and development using a population-based surveillance system. We hope that our findings will inform policymakers, medical practitioners, and public health experts, and provide guidance for developing a nationwide follow-up program for public services, especially healthcare-delivery and social welfare delivery systems.We initially identified 430,541 infants who were born in 2013 and examined their infant health check-up records for the 1st to 6th visits from the National Health Insurance Service (NHIS) database. Healthcare claims including diagnostic codes of almost all Korean residents, approximately 98% covered by NHIS and 2% by medical aid, were linked to health check databases. The data, including gestational age and birth weight, were also grouped according to the International Classification of Diseases-10 codes  [The national health screening program for infants and children in Korea, launched in November 2007 is a kind of population surveillance system that consists of history taking, physical examination, anthropometric measurements, screening for visual acuity, and administration of Korean Developmental Screening Test (K-DST), oral examination, and questionnaires with anticipatory guidance . The queThe period for national health screening program (1st to 6th visits) was divided and classified as follow; 6 months for 4–6 months of age, 12 months for 9–12 months of age, 24 months for 18–24 months of age, 36 months for 30–36 months of age, 48 months for 42–48 months of age, and 60 months for 54–60 months of age. The age at exam was defined as chronologic ages.For growth assessment, the National health screening program checks anthropometric parameters including body weight, height, and HC serially at every follow-up. The percentile of growth was assessed using the Korean growth curve, which provides sex specific data. Poor growth was defined as measurements below the 10th percentile of weight, height, and head circumference individually.The K-DST is used an effective screening tool for infants and children with neurodevelopmental disorders and has been used since 2011. It is used to verify whether infants are developmentally appropriate or neurodevelopmentally delayed in six domains: gross motor, fine motor, cognition, communication, social interaction, and self-control. The K-DST is conducted to screen children according to their corrected age before 36 months of age as recommendation and after that age, it is allowed to take tests according to chronological age. There is no K-DST at first visit, and at 5th, 6th visit  the participants take the test papers according to their chronological age. The participants take the tests papers at the time of their clinic visit and get the result as four categorized groups based on the standard deviation (SD) scores; the scores above 1 SD are defined as ‘high-level’, those between −1 and 1 SD as ‘peer-level’, those between −2 and −1 SD as ‘follow-up test’, and those below −2 SD as ‘further evaluation’ . AdditioIn this study, growth and developmental results were analyzed according to five stratified birth weight groups . LBW infants and VLBW infants were defined as having a birth weight below 2500 g and 1500 g, respectively. Preterm infants were defined as infants born before 37 weeks of gestation.p-values < 0.05 were considered statistically significant. The cohort was stratified according to the birth weight or the age of checkup. The characteristics of the subjects were expressed as means and standard deviations for continuous variables and as percentages for categorical variables. Correlations for height, weight and HC between 6 months and 60 months of ages as time periods were computed using Pearson’s correlation coefficient. Multiple logistic regression model was used to determine the independently associated factors with among infants with odds ratios (OR) and 95% confidence intervals (CI). Multivariate longitudinal data analysis was done using multivariate repeated measured model (PROC MIXED and GENMOD). All statistical analyses were performed using SAS version 9.4 . In this study, all identifiable variables, including claim-, individual-, and organizational-level identification numbers, were re-generated in random by the NHIS database to protect the patients’ privacy. This study used NHIS data (NHIS-2019-1-569) maintained by the NHIS. The study protocol was approved by the Institutional Review Board of Gangnam Severance Hospital (No. 3-2019-0147). Informed consent was waived.n = 347,153, 81%) were included in the health check at 24 months of age. The highest number of preterm infants underwent the health check at 36 months . The distribution of a number of infants who participated in the infant health check according to birth weight group were shown in Among 430,541 infants, born in 2013 and included in the study, 219,576 (51%) were male. The numbers of infants, who underwent health checks ranged from 286,331 (67%) to 347,153 (81%). The highest number of infants (p < 0.0001). The lower birth weight group showed a lower mean percentile of weight, height, and HC. There was a significant difference in height, weight, and HC between the low birth weight infants  and the reference group with birth weight of 2500–4500 g according to age at health checkup. The mean percentile of weight, height, and HC according to age at health check was seen in p < 0.0001)  infants had a poor HC growth at 60 months of age, 10,950 (7.92%) infants had poor height growth, and 12,481 (9.03%) infants had a poor weight growth. Using longitudinal analysis, this study found a significant difference in the incidence of poor height, weight, and HC growth according to age at health check, birth-weight group, and combination of age and birth weight, respectively ( 0.0001) . The lowThe Pearson correlation coefficient of the growth percentiles  at 6 and 60 months of age obtained using correlation analysis is shown as To analyze the relation between the growth at 6 months and 60 months, the risk of poor growth in the infants below 10th percentile of growth at 6 months was compared to the infants within 10–90th percentile of growth. The infant below the 10th percentile of HC and height at 6 months of age, respectively, showed the higher risk of HC and height below the 10th percentile at 60 months of age  1.62 (1.32–1.98); Height, 1.64 (1.38–1.95)). However, weight status at 6 months showed no significant association with the risk of weight below the 10th percentile at 60 months of age. The incidence of suspected developmental delay result at 60 months of age was 10% . In particular, further evaluation was recommended for 4572 (1.5%) infants, and the ‘follow-up test’ for 24,448 (8.5%) infants. According to the birth-weight group, K-DST results were presented in There is a significant difference in the incidence of suspected developmental delay results between the infants with poor weight, height, and HC growth and above 10th percentile at 60 months of age by birth weight group . The infLower birth weight, male sex, poor HC, poor height, and poor weight were confirmed as factors associated with suspected developmental delay results at 60 months of age using multivariate logistic regression analysis . InfantsThis is the first large study showing the longitudinal growth and developmental patterns of children born with low birth weight in Korea. LBW infants are subject to a significant burden of morbidities, such as postnatal growth failure and neurodevelopmental impairments. However, extreme preterm infants have been the primary focus of the research over the years. In this study, longitudinal growth outcome in LBW infants from birth to 60 months was shown using nationwide population-based health check-up data. We confirmed an association between poor post-natal growth and developmental delay, both of which are persisting on long term follow-up, especially among LBW infants.Our findings are consistent with those of previous international studies, which reported that a lot of preterm infants born lighter and shorter than full-term infants remain growth-restricted beyond the catch-up period . We founBoth the severity and duration of the growth retardation are related to the degree of prematurity of an infant . We founChildren with poor growth have greater neurodevelopmental functioning problems than those with normal growth . A natioEarly postnatal growth is positively related to neurodevelopmental outcomes, especially Intelligence Quotient ; PostnatPrevious studies reported that growth restriction was more common in preterm infants but recent studies have shown positive reports of catch-up growth through nutritional support and quality improvement . Small fChildren who fail to achieve catch up growth within 2 years of life remain short after childhood so an early initiation of growth hormone treatment was recommended by previous research ,30. The The main strength of this study was that it was a nationwide study with a large population and it was able to report an association between growth and neurodevelopmental outcomes overtime. A total of 99% of eligible infants participated in the national health screening program for infants and children, so these results are an accurate representation of the growth of the infant population in Korea. These nationwide data accounts for all infants, including LBW but not VLBW infants, who participated in health check-ups during the first five years of life in addition to the infants weighing 2500–4500 g infants as a reference.There are some limitations to this study. Since weight is the most important factor in the growth assessment of newborns and infants, this study design was analyzed based only on birth weight. Because birth weight is usually related with gestation, and SGA status can make some discrepancy, we just display the infants dividing birth weight rather than gestational age. Poor growth was defined as weight, height, and HC individually below the 10th percentile. VLBW infants accounted for 0.7% of total birth infants in this cohort, which is a very small proportion. Preterm infants with intraventricular hemorrhage or post-hemorrhagic hydrocephalus have larger HC but the effect isn’t considered due to a small population. There are many factors having affecting on growth including nutrition and co-morbidities, but we lack detailed data that may provide information on important confounders. For the integrity of data on growth in preterm infants, we included the growth parameter at only postnatal age, but not the corrected age.This Korean population-based study showed that a significant number of LBW infants did not achieve catch up growth even at 60 months of age. Close monitoring of appropriate weight gain, nutritional intervention, and early intervention programs will be needed for improving children’s growth and developmental outcomes. Our findings provide guidance for developing a nationwide follow-up program for infants with perinatal risk factors.


