To describe the epidemiology of EOS including blood culture utilisation, across a large and geographically diverse Australian health district.Streptococcus (GBS) and Escherichia coli (E. coli) have dominated as causes of EOS for five decades.Sepsis in the first three days of life remains a leading cause of death and morbidity. In high-income countries, group B An 11-year retrospective cohort study to determine the epidemiology of EOS. Incidence rates were calculated per 1000 live births. Logistic regression with linear temporal trend and covariates for potential effect modifiers were employed. Blood culture utilisation was determined by examining the rate of babies undergoing blood culture within 72 hours of birth.Across the 4 largest birth units, the proportion of babies having blood culture within 72 hours of birth varied from 1.9–5.1% for term and 21–35% for preterm babies. The annual change in the EOS rate was significant, OR 0.91 . Group B Streptococcus was the most common cause of EOS in term neonates at 0.35/1000 live births  in 2006 and 0.1/1000 live births  in 2016. Escherichia coli was the most common cause in preterm babies at 3.4/1000  in 2006 reducing significantly to 1.35/1000 live births  by 2016.Among 93,584 live born babies, 65 had confirmed EOS (0.69/1000 live births); 22 term, 43 preterm. Escherichia coli and GBS were the most common causes of EOS in preterm and term babies respectively. Rates of all cause term and preterm EOS declined significantly as did preterm sepsis due to E. coli. While rate of sepsis due to early-onset GBS declined, this did not reach significance. Given the high proportion of preterm babies undergoing blood culture, it is unlikely that any EOS events were missed. Neonatal EOS refers to culture-proven bloodstream and/or central nervous system infection occurring in live born neonates soon after birth. It remains a significant cause of infant morbidity and mortality in both high and low-income countries . Most evPerinatal maternal risk factors reported to be associated with EOS include recto-vaginal GBS colonisation, rupture of membranes (ROM) ≥18 hours, prematurity, and intrapartum fever . RecentlE. coli is associated with high rates of mortality and morbidity, especially in preterm newborns , and remained in hospital (NICU and/or ward) for a median of 7.5 days . Forty-one (95%) preterm babies were known to have antibiotics. Preterm babies with EOS also remained on antimicrobials for a median of seven days  and remained in hospital for a median of 19 days .Thirty-three (50%) babies had serious short-term morbidity, in particular, ventilatory support requiring neonatal intensive care. Serious, short-term morbidity occurred in 8/13 (62%) term babies with non-EOGBS sepsis and 4/10 (40%) term babies with EOGBS. It was not possible to report on long-term morbidity.E. coli infection. Mortality occurred at a median of three days after birth [range 6 hours to 44 days]. All deaths occurred at the metropolitan hospital.Overall, 10/65 (17%) babies with EOS died; all were preterm. The rate of preterm mortality was 1.1/1000 preterm births and rate of mortality per total live births was 0.1/1000. Gestation ranged from 24 to 34 weeks and weight from 630 to 2440 grams. Six of the 10 babies that died had early-onset This study provides an eleven-year, “real world” view of the epidemiology of EOS in a geographically and socially diverse setting. The EOS surveillance intensity varied with up to a two-fold difference in the proportion of term babies undergoing blood culture testing across the four largest neonatal units. Aside from the variation caused by different case mix, there are likely to be significant differences in clinician thresholds for blood culture collection, which will impact on measured culture proven EOS rates. Blood culture utilisation should be included in future studies in accord with best epidemiological practice.Escherichia coli (n = 18) and GBS (n = 18) were the most common bacteria causing EOS events. The very low frequency of EOS events limited what could be established statistically, however, the modelling showed a significant reduction in E. coli but no evidence of a significant change in EOGBS over time.All-cause EOS events declined significantly with a multiplicative change in the odds of EOS reducing by approximately 9% per year over the study period. Historically, babies of ATSI mothers have been over-represented in early-onset sepsis data. In our study, there were six babies whose mothers were identified as ATSI. These babies represent 9% of all infants with EOS. This finding is similar to the proportion of ATSI women in our total cohort The estimated incidence in 2016 of all-cause EOS in term babies was 0.19/1000 live births  at the overall median birth weight of 3.42 kg. After adjustment was made for gestation, birth weight, positive maternal GBS, ROM ≥18 hours and maternal age, this represented a non-significant decline from 0.5/1000 live births  in 2006 As expected, EOS was highest in preterm infants with two-thirds of events occurring in this group. All-cause EOS events in preterm babies showed a significant decline over the years. Adjusted rates were 3.4/1000 live births in 2006  to 1.35/1000 live births in 2016 . The most dramatic reduction occurred in babies <30 weeks gestation. After adjustment, rates in this group fell from 22/1000 live births  in 2006 to 8.8/ 1000  in 2016. Preterm events that occurred from 2014–2016 