How are neonatal intensive care unit (NICU) admission rates and NICU patient-days changing over time for various birth weight, gestational age, and acuity subgroups?In this cohort study of neonates in a large integrated health care system, the risk-adjusted NICU admission rate and NICU patient-days decreased from 2010 through 2018 without an increase in readmission or mortality rates. The decrease was associated with the high gestational age and birth weight subgroup.These findings suggest that substantial decreases in NICU utilization across large birth populations are possible, and the remaining unexplained variation suggests that further changes are also possible. This cohort study describes population-based trends in neonatal intensive care unit admissions and patient-days, readmissions, and mortality rates in the birth population of a large integrated health care system. There are few population-based studies addressing trends in neonatal intensive care unit (NICU) admission and NICU patient-days, especially in the subpopulation that, by gestational age (GA) and birth weight (BW), might otherwise be able to stay in the room with their mothers.To describe population-based trends in NICU admissions, NICU patient-days, readmissions, and mortality in the birth population of a large integrated health care system.This cohort study was conducted using data extracted from electronic medical records at Kaiser Permanente Southern California (KPSC) health care system. Participants included all women who gave birth at KPSC hospitals and their newborns from January 1, 2010, through December 31, 2018. Data extraction was limited to data entry fields whose contents were either numbers or fixed categorical choices. Rates of NICU admission, NICU patient-days, readmission rates, and mortality rates were measured in the total population, in newborns with GA 35 weeks or greater and BW 2000 g or more (high GA and BW group), and in the remaining newborns (low GA and BW group). Admissions to the NICU and NICU patient-days were risk adjusted with a machine learning model based on demographic and clinical characteristics before NICU admission. Changes in the trends were assessed with 2-sided correlated seasonal Mann-Kendall test. Data analysis was performed in August 2019.Admission to the NICU and NICU patient-days among the birth cohort.The primary outcomes were NICU admission and NICU patient-days in the total neonatal population and GA and BW subgroups. The secondary outcomes were readmission and mortality rates.P for trend = .002); 92% of the change was associated with changes in the care of newborns in the high GA and BW group. The number of risk-adjusted NICU patient-days per birth decreased from a mean of 1.50 patient-days  to 1.40 patient-days  (P for trend = .03); 70% of the change was associated with newborns in the high GA and BW group. The unadjusted 30-day readmission rates and mortality rates did not change.Over the study period there were 320 340 births . The risk-adjusted NICU admission rate decreased from a mean of 14.5%  to 10.9%  (Admission rates to the NICU and numbers of NICU patient-days decreased over the study period without an increase in readmissions or mortality. The observed decrease was associated with the high GA and BW newborn population. How much of this decrease is attributable to intercurrent health care systemwide quality improvement initiatives would require further investigation. The remaining unexplained variation suggests that further changes are also possible. This is especially true for the 98% of births at gestational age 34 weeks or older and the 80% of NICU admissions that do not meet high acuity criteria.13 The studies vary in time period of study, choice of birth subpopulations, definition of NICU admissions, and NICU patient-days. Although the overall rate of NICU admissions increased in the last few decades as modern NICU care became established,10 we are aware of only 1 recent study14 that examined temporal trends in NICU admissions.There are few population-based studies in this area.15 All patient care documentation and records are contained within a single electronic health record (EHR) system. This allowed us to look at the whole birth population regardless of patient acuity or birth hospital acuity level. It also allowed us to obtain maternal and neonatal data directly from the EHRs, rather than abstracted data such as coding or claims data. We also could identify patients in the NICU according to care physically occurring in the NICU, rather than claims or birth certificate proxies for NICU care. Finally, KPSC was also in the midst of a number of systemwide quality improvement initiatives expected to decrease NICU admissions and patient-days. The aims of this study were to describe the contribution to NICU admissions and NICU patient-days by several subpopulations of interest, temporal trends in rate of NICU admission and NICU patient-days, a risk adjustment model controlling for the contribution of pre-NICU risk factors, and readmission and mortality balancing factors.The Kaiser Permanente Southern California (KPSC) health care system provides integrated health care for a large (4.7 million), socioeconomically diverse population that is broadly representative of the Southern California population.For this retrospective cohort study of NICU utilization, we extracted data from the EHR on neonates born in 13 of 14 KPSC facilities from January 1, 2010, through December 31, 2018, regardless of membership status at the time of NICU stay. This study was approved by the KPSC institutional review board with exemption of the requirement to obtain informed consent because the data were deidentified.16One of the 14 hospitals was excluded from this study, because this level I nursery did not have a formal NICU. Furthermore, we excluded member mothers whose newborns were delivered at non-KPSC (contracting) hospitals. Information stored within the EHR includes demographic data, including maternal race/ethnicity, age, education, medical insurance type, address, all inpatient and outpatient care, linkage of individual newborns’ and mothers’ charts, and care interventions entered at the time they occurred often in number- or list-delimited fields. California Perinatal Quality Care Collaborative registry data on the population was downloaded from the California Perinatal Quality Care Collaborative website.0/7 and 316/7 weeks, death, invasive or noninvasive assisted ventilation for 4 hours or more, early bacterial sepsis, major surgical procedure requiring anesthesia, interhospital transport to or from the NICU for higher acuity care, suspected encephalopathy or suspected perinatal asphyxia, and active therapeutic hypothermia.16 Newborns who did not meet 1 or more of the high acuity criteria were classified as low acuity. Surgical newborns were defined as newborns who had a completed surgical procedure recorded in the Electronic Privacy Information Center OpTime surgery log, which is the EHR module used for all surgical procedures. Operations performed outside KPSC facilities were identified through claims data associated with the neonates born in KPSC facilities.Care in the NICU was defined as care physically occurring in a NICU bed on the basis of coding of the bed to a NICU cost center. The NICU admission rate was defined as the frequency of neonates born at KPSC hospitals who received NICU care between birth and discharge to home or mortality. The NICU patient-days were determined by the sum of patient-hours assigned to NICU cost center across the birth admission and any stay associated with subsequent intrahospital or interhospital NICU transfers. Intrahospital or interhospital NICU transfer was defined as a new admission to another medical center within 24 hours where the previous admission’s discharge order did not indicate discharge to home. Information on patient-days for NICU services provided in contracting hospitals was obtained from insurance claims. Readmission was defined as a NICU admission to any KPSC hospital occurring 24 hours or more after the previous discharge or an admission occurring less than 24 hours after previous discharge with documented discharge order indicated as discharge to home or if the new admission was to the same medical center. In this study, mortality was defined as death from the time of birth to 30 days after discharge from NICU. Neonates in the high GA and BW group were defined as having gestational age 35 weeks or older and birth weight 2000 g or higher. Low GA and BW newborns were defined as those with gestational age less than 35 weeks or birth weight less than 2000 g. High acuity newborns were defined as patients meeting 1 or more California Perinatal Quality Care Collaborative high acuity inclusion criteria: birth weight of 401 to 1500 g, gestational age between 22The contribution of high GA and BW trends to the total population trends was calculated as follows: the difference between the 2010 and 2018 rates was calculated for each population. Next, the high GA and BW difference was divided by the total population difference, weighted by the total number of newborns in each population.17 a machine learning model, was used to model NICU admission and NICU patient-days. LightGBM has outstanding predictive performance while accommodating issues such as complex interactions of candidate factors, nonlinearity, and missing data.17 A detailed description of the risk adjustment model variables is presented in the eAppendix in the This study was designed to assess the association of postnatal care practices with neonatal outcomes while controlling for independent factors. For this reason, we developed an adjustment model focused on socioeconomic, prenatal, and delivery room variables that have been extracted from the maternal and newborn records that might affect or describe patient acuity risk independent of postnatal care management. LightGBM,2 test for categorical variables and t test for continuous variables using SAS statistical software version 9.4 (SAS Institute). We performed trend analyses of monthly NICU admissions per live birth, NICU patient-days, readmissions, and mortality per 100 live births. The analyses tested whether these metrics had statistically significant trends over time. The trend analysis included assessments of both crude and risk-adjusted trends for the NICU utilization metrics and only crude trends for the readmission and mortality metrics. Confidence limits for risk adjusted trends were calculated using bias-corrected bootstrapping performed with Python statistical software version 3.7.4 and Python Package SciPy version 1.3.1.18 (both from Python Software Foundation). Confidence limits for readmissions and mortality were calculated using Agresti-Coull confidence intervals for binomial proportions18 using Python statistical software version 3.7.7 and Python Package statsmodels version 0.11.1 (both from Python Software Foundation). The trend analyses were performed with 2-sided correlated seasonal Mann-Kendall tests calculated using Python statistical software version 3.7.4 and Python Package PyMannKendall version 1.2 (both from Python Software Foundation).19P < .05 was considered statistically significant. Monthly means were used to ensure the analyses had sufficient power. Data analysis was performed in August 2019.We assessed differences in the distribution of maternal characteristics using the χ20 (implementation in October 2013), minimization of elective deliveries at GA less than 39 weeks22 (implementation in March 2014), and maximization of vaginal delivery for nulliparous, term, singleton, vertex pregnancies (implementation in May 2017).23 Each of these initiatives has been associated with decreasing the need for NICU care.25Systemwide quality improvement initiatives over the study period included decreasing obligate NICU admission guidelines for well-appearing newborns to GA less than 35 weeks and BW less than 2000 g (implementation in October 2014), use of a newborn early-onset sepsis risk calculator for decision support A total of 320 340 eligible women  gave birth during the study period, representing 16% of births in Southern California. Neonates had a mean (SD) gestational age of 38.6 (1.97) weeks and a mean (SD) birth weight of 3302 (573) g. Approximately 10% of KPSC members who were pregnant did not receive their birth hospitalization care in KPSC hospitals or gave birth at the 1 KPSC hospital without a NICU. Compared with mothers of newborns not admitted to the NICU, mothers of newborns admitted to the NICU were more likely to be older , black (23 014 mothers [8.19%] vs 4707 mothers [12.00%]), nulliparous (56 466 mothers [20.09%] vs 10 823 mothers [27.60%]), have lower household income , non-Medicaid recipients , and with multiple gestation (5743 mothers [2.04%] vs 5169 mothers [13.18%]) . NeonateAmong the live births during the study period, 39 220 newborns (12.24%) were admitted to the NICU, generating a mean of 1.46 NICU patient-days per birth . High GAThe overall readmission rate in the 30 days after discharge was 2.39% . The oveR2 of 0.729 and a root mean squared error of 10.712 for the total population and an R2 of 0.233 and a root mean squared error of 7.312 days for the high GA and BW newborns.The NICU admission model adjusted for demographic, antenatal, and delivery room risk factors had an area under the receiver operator curve of (0.895) for the total population and (0.849) for newborns with high GA and BW. The mean precision  was (0.740) for the total population and (0.529) for newborns with high GA and BW. The NICU patient-days risk-adjustment model had an P for trend = .002) (P for trend = .002), accounting for 92% of the total decrease. The NICU admission rate for the low GA and BW subgroup decreased from a mean of 4.1%  of births to 3.7%  of births (P for trend = .005). Over the study period, the risk-adjusted total NICU patient-days per birth decreased from a mean of 1.50 patient-days  to 1.40 patient-days  (P for trend = .03). This represented a 7% relative decrease; 70% of the change was associated with newborns in the high GA and BW group (P for trend = .003). The decrease in NICU patient-days per birth for the low GA and BW subgroup from 1.09 patient-days  to 1.05 patient-days (1.01-1.12 patient-days) was not statistically significant (P for trend = .88).Over the study period the risk-adjusted total population NICU admission rate decreased from a mean of 14.5%  of births to 10.9%  of births, a 25% relative decrease ( = .002) . The NICBW group . The risP for trend = .12). The High GA and BW subgroup decrease from 2.6%  to 2.0%  of births (P for trend = .10) and low GA and BW decrease from 0.2%  to 0.1%  of births (P for trend = .62) were also not statistically significant.There were no statistically significant trends in 30-day readmission rates during the study period. The total birth population’s 30-day readmission rates mean decrease from 2.7%  to 2.1%  was not statistically significant (P for trend = .88). The rate for the high GA and BW subgroup ranged from 0.08%  to 0.14%  (P for trend = .79). The rate for the low GA and BW subgroup ranged from 0.16%  to 0.20%  (P for trend = .87).There were no statistically significant trends in mortality rates during the period. The total birth population’s mortality rate from birth to 30 days after discharge to home ranged from 0.25%  to 0.32%   and 14.9 days per late preterm birth among 37 460 singleton late preterm births.26 Fourth, in Norway between 2009 and 2014, the overall NICU admission rate was 9.4% among 368 068 births, 45% in among births at GA 340/7 to 366/7 weeks, and 6% for GA 37 weeks or later, with a mean of 5.3 NICU patient-days for GA 37 weeks or later, 11.3 NICU patient-days for GA 340/7 to 366/7 weeks, and 40 NICU patient-days for GA less than 34 weeks.27 Finally, a March of Dimes study13 from July 2009 to June 2010 of 183 030 births from hospitals contributing data to the National Perinatal Information Center Quality Analytic Services reported an overall NICU admission rate of 14.4% and 1.9 NICU patient-days per birth. In that study,13 the NICU admissions included neonates admitted from referring hospitals, which may have resulted in an overestimate of NICU admissions and NICU patient-days arising from the reporting hospitals’ birth populations. In the present study, the mean NICU admission rate of 12.24% was similar to those in 2 US studies26 but higher than that in the Norwegian study (9.8%).27 By the end of our study period, our NICU admission rate of 10.9% was approximately one-half the difference between the Norwegian and US studies.Recently published population-based cross-sectional studies showed notable interhospital variation in permutations of NICU admission rates, NICU patient-days, and other measures of utilization, especially in the lower acuity patients, such as newborns with high GA and BW. First, in a study26 where overall NICU patient-days ranged from 1.9 to 2.0 NICU patient-days per birth, although they were higher than 1.2 NICU patient-days per birth reported from Norway.27 Although these differences appear small, they are associated with a very large number of actual NICU patient-days. For instance, the US has approximately 4 million births per year30; thus, a change of 0.1 NICU patient-day per birth would generate 400 000 NICU patient-days per year.There was also a 7% relative decrease in NICU patient-days, from 1.50 to 1.40 days per birth, during the study period. The smaller change in NICU patient-days compared with NICU admissions is consistent with the small proportion of total NICU patient-days contributed by the high GA and BW newborn admissions. These rates were lower than those in the US studies,33 and mortality34 rates compare favorably with published rates. This suggests that the observed temporal decrease in NICU utilization have not been at the cost of these complications.The decreases in our NICU admissions and NICU patient-days were not associated with increases in readmission rates and mortality. The readmissionOur risk adjustment model was designed to reveal changes in postnatal care practices by adjusting for a rich range of clinical factors and excluding any adjustment for care at or after the decision to admit to the NICU. This suggests that the changes in NICU admissions and patient-days we observed were less likely to be associated with differences in case mix and more likely associated with changes in the decision-making around NICU admission and NICU care. The model still shows a significant amount of unexplained variation in both NICU admissions and patient-days. For instance, in the high GA and BW subgroup, the area under the precision-recall curve was 0.529 for NICU admissions and 0.233 for NICU patient-days. Because we controlled for primary patient acuity factors, the unexplained variation is likely associated with heterogeneous care practices rather than the clinical characteristics of the newborns, suggesting that there are still large opportunities for improving care practices in NICU care.The high GA and BW newborns were associated with the majority of the decrease in total NICU admissions observed in our study. These changes may have been associated with the intercurrent systemwide quality improvement initiatives during the study period that primarily targeted the high GA and BW subgroup.Our health care system’s financial structure is population based rather than fee-for-service based, so financial incentives are more aligned with decreasing rather than increasing the amount and cost of NICU care. The association of this form of reimbursement with observed NICU care trends may be worth assessing further.35 Second, the size of the study population was similar to that of studies by Schulman et al2 and Moen et al,27 approximately one-third the size of the Texas study26 and the Anthem study,10 but much smaller than the study by Harrison et al.14 The BW and GA birth subpopulation distribution was similar to other population-based studies.27 Third, 9.60% of our member population is Medicaid insured. Furthermore, our analyses adjusted for type of insurance and US Census tract–based socioeconomic characteristics. Fourth, we also were able to use a more direct measure of NICU care based on the daily physical location of the newborn as recorded in the EHR, avoiding errors introduced by other NICU admission proxies, such as self-reports,2 insurance claims,10 and birth certificate data.29 Fifth, we included care across interhospital transfer admissions, avoiding underestimates of NICU patient-days from studies relying on birth admission data alone. Sixth, our approach did not require geographical proxies to match births to NICU admissions, avoiding mismatching of births to NICU care. Seventh, we chose the high GA and BW subgroup as a focus because this is a large population and one of low enough endogenous risk for decompensation that, barring specific individual problems, they would be permitted by many physicians to room in with their mother. This made the high GA and BW population particularly likely to benefit from the intercurrent NICU-sparing quality improvement initiatives we enumerated, where NICU admission itself was the major modifiable care decision. In this report, we did not provide data to quantify the absolute or relative effects of these quality improvement initiatives. There are challenges to this work, including identifying quantifiable measures of patient-level compliance and determining to what extent the initiatives complemented or conflicted with the effects of other initiatives. These would be a worthwhile area for future research. In a related way, the remaining unexplained variation in NICU admissions among high GA and BW newborns suggests that there is potential for further optimization of care, possibly through improved compliance with the listed initiatives, as well as the introduction of additional changes in obstetrical or neonatal practice.This study has multiple strengths. First, the findings of this study can be generalizable to Southern California pregnant women and their newborns because it is based on a large cohort  that is demographically representative of the Southern California population.This study also has several limitations. First, NICU patient-days were not weighted by nursing or respiratory care acuity, so the extrapolation of changes in NICU patient-days on NICU resources is limited. Second, approximately 10% of KPSC members who were pregnant did not receive their birth hospitalization care in KPSC hospitals or gave birth at the 1 KPSC hospital without an NICU; this raises the possibility of selection bias. Because most of these hospitals are geographically peripheral to the KPSC population, the selection choice of delivery hospital was less likely to be associated with nongeographical factors. We did not do sensitivity analysis to confirm whether there was not a difference in case mix in this population because information allowing for sensitivity analysis for this population was limited.We observed a decrease in NICU admissions and patient-days in a large, Southern California–representative population in an integrated health care system. This trend was the opposite of that reported in another population-based study on NICU admissions. Most of the decrease was associated with the decrease in NICU use among the high GA and BW population. It would require further investigation to understand how much of this decrease was attributable to intercurrent health care systemwide quality improvement initiatives. The remaining unexplained variation suggests further changes are also possible.