were confined to babies of gestation <30 weeks The decline in incidence of all preterm EOS events possibly represents the effect of local changes in the management of preterm birth which, since 2011, has included routine pre-emptive antibiotic treatment upon presentation of mothers in preterm, or suspected preterm labour  and advances in neonatal intensive care provision over the study period.A universal screening approach was recommended in our LHD across the study years, with risk factors considered if a woman was GBS unknown. The crude incidence of EOGBS across term and preterm groups in our study was low at 0.19/1000 live births and, despite minor fluctuations, did not change significantly over time. Whilst we acknowledge that EOGBS rates have increased and decreased across various jurisdictions during our study period, our results compare favourably with the contemporary incidence of EOGBS recorded by the English Neonatal Infection Surveillance unit, 0.57/1000 live births, using a risk factor approach ; a largeE. coli (7.5% in 2015) is documented in Australia and may, in future lead to increasing EOS events due to such strains [E. coli EOS events subsequent to this study’s time period with isolates that were both resistant to gentamicin. One isolate was also resistant to ceftriaxone .The use of IAP in our cohort has not been associated with a detectable increase in antimicrobial resistance or EOS due to non-GBS causes. However, increasing community colonisation with extended spectrum betalactamase-producing  strains  Table 2.Limitations of this study include the focus on reported culture-proven EOS events, which may have under-estimated the true burden of EOS due to false negative culture results. While our models adjusted for relevant variables, we were unable to use all EOS risk factors, as history of GBS bacteriuria and having a previous child with EOGBS were not available from the database. Fever is currently stated as a risk factor for EOS but was poorly documented and therefore not used in our analysis.The observational design may limit generalisability and is unable to rule out all possible biases. Our study is however, generalisable to other diverse jurisdictions that can link pathology data with a maternity outcomes database such as ObstetriX or e. Maternity.We believe strengths of this study are the inclusion of women with low and high-risk pregnancies across a geographically and socially diverse region, over a long period of time, in a setting where maternal universal screening for GBS was in place throughout the study period. Further, unique to our study, the inclusion, and evaluation of EOS surveillance intensity by studying blood culture utilisation.Neonatal sepsis is an important issue in both low and high-income countries. At best, these invasive infections separate mothers and babies and strongly impact on the health care budget. At worst, invasive sepsis increases preterm birth, stillbirth, neonatal morbidity, and mortality. Although rates of GBS, the most common bacteria affecting term babies, remained low throughout our study, the potential for a vaccination to reduce risk of EOS due to GBS is attractive. In a recent multi-centre trial, GBS CPS III-TT conjugate vaccine significantly delayed maternal vaginal and rectal GBS serotype III colonisation .However, a significant proportion of EOS occurs before a pregnancy is term and is due mainly to non-GBS causes. Most preterm babies do not benefit from maternal third trimester GBS screening and may not benefit from GBS vaccination. Whilst antenatal and intrapartum vigilance for signs of sepsis is crucial, a more upstream prevention such as optimisation of maternal factors that influence the neonatal and vaginal microbiome is worth consideration.Finally, a tool that can assist clinicians in predicting the probability of EOS based on maternal risk factors as well as the baby’s clinical presentation is being used in West Australia. Using this tool, the risk of EOS can be calculated in a baby born ≥34 weeks gestation . The int


As supine maternal position is associated with reduced uterine blood flow, is going to sleep in a supine position in the third trimester associated with reduced birth weight?This prespecified subgroup analysis of control participants in an individual participant data meta-analysis found that women at 28 weeks’ gestation or more who usually went to sleep in a supine position gave birth to infants with significantly lower mean birth weights (3410 g vs 3554 g for nonsupine sleep). This finding was independent of variables known to be associated with birth size.A reduction in birth weight associated with third-trimester back sleeping is clinically significant, biologically plausible, and likely modifiable. This prespecified subgroup analysis of control participants in an individual participant data meta-analysis examines the association between supine vs nonsupine maternal sleeping position in the third trimester of pregnancy and infant birth weight. Supine maternal position in the third trimester is associated with reduced uterine blood flow and increased risk of late stillbirth. As reduced uterine blood flow is also associated with fetal growth restriction, this study explored the association between the position in which pregnant women went to sleep and infant birth weight.To examine the association between supine position when going to sleep in women after 28 weeks of pregnancy and lower