Preterm infants have high risk of developing growth restriction and long-term complications. Enteral feeding is often delayed in neonatal intensive care units (NICUs) for the fear of feeding intolerance and the associated necrotising enterocolitis, and recent advances in nutritional support are unavailable in low-income countries.The aim of this study was to assess the incidence and associated factors of extrauterine growth restriction (EUGR) among preterm infants in selected NICUs in Ethiopia.This was a cross-sectional study involving a subgroup analysis of preterm infants admitted to hospitals, from a multicentre descriptive study of cause of illness and death in preterm infants in Ethiopia, conducted from 2016 to 2018. EUGR was defined as weight at discharge Z-scores <−1.29 for corrected age. Clinical profiles of the infants were analysed for associated factors. SPSS V.23 software was used for analysis with a significance level of 5% and 95% CI.From 436 preterm infants included in the analysis, 223 (51%) were male, 224 (51.4%) very low birth weight (VLBW) and 185 (42.4%) small for gestational age (SGA). The mean (SD) of weight for corrected age Z-score at the time of discharge was −2.5 (1.1). The incidence of EUGR was 86.2%. Infants who were SGA, VLBW and longer hospital stay over 21 days had increased risk of growth restriction . SGA infants had a 15-fold higher risk of developing EUGR at the time of discharge from hospital than those who were appropriate or large for gestational age (OR (95% CI)=15.2 (4.6 to 50.1).The majority of the infants had EUGR at the time of discharge from the hospital, which indicates suboptimal nutrition. Revision of national guidelines for preterm infants feeding and improvement in clinical practice is highly required. Preterm infants’ growth is expected to be similar to that of the intrauterine foetus, however small preterm infants often develop extrauterine growth restriction (EUGR).EUGR is associated with increased risk of post-neonatal mortality and long-term morbidities such as adverse metabolic and neurodevelopmental outcomes in subsequent years.There is paucity of data regarding preterm nutrition in low-income and middle-income countries; parenteral nutrition and use of human milk fortifiers are often unavailable.Neonatal mortality rate of hospital admitted preterm infants in Ethiopia is 29%, 86.2% of the infants who survived the immediate complications were discharged with extrauterine growth restriction (EUGR).The high incidence of EUGR indicates insufficient nutritional support of the preterm infants.Infants with very low birth weight, hospital stay over 21 days and small for gestational age had increased risk of developing EUGR.Complications of preterm births are the leading causes of newborn deaths worldwide. Survivors of preterm birth are at increased risk of adverse metabolic and neurodevelopmental long-term outcomes.5Improved nutritional support may decrease the rate of EUGR. This support may include early administration of parenteral nutrition, use of human milk fortifiers and preterm formula when mother’s milk is unavailable.13For LMICs WHO guidelines on feeding stable low birth weight infants whose birth weight is greater than 1000 g recommend feeding mother’s own milk starting from the first day. Those who cannot be fed mother’s own milk should be fed donor human milk (when available); if this is not possible standard infant formula has to be given, those who fail to gain weight despite adequate feeding with standard infant formula should be given preterm infant formula. And very low birth weight (VLBW) infants who fail to gain weight despite adequate breast milk feeding should be given human-milk fortifiers.This is a cross-sectional study involving the analysis of a subgroup of 436 preterm infants from a multicentre descriptive study conducted in five selected hospitals, ‘Study of causes of illness and death in preterm infants (SIP)’. The primary study and methodology papers have been previously published.15Preterm infants with a GA of 28–36 weeks, who were discharged alive from the hospitals, were considered for the analysis. The exclusion criteria included infants with a congenital malformation, chromosomal abnormalities; those who died before discharge from the hospital, and had a hospital stay less of than 2 weeks. GA estimation was done by a combination of last menstrual period, ultrasound and New Ballard Score assessment. Variables such as birth weight, discharge weight, estimated GA, clinical profile of the infants, corrected age and duration of hospital stay were analysed.Fenton growth chart calculation spreadsheets.Weight for GA and weight for corrected age Z-scores were calculated using gender specific 2 test was used to check the cell count adequacy before performing univariate logistic regression. Factors that could be associated with the dependent variables were identified from univariate logistic regression . Stepwise multivariate logistic regression was performed to identify independent risk factors for EUGR with significance level of 5% and 95% CI.Statistical analyses were done using SPSS V.23 software. Following descriptive analysis, the χStudy participants were not involved in the design of the study.Nearly half of the infants, 214 (49.1%) had neonatal infections such as neonatal sepsis, pneumonia, meningitis and NEC, while 190 (43.6%), 111 (25.6%), 253 (58%) and 19 (4.4%) had respiratory distress syndrome, feeding problems, hypothermia and perinatal asphyxia, respectively. The mean (SD) duration of hospital stay was 21.5 (5.1) days and the mean (SD) of corrected age at discharge was 35.4 (1.9) weeks.The overall incidence of EUGR was 86.2%. Almost all (98.4%) of the infants born SGA had EUGR at discharge, while fewer of the LGA cases (22.2%) were classified as EUGR at the time of discharge from the hospital. Comparable rates of EUGR were observed across the infants’ major diagnoses. Birth weight, weight for GA and duration of hospital stay were found to be associated with the occurrence of EUGR  . VariablThe SIP study has showed a very high mortality rate (29%) among hospital admitted preterm infants.21 22et al from the USA,et al; Lima et al from Brazil and Clark et al from the USA, 56.8%,The incidence of EUGR observed in this study was comparable to the 89% EUGR rate in extremely low birth weight infants (birth weight less than 1000 gm) reported by Dusick et al have shown risk factors related to EUGR, such as male gender, low GA at birth, low birth weight and long length of hospital stay.et al from Japan have also reported lower GA, IUGR, severe chronic lung disease and poor nutrition as relevant risk factors associated with EUGR, the SGA infants in our study are likely to have had IUGR, but none of the comorbidities the infants had was associated with increased risk EUGR.The mean Z-score of birth weight and weight at discharge in this study was significantly lower than the averages reported in other literature.Aggressive nutritional support has been shown to promote growth without increased risk of adverse effects.31This study has several limitations, the mean corrected age at discharge was 35.4 weeks, and follow-up at around 40 weeks could have possibly shown catch up growth. We used similar definition of EUGR for all infants in the study, SGA infants’ growth velocity was not considered for diagnosis EUGR. Nutritional data, maternal conditions and delivery relating factors were not assessed as risk factors. This was a cross-sectional study design, the main aim was to assess the incidence of EUGR, associated factors were analysed with the available data. Further study is required to identify all the predictors of EUGR.The high incidence of EUGR observed in this study indicates that the nutritional support of the preterm infants was insufficient. The risk of developing EUGR was higher in preterm infants who were VLBW, SGA and hospitalised for over 21 days. Much attention needs to be given to improve preterm nutrition in low-income countries. Country infant feeding guidelines need revision based on recent evidences to improve preterm nutrition. Regular monitoring of nutritional status and individualised timely nutritional intervention has to be the standard of care of preterm infants in the NICUs.


Echinococcus multilocularis or E. granulosus. There is, however, no standard treatment during pregnancy. Hydatid cyst disease is life-threatening for the mother/fetus , has a teratogenic potential for the fetus.The main goal of this article is to answer the following question: Is pregnancy termination a perquisite of surgery? What is the best way of managing pregnant patient with hydatid cyst?We did an extensive review of relevant literature but could not find any article about termination of pregnancy before surgery or medical treatment of hydatid cyst disease.In a multi-center retrospective study, 24 pregnant women with complicated hepatic hydatid cyst and gestational age of 5–29 weeks were treated surgically. They rePercutaneous treatment with oral albendazol before and after procedure was investigated in 13-week pregnant woman for multiple hepatic and splenic hydatid cysts .Sobhani et al. also reported symptoms of anaphylactic shock caused by intraperitoneal rupture of hydatid cyst in 11-week pregnant woman, who had to undergo surgery and then medically treated with albendazole . A case We examined a 26-year-old nulligravida woman with a known case of liver and lung hydatid cysts who had an unplanned pregnancy referred to the hospital. During the pregnancy, the patient was monitored for symptoms of the illness. She had severe and frequent coughing. During the first two months of pregnancy, the lung large cyst ruptured, causing the enlargement of cysts size , 2. She After abortion, she was treated with thoracotomy and laparotomy simultaneously. The cysts were evacuated and treatment with albendazole was initiated. The results of 2-year follow-up suggest that she has no signs or symptoms.Finally, we emphasize that in previous studies and WHO Staging, we did not find any recommendation to terminate a pregnancy before treating a hydatid cyst.However, the question is “what signs/symptoms or the disease stages do call for early termination of pregnancy?” Should termination really occur in a pregnant woman with hydatid cyst? Surgery may cure the patient, but broad replacement rate is a problem at the reproductive age. Given the above, there is still debate about proper procedure for the treatment and management of a pregnant patient with hydatid cysts.


Background: Being born with non-optimal birth characteristics has several long-term consequences on health in general but also for the individual’s reproductive pattern. In premature ovarian insufficiency (POI) the follicles are depleted or dysfunctional. This results in menopause before the age of 40, and for most of the affected women, it causes infertility. The objective of this study was to evaluate the potential effects of being born with non-optimal birth characteristics on the risk of developing POI.Methods: This population-based cohort register study included all women born in Sweden between 1973 and 1993 who were followed until the end of 2012 (age at the end of follow-up ranged between 39 and 59). Women diagnosed with POI were compared with women without this diagnosis with respect to being born small for gestational age, preterm, or with low birth weight. Data on birth characteristics and diagnosis of POI were collected from national registers.Results: A total of 1,033,878 women were included. Being born small for gestational age was associated with a slightly increased odds ratio of POI with 10%. Preterm birth and low birth weight were associated with somewhat increased ORs of POI after exclusion of those born small for gestational age. Similarly, being born preterm or with a low birth weight was also found to be associated with POI to the same extent.Conclusions: Being born with non-optimal birth characteristics may increase the risk of premature ovarian insufficiency. Being born with non-optimal birth characteristics – defined as being small for gestational age (SGA), or preterm birth, or with low birth weight (LBW) – has several long-term consequences on health in general but also for the individual’s reproductive pattern . Organ dThe medical reasons for these risks include the foetal intrauterine environment and the mother’s health and lifestyle prior to and during pregnancy ,6. DurinIn premature ovarian insufficiency (POI) the follicles are depleted or dysfunctional, resulting in menopause before the age of 40 and for most of the affected women causing infertility . In a reThere is a lack of studies evaluating the potential effects of being born with non-optimal birth characteristics on the risk of developing POI. The aim of this study was to test the hypothesis that women born with non-optimal birth characteristics, that is, preterm, with low birth weight, being large for gestational age (LGA) or SGA have an increased risk of developing POI later in life.Data were collected from Swedish health data registers. The Swedish Medical Birth Register was established in 1973 and contains valid data on pregnancies, deliveries, and the new-born. The Swedish Medical Birth Register covers ∼99% of all births in Sweden . Data inIn addition, we used data from the Swedish Prescribed Drug Register , which iThe study has been approved by the Regional Ethical Review Board in Linköping .n = 302). Furthermore, women having the diagnoses Turner’s syndrome (Q960-Q969), ovarian cancer (C569), and/or thyroid disease  were excluded (n = 3040) leaving 1,033,878 women in the final study population.The study population was a cohort of 1,036,918 women born in Sweden between 1973 and 1993 and were followed until 31 December 2012. Cases with POI were identified from the National Patient Register. The ICD diagnosis codes used to define POI were: 2561, 6159, 627 (ICD-8), 256.3 (ICD-9), and E28.3 (ICD-10). The personal identity number unique for each resident in Sweden allowed individual linkages of all women between the registers used. Cases with POI were also identified by dispensed systemic hormone replacement therapy for climacteric symptoms by women younger than 40 years of age. This therapy included oral and transdermal products within the ACT-groups G03CA03 oestradiol , G03CA57 conjugated oestrogens, G03CX01 tibolone, G03FA01 norethisterone and oestrogen, G03FA12 medroxyprogesterone and oestrogen, G03FA15 dienogest and oestrogen, G03FA17 drospirenone and oestrogen, G03FB05 norethisterone and oestrogen, G03FB06 medroxyprogesterone and oestrogen, and G03FB09 levonorgestrel and oestrogen. Since these drugs are mainly prescribed to treat menopausal women and cannot be used for contraception, women prescribed these drugs who were younger than 40 years of age were considered to have POI. However, since hormone replacement therapy is also prescribed to patients with iatrogenic POI (e.g. after oophorectomy), all women with a cancer diagnosis were excluded if diagnosed with a spontaneous POI. These women were identified in the National Patient Registry using the following ICD-codes: all diagnoses starting with C in ICD-10, codes 140–239 in ICD-9, and codes 140–239 in ICD-8. Furthermore, women who had had a bilateral oophorectomy (ICD-10 code LAF10) and been prescribed and dispensed hormone replacement therapy were determined to have POI and were thus included in the study . Furthermore, we categorized study infants into quartiles regarding the severity of SGA to investigate potential dose-response associations. SGA was defined as birth weight ≤2 standard deviations (SD) of the mean weight at a specific gestational age according to the Swedish standard. Large for gestational age (LGA) was defined in a similar manner but with the limit >2 SD of the mean weight for gestational age. LBW was defined as birth weight below 2500 g and very low birth weight as a birthweight below 1500 g. Moderate preterm birth was defined as being born between gestational weeks 32 and 36, and very preterm birth as being born before gestational week 32.p-value <0.05 was considered statistically significant. The Mantel–Haenszel test for trend for the different levels of SGA was used. All statistical analyses were performed using IBM SPSS, version 24.0 .Pearson’s chi-square statistic was used to explore the bivariate association between POI and socio-demographic factors and birth characteristics. To investigate whether being born preterm, with low birth weight, SGA, or LGA was related to an increased risk of POI later in life, we analyzed the data using a single and multiple logistic regression, providing odds ratios (ORs) with 95% confidence intervals (CIs). In the multiple logistic regression models, data were adjusted for attained educational level  among the study participants and year of birth. Each birth characteristic was modelled separately. A A total of 1,033,878 women born between 1973 and 1993 were included in the final study cohort, and 18,627 (1.8%) of these women had POI.p = 0.407)  had POI. That was identical to the proportion of women with POI among women born at term. Also, 5.0% of the women not diagnosed with POI were born preterm, while the corresponding number for women diagnosed with POI was 5.2% (= 0.407) . The una= 0.407) . However= 0.407) . When ex= 0.407) .p ≤ 0.1)  of them had POI compared with 1.8% in women born with normal birth weight. Additionally, 4.7% of the women diagnosed with POI were born with a low birth weight compared with 4.3% among the women born with normal birth weight (p ≤ 0.1) . LBW wasp ≤ 0.1) .p < 0.001, data not shown).Among 211,362 women born SGA, with a weight less than 1 SD below the mean (1SD), 39,023 women were born 2 SD below the mean (2SD), and 5,842 were born 3 SD below the mean (3SD) . Being bBeing born LGA was not associated with the risk of developing POI .This study found an association between being born with non-optimal birth characteristics and risk of POI later in life. Being born in SGA, preterm, or LBW was associated with a somewhat increased likelihood of being diagnosed with POI.To our knowledge, there are no published studies investigating the relation between non-optimal birth characteristics and risk of POI. However, an association of being born LBW or SGA with the risk of infertility has been shown ,20. AlsoThe increased risk of POI among individuals born SGA and LBW may be due to the influence of under-nutrition during the intrauterine life, which in turn affects the development or survival of the follicles. This might lead to dysfunction of the follicles or lower numbers of follicles, resulting in an increased likelihood of developing POI later in life. Preterm birth might not affect the follicles since the follicles usually develop normally if no under-nutrition is present. However, potential explanations for the associations between non-optimal birth characteristics  and POI is that being born with these characteristics increases the risk of several autoimmune diseases, many of which in turn are associated with POI, for example, primary adrenal failure (Addison’s disease), autoimmune thyroid disease (Schmidt’s syndrome), and type 1 diabetes ,25. It iPOI results in premature cessation of ovulation and infertility. This can lead to involuntary childlessness if it occurs among women who have not yet considered becoming pregnant, especially since women increasingly postpone childbearing. Since there is no medical therapy today that is proven to improve the ovarian function and fertility for women with POI, fertility preservation is the only solution if the women want children later in life . This muThis study has a methodological strength in using a national population-based design, the high validity and completeness of the databases, the large size of the study cohort, and the long follow-up of the study participants. A limitation is a fact that there probably are women with amenorrhoea who have not been diagnosed with POI, making it likely that we underreported the prevalence in our study. The missing of the outcome is, however, not dependent on the birth characteristics, which means that this issue would dilute associations rather than cause them. Moreover, by using POI identified not only from the National Patient Register but also from the Swedish Prescribed Drug Register, we found additional women and reduced the figure missing the diagnosis. It should be emphasized, however, that some of the POI cases identified by means of the Swedish Prescribed Drug Register maybe women prescribed hormonal therapy due to causes other than POI, such as in conjunction with the treatment of infertility. Another limitation is the lack of some potential confounding factors for which we did not have data, for example, body mass index, smoking or alcohol consumption, or year of diagnosis in the Swedish Prescribed Drug Register. However, these factors probably do not cause POI  but may In conclusion, this population-based and nationwide Swedish cohort study show that being born with non-optimal birth characteristics was associated with a slightly increased risk of POI. These findings not only provide new knowledge of the origin of POI but can also help identify women at an increased risk of POI, who should be informed about the risks and the consequences of POI. An implication is that women born SGA may be advised not to postpone their pregnancies too long.