birth weight and birth weight centiles.Prespecified subgroup analysis using data from controls in an individual participant data meta-analysis of 4 case-control studies investigating sleep and stillbirth in New Zealand, Australia, and the United Kingdom. Participants were women with ongoing pregnancies at 28 weeks’ gestation or more at interview.The primary outcome was adjusted mean difference (aMD) in birth weight. Secondary outcomes were birth weight centiles (INTERGROWTH-21st and customized) and adjusted odds ratios (aORs) for birth weight less than 50th and less than 10th centile  for supine vs nonsupine going-to-sleep position in the last 1 to 4 weeks, adjusted for variables known to be associated with birth size.P = .009), representing an approximate 10-percentile reduction in adjusted mean INTERGROWTH-21st  and customized  centiles. There was a nonsignificant increase in birth weight at less than the 50th INTERGROWTH-21st centile  and a 2-fold increase in birth weight at less than the 50th customized centile . Going to sleep supine was associated with a 3-fold increase in small for gestational age birth weight by INTERGROWTH-21st standards  and a nonsignificant increase in small for gestational age birth weight customized standards .Of 1760 women , 57 (3.2%) reported they usually went to sleep supine during the previous 1 to 4 weeks. Adjusted mean (SE) birth weight was 3410 (112) g among women who reported supine position and 3554 (98) g among women who reported nonsupine position (aMD, 144 g; 95% CI, −253 to −36 g; This study found that going to sleep in a supine position in late pregnancy was independently associated with reduced birth weight and birth weight centile. This novel association is biologically plausible and likely modifiable. Public health campaigns that encourage women in the third trimester of pregnancy to settle to sleep on their side have potential to optimize birth weight. Given that impaired utero-placental flow is associated with fetal growth restriction,15 it is plausible that repeated exposure to supine maternal position during sleep in late pregnancy may adversely affect fetal growth.Maternal supine position in late pregnancy is associated with significant hemodynamic changes that can result in a reduction in blood flow to the fetus.16; therefore, going-to-sleep position is likely to have the greatest impact on blood flow to the developing fetus.The initial going-to-sleep position is the sleep position that women maintain for the longest duration throughout the nightIn this prespecified subgroup analysis of the control participants included in an individual participant data (IPD) meta-analysis of going-to-sleep position and risk of late pregnancy stillbirth, we hypothesized that women in the third trimester who reported going to sleep in a supine position during the previous 1 to 4 weeks would have babies with lower birth weight and birth weight centiles compared with women who did not go to sleep in a supine position.6 This was a 1-stage meta-analysis stratified by study and site. The IPD search strategy, search results, and PRISMA checklist have been published elsewhere,17 and the CRIBBS study was registered with the PROSPERO register of systematic reviews.18 Five international case-control studies that collected data regarding maternal going-to-sleep position and late stillbirth were included in the CRIBBS IPD.19 Ethical approval was obtained by each individual case-control study.2 Each participant in the case-control studies provided written informed consent. Additional approval for the IPD meta-analysis was obtained from the New Zealand Health and Disability Ethics Committee; this approval applied to the study reported here. Reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.We selected women from the control group with ongoing pregnancies from the Collaborative Individual Participant Data Meta-analysis of Sleep and Stillbirth (CRIBSS) study population.6 Australia,3 and the United Kingdom,4 between June 2006 and March 2016), gestational age at birth collected in weeks and days , gestation at study interview of 28 weeks and 0 days or more, gestation at birth less than or equal to 42 weeks and 6 days, and data available for usual going-to-sleep position up to 4 weeks before the study interview.20 A further case-control study that was included in the CRIBBS IPD was excluded from the current analysis as this online survey collected gestational age in completed weeks only.19 Individual participants were also excluded if they had missing variables required for calculation of birth weight centiles. There were no missing data for the variables included in the analyses and no imputation was therefore undertaken. In all studies, a detailed face-to-face interview was undertaken with participants during pregnancy. Maternal ethnicity was included in the analyses as ethnicity has been associated with birth weight and fetal growth.23 Ethnicity data were self-reported from the original studies5 and harmonized by criteria agreed on by the CRIBSS IPD collaboration: white , black , South Asian , Southeast and East Asian , Maori, Pacific Islander, and other ethnicity.17 Birth weight data were collected after birth from hospital records.Inclusion criteria for the current study were participation in the control group in the CRIBBS IPD study  and less than the 50th centile. Specifically, birth weight less than the 50th centile was included as well as SGA as per