Twin infants are likely at great risk for ROP, but studies reported conflicting findings and population studies examining the risk of retinopathy of prematurity (ROP) in twins is limited. We aimed to evaluate the ROP risk in the cohort of one of twins, comparing to singletons.Using insurance claims data of a half of children in Taiwan ages 18 and less, we established a twin cohort (N = 27830) born in 1998–2009 and a randomly selected singleton cohort (N = 111080) frequency matched by sex, birth year, residential area and parental occupation and followed up to 2012 years.The overall incidence rate of ROP was 13.6-fold greater in the twin cohort than in the singleton cohort . The ROP incidence was slightly higher in boys than in girls, higher in children in more urbanized areas and born to mothers without works. The incident ROP increased with decreasing birthweight. For children with birthweight <1000 grams, the ROP incidence was 1.2-fold greater in the twin cohort than in the singleton cohort . The use of mechanical ventilation was associated with increased ROP risk for both cohorts, particularly for infants who were under invasive treatment.Infants who were born as twins or born with low birthweight were at an elevated risk of developing ROP. Extreme cautious and close monitor are required for new born with low birthweight and have undergone with mechanical ventilation. Retinopathy of prematurity (ROP) is an eye disorder characterized by neurovascular disruption in the immature retina and is known to lead to visual impairments and blindness. –4 This dFurthermore, ROP is characterized by progressive degenerating retinal vasculature and is classified on the basis of location (ZoneⅠto Zone Ⅲ) and severity (stage 1 to stage 5) and extent. In generBecause of disagreements in study designs, findings from these studies may not be generalizable to the population of twins. Population-based studies are encouraged to seek further detailed evaluation on the progress of ROP for infants of twins or multiple births comparing with singletons. We therefore used insurance claims data of Taiwan to compare the ROP risk between infants of twin births and singletons.This study used a subset of claims data of the Taiwan National Health Insurance (TNHI) program, consisting of medical records of a half of all children ages 18 years and less randomly selected from all children in Taiwan. TNHI is a universal health insurance system, which has covered over 99 percent of population in Taiwan.  We obtaiFrom the claims data of children , we randomly selected one infant from each pair of twin birth (N = 38808), after excluding triplets and multiple births. Among them, infants born from 1998 to 2009 with demographic information were included as the twin cohort (N = 27830) . From thFrequency distributions of gender and birth year of infants, and their residential areas and parental occupations were expressed as categorical variables and examined using the Chi-square test between the two cohorts. The person-years of follow-up time was estimated for each infants from the birth date to the diagnosis of ROP, death, withdrawal from the insurance, or the end of 2012. The incidence density rates of ROP per 10,000 person-years were computed for each cohort by the demographic variables. The Cox proportional hazards regression analysis was used to calculate hazard ratios (HRs) and 95% confidence interval (CIs) of ROP for the twin cohort compared to the singleton cohort. We further calculated the incidence density rate of ROP by birthweight for both cohorts and calculated HRs compared to normal birthweight singletons. The incidence rates and HRs of ROP associating with the use of non-invasive and invasive mechanical ventilation with oxygen in the early postnatal care were also estimated. We categorized infant weight into 6 groups: < 1000 gram, 1000–1249 gram, 1250–1499 gram, 1500–1749 gram, 1750–1999 gram, and 2000–2499 gram for analysis purpose. We used the SAS statistical package  to conduct data analyses. The Research Ethics Committee at China Medical University and Hospital in Taiwan has approved the use of insurance claims data for the study (CMUH-104-REC2-115).The study population included 111080 singletons and 27830 twin neonates. The overall incidence rate of ROP was 13.5-fold greater in twins than in singletons (35.1 vs.2.6 per 10000 person-years), with an adjusted HR of 13.4  after controlling for sex, urbanization, and parental occupation . The ROPNeonates with mechanical ventilation treatment had a higher ROP incidence in both cohorts, and were higher for twins than for singletons . The higROP is a commonly known complication for preterm birth infants, whom were most likely born at a low birth weight. Studies evaluating ROP risk for preterm babies associated with very low and/or extremely low birthweight may not make comparison with term babies or babies with normal birth weight which may lead to undermine the risk of ROP in clinical condition. Our study was to evaluate the ROP risk for low-birth-weight infants compared to normal birth weight singleton infants based on population data. Limited studies have compared the ROP risk between singletons and multiple birth neonates. – 19 We fPrevious studies may fail to find significant difference in the ROP risk between twins and singletons because of small sample sizes. With a large sample size, the present neonate population study showed that babies who developed ROP were much more common in twins than in singletons (3.35% vs. 0.25%) in Taiwan. This is mainly because the low-birth-weight infants were more prevalent in the twin cohort than in the singleton cohort (25.7% vs. 1.57%). The proportion of infants with extreme low birth weights of <1000 gm was also greater in twins than in singletons (0.81% vs. 0.10%). It is well known that preterm delivery rate and low birth weight rate are much greater in twins than in singletons.  The overAn Israel study found that singletons are at a higher risk of advanced ROP than multiple gestations with birth weights of 1500 grams and less.  Our studThe Swedish guidelines for ROP screening program evaluated 1744 preterm infants with a mean birth weight of 1239g (382–2615) and found 24.1% of them developed ROP. In this It is well-known that excessive oxygen supply is an important risk factor involving in ROP pathogenesis and restricted oxygen delivery may reduce the ROP development.– 28 ReceOur study has strengths of reducing selection bias on its nationwide population-based retrospective cohort design to exam the ROP risk between the twins and the singletons. Moreover, we established study cohorts with large sample sizes, matched by sex, birth year, urbanization level of residential area and parental occupation, to eliminate confounding effect.However, this study has limitations. First, information on most severity stage of ROP and the gestational age at birth was unavailable in the claims data. In a review, Fuchs and Senat reported that preterm birth account for almost 50% of twin pregnancies . Twins aIn summary, the overall incidence of ROP is higher in twin birth infants because of higher portion of low-birth-weight infants with, which could be mainly due to preterm birth. Twins are at a higher risk of ROP after being cared with mechanical ventilation. Oxygen management should be approached with caution for low-birth-weight infants of both singletons and twins. Additional work is needed to identify the adequate strategies for ROP prevention.


The study included 74 pregnant women . ETS exposure decreased birth length by ≥1 cm, and potentially is an independent risk factor for fetal growth restriction, and pregnant women should avoid indoor and outdoor ETS. However, neither PM2.5/PM10 nor ETS was associated with low birth weight or small for gestational age. This study adds to the evidence base that ETS exposure of nonsmoking pregnant women affects the fetal birth length. Family members should refrain from smoking near expectant mothers, although smoking in the vicinity of their residential surroundings potentially exposes mothers and their fetuses to ETS. Public pollution and childbirth education classes should include details of indoor ETS.Exposure to air pollution during pregnancy leads to adverse pregnancy outcomes. Few studies have evaluated the influences of air quality, including environmental tobacco smoke (ETS) and particulate matter (PM), on fetal development, which this study examined. This longitudinal correlation study used multiple linear regression data analysis of PM The mone O3) , and sec , and se10, SO2, NO2, CO, and O3, found small (odds ratio (OR) = 1.04–1.22) to moderate (OR = 2.6) effects of the studied toxicants on low birth weight and fetal growth restriction. The OR (1.04–2.6) of term low birth weight, which was defined as birth weight below 2500 gm, and small for gestational age (SGA), which is defined as the neonate’s weight at birth, was below the 10th percentile with maternal exposure to PM2.5 of 35.6 µg/m3. In concordance with the report of Maisonet et al. [2.5 exposure of 36.3 µg/m3 over a 48 hour period was associated with a 0.9 cm, 0.3 cm, and 128.3 g reduction in birth length, head circumference (HC), and birth weight, respectively; however, a significant interrelationship between environmental tobacco smoke (ETS) and PM2.5 could not be ascertained, although the analytical models with both ETS and PM2.5 showed a nonsignificant effect of ETS.Maisonet and colleagues , in theit et al.  conducte2 exposure in the first trimester reduced birth length by 0.27 cm : −0.51 to −0.03) and birth weight by 40.3 g (CI: −96.3 to 15.6); the OR of SGA by weight and length were 1.37 to 1.42, respectively. [10 >70 µg/m3 on low birth weight. Guo et al. [Ballester et al.  investigN = 48,439) had a 16% higher risk of their baby’s birth weight being less than 2500 g than women without ETS exposure . In Taiwan, the proportion of female adults who smoked decreased from 5.3% to 2.8% from 2004 to 2006 [Active maternal smoking is known to affect the health of children ,17,18. HThis prospective study involved data collection between March 2017 and September 2019 at two time points during each pregnancy. Ethics approval (certificate no: 106059) for study conduct was obtained from the Institutional Review Board of Ditmanson Medical Foundation Chia-Yi Christian Hospital, and our research work was undertaken in accordance with ethical principles of autonomy and confidentiality at all times. The anonymity of study participants was ensured with the use of a study identification number without any personal identifiers.Purposeful sampling was used to recruit the study participants. The inclusion criteria were: (1) singleton pregnancy of 12–16 weeks; (2) age of 20–45 years; (3) ability to read Chinese and speak Mandarin; and (4) residence in Chaiyi  for at least 6 months. We excluded women who smoked after pregnancy confirmation or had pregnancy-related complications, such as placenta previa, gestational diabetes mellitus, pregnancy-induced hypertension, cardiac disease, and premature rupture of membranes. No previous studies have reported an association between maternal urinary cotinine concentrations and fetal growth parameters. Therefore, assuming that the body length of the newborn was 47.5 cm in the none-to-low cotinine group and 49 cm in the moderate-to-high cotinine group with a common standard deviation of 2 cm, a minimum sample size of 78 subjects was required to achieve an alpha level of 5% and a power level of 90%.The two time points of data collection were: (1) at 12–16 weeks of gestation and (2) at the birth of the baby. Data collection of ETS exposure was obtained from self-reported questionnaires and laboratory confirmation of cotinine in urinary sample at each time point.The questionnaire comprised four sections. In the first section, personal details, including age, weight, height, last menstruation date (LMP), estimated date of delivery (EDD), parity, education level, employment, insurance type, and religion, were collected. The second section contained questions on women’s pre-pregnancy ETS status, ETS exposure at home during pregnancy, and ETS exposure in their place of employment and in public places within the previous 30 and 7 days, respectively. A sample question is as follows: In the past 30 days, how often were you exposed to ETS: “never”, “occasionally (1–2 days/week)”, “sometimes (3–4 days/week)”, “always (5–6 days/week)”, or “everyday”. The third section collected ultrasonographic measurements, such as crown–rump length (CRL), biparietal diameter (BPD), head circumference (HC), femur length (FL), abdominal circumference, and birth weight and length.The CRL was used as a baseline fetal growth indicator in the first trimester, as it is the most accurate method to confirm gestational age, especially if the report of the woman’s LMP is unreliable. Prior to 14 weeks of gestation, the CRL is accurate to within 5 to 7 days. Beyond 14 weeks of gestation, the CRL was not used; instead, the BPD, HC, abdominal circumference (AC), and FL were measured at 20–21 weeks of gestation to estimate fetal growth. The BPD most accurately corresponds to gestational age, with a variation of 7–10 days after the second trimester, whereas the HC may be influenced by the shape of the head. The FL correlates with BPD and gestational age, and AC is the most responsive indicator of fetal growth. Birth weight and length were recorded at birth. Fetal growth was considered SGA if the baby’s weight was below the 10th percentile of reference measurements after 37 weeks of gestation. Alternatively, the term low birth weight was used to assess fetal growth restriction if the baby’s birth weight was less than 2500 g.Nicotine is a biomarker of cigarette smoking. Cotinine is a metabolic byproduct of nicotine and 70–80% of absorbed nicotine is estimated to be converted into cotinine. Serum, urinary, and salivary levels of cotinine have been measured to assess ETS exposure. Because the average half-life of cotinine in the serum, urine, and saliva is nearly similar , we deci2.5/PM10 was collected from the Taiwan Air Quality Monitoring Network (TAQMN) and calculated from the hourly PM2.5/PM10 monitoring records of the Yun-Chia-Nan air-quality region. The TAQMN, established by the Taiwan Environmental Protection Administration (EPA), R.O.C. in 1993, had 76 stationary monitoring stations distributed throughout the island in 2015 [2.5/PM10 concentrations in Taiwan have been measured continuously since 2006 [2.5/PM10 during pregnancy were defined as averages of monthly level of PM2.5 from one month before the last menstruation date (LMP) to delivery date.Data on the concentration of PM in 2015 . Accordince 2006 . Exposur2.5 by the median value) by using one-way analysis of variance. Finally, the association of urinary cotinine level with birth length was investigated by linear regression analysis, with and without possible confounders. Several possible maternal confounders, including age and body mass index (BMI), subjective frequency of smoke exposure during pregnancy, nutritional supplements, and alcohol intake were adjusted in the multivariate linear regression model. All tests were two-tailed and a p-value <0.05 was considered indicative of statistical significance. Data analyses were conducted using SPSS 25 .Data analysis included four items of subjective exposure frequency to smoke during pregnancy. We obtained the factor score of each maternal parameter using the exploratory factor analysis, which included only one factor. The relationship between continuous variables of exposure  and neonatal parameters was assessed using the Pearson correlation or Spearman rank correlation . The relationship between categorical variables of exposure  and neonatal parameters were tested using the independent sample t-test or one-way analysis of variance. The birth length among different urinary cotinine levels was further compared in each stratum of the other exposure variables  of the study participants consumed nutritional supplements whereas a few (3%) reported alcohol intake during pregnancy. Approximately half (48.6%) of the family members of the study participants smoked before their pregnancy, whereas only a few (36.5%) of the study participants perceived an exposure to passive smoking from their partner and family members during their pregnancy. The scores for the items on subjective exposure frequency to smoke ranged from 2 to 3. The average levels of urinary cotinine was 4.7 ng/mL at birth, and 7 (9.5%) of the participants had no residual urinary cotinine. The average PM2.5 and PM10 levels in the previous year were 28.0 and 48.4 μg/m3, respectively  women had a vaginal birth whereas 13 (18%) women had a planned cesarean section. The mean age was 31.9 years (standard deviation (SD = 4.2 years) with an average education level of 15.4 years (SD = 1.7 years). The mean body weight was 60.9 kg and the BMI was 23.6 kg/mectively .All infants had a normal Apgar score at 1 and 5 min  after birth. In addition, all infants had a normal appearance. With regard to the neonatal parameters, the average gestational age was 38.5 weeks, with a low variation (SD = 0.8 weeks). The mean body weight was 3033 g (SD = 317 g). The HC, birth length, and chest circumference were 33.4, 48.5, and 32.1 cm, respectively .2.5/PM10 and ETS) and neonatal parameters . In further analyses, we categorized the continuous variables of exposure. The factor score of subjective frequency of smoke exposure during pregnancy was used to equally divide the study population into three subgroups. Based on the urinary cotinine level, the study population was divided into the “none”, “low”, and “high” subgroups . Similarly, based on the PM2.5 and PM10 levels, the study population was equally divided into two subgroups. The results suggested that the birth length significantly differed among subgroups with different urinary cotinine levels (p = 0.049). In the multivariate comparison, the birth length was significantly shorter in the high cotinine subgroup than in the low cotinine subgroup (p < 0.05). Moreover, the birth length was significantly shorter in the high urinary cotinine subgroup than in the none and low urinary cotinine subgroups combined . We observed that the average birth length was more than 48 cm in the none and low urinary cotinine subgroups regardless of the levels of other exposure variables. Moreover, the average birth length was less than 47 cm in the high urinary cotinine subgroup regardless of the subgrouping by the other exposure variables . This effect persisted after adjusting for several confounders , showed that high levels of cotinine exposure during pregnancy significantly reduced birth length, but had an insignificant effect on the birth weight of term infants  −0.51 to −0.03) and with a change in birth weight of −40.3 g (−96.3 to 15.6). Moreover, a 10 μg/m3 increase in NO2 exposure levels during the second trimester was associated with neonates being SGA by birth weight (OR 1.37 (1.01–1.85)), whereas the OR for being SGA by birth length was 1.42 (0.89–2.25). Unlike Ballester et al. [2 and benzene with fetal growth and found that an increase of 10 µg/m3 in NO2 exposure during pregnancy was associated with a birth-length change of −0.9 mm (95% CI −1.8 to −0.1 mm). The findings from this study may contribute a new perspective for future studies on ambient pollutants that affect the fetal body length. Our results are supported by an appropriate cross-validation of the research process and the outcomes. Firstly, all infants were normal in appearance on the physical examination conducted immediately after birth, wherein we ruled out Down’s syndrome, which may be associated with a shorter birth length. Secondly, no participants were identified as being at high risk of having trisomy 21. Thirdly, we excluded women with pregnancy-induced hypertension, which can compromise placental blood supply and consequently affect fetal growth. The absence of this effect in all infants was indicated by the normal Apgar scores . Nevertheless, unlike in Jedrychowski et al.’s [To the best of our knowledge, this study constitutes the first investigation of urinary cotinine to assess the influence of ETS on fetal growth. The potential mechanisms underlying the effect on birth growth is that trans-placental exposure to ambient air pollutants and ETS could trigger an oxidative stress process that may lead to DNA damage and fetal growth restriction ,26. Ther infants . Our resr et al.  investiget al.’s  and Krst2.5/PM10 and self-reported exposure to smoke) and birth weight. One possible reason for this finding might be maternal nutrition, which we could not evaluate because of inadequate sample size and the many participants with missing data. Further studies need to investigate the correlation of birth weight with the exposure to air pollutants, maternal nutrition, and nutritional supplements as potential confounders. The small sample size of this study may be another reason for the finding with regard to birth weight. A study [The findings of this study showed that there was no significant relationship between air quality  with PM2.5 above 35 µg/m3. Some studies [2.5 exposure (PM2.5: 35.6–36.3 µg/m3). However, the abovementioned previous studies did not evaluate ETS or undertake objective measurements. Thus, the possible influence of toxicant exposure during pregnancy is a vital issue that is a concern for healthcare professionals, and further research in well-designed case–control studies should be undertaken in areas with abnormal and normal PM concentrations. In addition, smoking in front of expectant mothers may expose them to ETS. The ETS rate of pregnant women during their pregnancy in Taiwan increased from 75.84% in 2012 to 85.65% in 2016, based on a government regular survey [With regard to whether outdoor ambient air pollutants and ETS affect fetal growth, the results of this study indicated that there was no additive effect between the urinary cotinine level and exposure to PM studies  have revr survey ,33. Publ2.5/PM10 might be a good research tool.This study has limitations that should be acknowledged. Firstly, the data collection from a single center with convenience sampling could limit the generalizability of the findings. However, our population characteristics are representative of the Taiwanese national profile specified in the 2016 Family and Fertility Survey Report , which mETS may result in a 1.4 cm reduction in birth length. This relationship may reflect an independent risk factor for fetal growth, and pregnant women should avoid passive smoking in addition to exposure to PM. The urinary cotinine level might be applicable as a reliable objective parameter for measuring ETS exposure. Smoking in front of expectant mothers may heedlessly expose them to ETS. Public education should include strategies to counter indoor ETS. Childbirth education classes should include education on ETS within the home.


ObjectivesThe aim of this study was to assess the effects of ligation and excision of femoral artery pseudoaneurysm without revascularization in intravenous drug abusers presenting in the tertiary care center.MethodsThis was a retrospective study conducted at Shaheed Mohtarma Benazir Bhutto Institute, Karachi, Pakistan, and included 119 patients admitted for vascular injuries of the groin between June 2016 and June 2020. Data collected from the hospital's medical records included all intravenous drug addicts presented with mass near or at groin area only, while other pseudoaneurysm locations secondary to vascular trauma, arteriovenous fistula, and hemodialysis were excluded. SPSS Version 20.0  was used for data analysis.ResultsThis study included 119 patients, all of whom presented and admitted to the Accident and Emergency Department, with a mean age of about 32 years ± 11.34 years and a mean duration of addiction of 2.47 years ± 1.37 years. Males constituted 83.2% of the patients, while females constituted 16.8%. The left femoral artery was affected more commonly than the right femoral artery, with an average of 75.6% and 24.4%, respectively. The most common presentation was bleeding from ruptured pseudoaneurysm (76.5%) and oozing with pulsatile mass (17.6%), while infected pulsatile swelling and misdiagnosis were uncommon. After surgical intervention, limb salvage was 95.8%, whereas mortality and amputation rate were 2.5 % and 1.7%, respectively.ConclusionThe optimal management of femoral artery pseudoaneurysm in intravenous drug addicts is ligation and excision of the pseudoaneurysm without revascularization. The world is facing a surge in a contagious addiction to illicit drug abuse among the nations' youth. Though no current national data are available for an accurate estimate of drug addiction among Pakistanis, around 7.8 million people are drug addicts than a global estimated 35 million . This ilAfter compromising their superficial veins, intravenous drug users (IVDUs) find easy access to their groin for the femoral vein, where they accidentally puncture the femoral artery leading to a pseudoaneurysm formation . RepeateControversies in the management of femoral artery pseudoaneurysm are still prevalent around the globe. Nevertheless, primary repair following ligation and excision of pseudoaneurysm has been reported in the literature with acceptable results ,7. HowevA recent study in Pakistan revealed intermittent claudication and amputation rate following the above treatment as 8% [This retrospective analysis was conducted at the Department of Vascular Surgery at Shaheed Mohtarma Benazir Bhutto Institute, Karachi, Pakistan. After institutional approval, 119 patients presented to the Emergency Department with femoral artery pseudoaneurysm and underwent surgical treatment for vascular injuries due to intravenous drug abuse.The data of interest were obtained from hospital medical records, including patient's demographics , site of injury, duration of addiction, laboratory investigations , and post-operative complications/outcomes . The pseudoaneurysm diagnosis was confirmed with a detailed history, examination, and color Doppler ultrasound routinely by one team member. Patients with pseudoaneurysm secondary to trauma, hemodialysis, arteriovenous fistula, and sites besides groin, and those who underwent primary revascularization were excluded.ProcedureThe surgical technique included a proximal ligation of the distal part of the external iliac vessels followed by femoral arteries through uninfected fields. The mass was excised, and debridement of the surrounding local tissue was performed . The wound was irrigated with saline and left open for secondary healing with the use of negative pressure Figure .The total hospital stay time was of about two weeks till the stitches were removed. Outcomes of surgical intervention were determined during this period.Statistical analysisThe data analysis was performed using SPSS Version 20.0 , with a p-value of <0.05 deemed statistically significant. Mean and standard deviations (SDs) were calculated for quantitative data, while frequency and percentages were calculated for qualitative data. The data were stratified for age, sex, co-morbidities, duration of addiction, mode of presentation, side of the limb, and outcome variables.A total of 119 patients presented to the Emergency Department with femoral artery pseudoaneurysm secondary to intravenous drug abuse and underwent surgical management. The mean age was 32 years (SD: 11.34 years). Out of 119 patients, 99 (83.2%) were males and 20 (16.8%) were females. All patients admitted to the Emergency Department, with the left femoral artery involvement about three times more common than its counterpart. The mean duration of addiction was 2.47 years (SD = 1.37 years), as shown in Table All patients had chronic infections, with the far more prevalent being hepatitis B virus (66%) followed by a combined infection of hepatitis B/C + HIV (19%) and HCV only (15%) Figure .Ruptured pseudoaneurysm (76.5%) and oozing with pulsatile mass (17.6%) were the most common presentation in the Emergency Department, with less frequent infected pulsatile swelling misdiagnosis being a rare presentation, as shown in Figure All patients underwent ligation, excision, and debridement of the surrounding tissue (if infected) without primary revascularization. Following this procedure, only two (1.7%) patients developed limb ischemia, for which amputation was performed. Overall, the mortality rate was 2.5%, while a limb salvage rate of 95.8% was recorded  results from prolonged, unintended, non-sterilized, peri-arterial, repeated injuries to the blood vessels for narcotics administration. Femoral vessels in the femoral triangle are convenient routes for drug administration due to their superficial position. Vascular injuries in drug abusers are common in this area followed by brachial and other vessels ,5. The mIn our hospital ( Shaheed Mohtarma Benazir Bhutto Trauma Center), which is the only public sector hospital and primary referral hospital providing vascular surgery services to the major bulk of the country population, 119 patients who had groin vascular complications in intravenous drug use have been treated so far. The most common presentation is ruptured pseudoaneurysm with bleeding (76%), which is consistent with that reported in the literature (40-70%) ,8,9. MosIVDUs are infected frequently with blood-borne viruses. Serological results are often unavailable at the surgery, and therefore strict precautions should be implemented in these particular patients. In these neglected patients, infections such as hepatitis C, hepatitis B, and HIV are rising ,3,11. InPseudoaneurysm ligation, resection, and thorough debridement of the surrounding tissue had been successfully applied as most of the groin pseudoaneurysms were infected. The only drawback of this treatment is severe claudication and threatened limb ischemia requiring amputation later on. Controversies are prevalent in the decision-making of the best strategy for surgical management of this complicated vascular problem. Most surgeons perform revascularization in fear of limb loss. In our study, the ligation of pseudoaneurysm followed by excision without revascularization was performed. An investigation revealed a higher amputation rate, i.e., >35, following arterial ligation, which is suggestive of a higher risk of amputation than previously published. However, in this study, ligation was higher than in our study, explaining this higher rate . ConversThe most extensive single-center research on pseudoaneurysm management in IVDU has reported no limb loss but forefoot amputation only . The onlA similar study has been conducted on brachial artery pseudoaneurysm in our department, which shows promising results of the ligation and excision of the pseudoaneurysm without revascularization among IVDUs . This stThis study provides strong evidence to support simple ligation and excision of femoral artery pseudoaneurysm without revascularization, an effective treatment option in the emergency. In comparison, others dangle in the controversies of revascularization. Nevertheless, studies with long-term follow-up are required to standardize this treatment in our institute.


Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity , and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process. Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity  are well-established markers of normal brain maturation –5 and agMore recently, peak width of skeletonized mean diffusivity (PSMD) , a new pTen independent data sets coming from cross-sectional cohort studies were gathered in the present study, namely, MRi-Share, BIL&GIN, SYS, LIFE-Adult, 1000 BRAINS, UKBiobank, ASPSF, OATS, LBC1936, MAS (see acronym definition in http://www.psmd-marker.com)  . This orker.com) , 24, usiDue to previously reported non-linear effects of age on DTI metrics , 3, 8, wFor each of the five DTI metrics and each age category, we performed an analysis of variance including “age” as the main effect, and “sex,” total intracranial volume (TIV), and “Cohort” as confounding factors. The Cohort effect was included in order to account for apparent large differences in DTI metric average values across cohorts contributing to the same age category data set see , 25–28, For each of the five DTI metrics and each age category, we also performed an analysis of variance including “Sex” and “TIV” as main factors and “Cohort” as confounding factors.All statistical analyses were performed using the JMP Pro Software .The evolution of PSMD across the adult life is different from that of the other metrics (This apparent specific lifespan profile of PSMD was confirmed by the quantitative estimates of the effects of age on PSMD and other DTI metrics provided by the between-cohort ANOVA (see p < 10−4) in all cases but RD (p = 0.53).Amplitude of sex effects on DTI metric average values were found to be quite variable across the various cohorts for the different age categories , mean FA values were higher and diffusivity values were lower when averaged over the white matter skeleton than when averaged over the entire white-matter compartment. However, the cross-subject variability measured as the CV of the mean DTI metrics decreased only marginally (a fraction of a percent for CVs ranging from 2% to 4%) when mean values were computed over the white matter skeleton rather than the whole white matter. In contrast, the CV of PSMD decreased markedly  when its computation was performed on the white matter skeleton rather than on than the global white-matter mask. This demonstrates the importance of choosing a measure of MD dispersion values over a white matter skeleton for controlling between subject variability.In the present work, we restricted the analysis to classical DTI metrics as only two of the contributing cohorts had high angular resolution and/or multi-shell acquisition schemes that could be used for estimating advanced white-matter microstructural parameters with more sophisticated models . Here, D2 = 6.7 × 10−3 for the sex effect to be compared with 7.6 × 10−2 for the age effect), which could explain the mixed findings in the literature, and suggests further investigations are required in order to understand their biological origins. TIV effects on DTI parameters are not well established in the literature. In our study, we found that TIV was positively correlated with all DTI parameters except for RD. Similar to sex, TIV effects when significant were very small . Here again additional investigations are needed to understand the origins of these effects.Mixed results have been reported regarding the impact of sex and TIV on DTI measures ) in a sample of healthy individuals aged 60 to 80 years drawn from the ASPF cohort The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The 10 cohort studies involving human participants were reviewed and approved by the following ethic committees: Comité de Protection des Personnes Sud-Ouest (MRi-Share), Comité d’Ethique de Basse-Normandie (BIL&GIN), Research Ethics Committee of the Chicoutimi Hospital (SYS), Ethics committee of the University of Duisburg-Essen (1000BRAINS), Ethics board of the Medical Faculty of the University of Leipzig (LIFE), North West Multi-center Research Ethics Committee (UKBiobank), Ethics Committee of the Medical University Graz (ASPS), Ethics committees of the Australian Twin Registry, University of New South Wales, University of Melbourne, Queensland Institute of Medical Research and the South-Eastern Sydney and Illawarra Area Health Service (OATS), Multi-Centre Research Ethics Committee for Scotland and the Lothian Research Ethics Committee (LBC1936), Ethics Committee of the University of New South Wales (MAS). The participants provided written informed consent to participate in these studies.Study conception: BM and SD. Data collection: GB, CT, SC, ZP, TP, RS, PS, HB, NK, JT, ID, AW, AV, and BM. Data analysis: GB, LPe, SC, JS, YP, LPi, PS, WW, NA, MB, SM, AW, MD, and BM. Drafting: GB, AT, and BM. Revising the manuscript: LPe, CT, SC, JS, ZP, YP, TP, RS, LPi, PS, WW, NA, ID, MB, JW, SM, AW, AV, MD, SD, and BM).www.jpnd.eu: Australia, National Health and Medical Research Council, Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; Netherlands, The Netherlands Organization for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 643417. This project has also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under grant agreement No 640643.GB has been supported by an EU-ERC starting grant . AT is supported by a grant from the Fondation pour la Recherche Médicale (DIC202161236446). SC was supported by the Initiative and Networking Fund of the Helmholtz Association and the European Union's Horizon 2020 Research and Innovation Program under Grant Agreement 785907 (Human Brain Project SGA2). The BRIDGET project is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of SVD of the Brain) and is an EU Joint Program -Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND—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.