our previous analyses of CRIBBS data.2 Furthermore, other publications have demonstrated an association with increased risk of stillbirth compared with infants with birth weight greater than the 50th centile.27 We also included data on large for gestational age (LGA), defined as birth weight greater than the 90th centile for each measure.We calculated the centiles for our study population according to INTERGROWTH-21st and customized centiles using published methods.5 previous 2 weeks,3 or previous month6 (whichever was longest) and varied by study. Position was recorded as left side, right side, supine, and other . For the main analysis, supine was compared with nonsupine. Secondary analysis was performed using all 4 going-to-sleep positions.For this analysis, maternal going-to-sleep position was the usual position over the previous week,6 Changes in maternal going-to-sleep position over time were therefore investigated in sensitivity analysis using this subset of participants.Data were available on going-to-sleep position last night and last month for the same participant from 2 of the included studies.P < .05. Statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute Inc).Birth weight and birth weight centiles were compared by maternal going-to-sleep position and adjusted for infant gestational age at birth and at time of interview, infant sex, and maternal age, height, weight, parity, ethnicity, preexisting diabetes, preexisting hypertension, antepartum hemorrhage, gestational hypertensive disorder, gestational diabetes, cigarette smoking, and recreational drug use. To account for possible study differences, multivariable analyses were also adjusted for individual studies as a covariate. For continuous outcomes (birth weight and birth weight centiles), a generalized linear model was used with predicted adjusted means obtained using least-squares means. For binary outcomes  logistic regression was used, stratified by study, and aORs and 95% confidence intervals were reported. The threshold for statistical significance was set at 2-tailed P = .03), but mean (SD) gestation at birth was 40.0 (1.4) weeks for both groups  met the eligibility criteria . Of thesh groups .P = .009)  weight of 3410 (112) g vs 3554 (98) g for participants who reported they usually went to sleep in a nonsupine position, an adjusted mean difference (aMD) of −144 g  . Supine  = .009) . Supine  = .009) . Supine  = .009) . There wAnalysis of all 4 going-to-sleep positions  are shown in Within the subset of women who had going-to-sleep position data for both last night and last month (1019 participants), 999 (98.0%) did not change going-to-sleep position between the 2 points. Of the 20 (2.0%) who did change their position, a similar proportion changed from supine to nonsupine (11 women [1.1%]) and from nonsupine to supine (9 women [0.9%]).In this analysis of women in their third trimester of pregnancy who participated in the control group of CRIBSS, maternal supine going-to-sleep position over the last 1 to 4 weeks was associated with a significant reduction in mean birth weight of 144 g and a 10-percentile reduction in mean INTERGROWTH-21st and customized birth weight centiles. A 3-fold increase in the adjusted odds of SGA by INTERGROWTH-21st centiles was also observed among those who reported they usually went to sleep supine. These reductions in birth weight were independent of variables known to be associated with birth size.2Our finding of similar birth weight and birth weight centiles in all 3 nonsupine going-to-sleep positions  is consistent with our previous findings suggesting no difference in stillbirth risk between left side and other nonsupine going-to-sleep positions.10 so it is biologically plausible that supine maternal going-to-sleep position could contribute to reduced birth size. Our finding of an independent mean reduction in birth weight associated with supine going-to-sleep position is clinically relevant. Rates of LGA did not differ between supine and nonsupine groups, but our study may be underpowered to detect a difference. However, rates of LGA in the nonsupine group (22.6% by INTERGROWTH-21st and 9.3% by customized centile) were similar to those reported in general populations.28Supine maternal position is associated with a reduction in maternal cardiac output and subsequent fetal blood supply,29 from Ghana reported an increased odds of low–birth weight infants (<2500 g) among maternal supine sleepers but did not report birth weight or birth weight centiles. The study speculated that the association between stillbirth and supine sleep may be mediated by fetal growth restriction.This is the first study, to our knowledge, to describe the association between supine maternal going-to-sleep position and reduced birth weight in a general obstetric population of women with ongoing pregnancies from a high-income setting. A small observational study30 and relates to conceptual differences between the birth weight references: INTERGROWTH-21st is a birth weight standard derived from low-risk pregnancies, while customization is a fetal growth standard adjusted for maternal characteristics that influence birth weight. In this study, this is demonstrated by lower mean customized centile and greater numbers of infants with birth weight less than the 10th centile using customized compared with INTERGROWTH-21st centiles. Among nonsupine sleepers, 4.5% of infants were SGA and 22.6% were LGA by the INTERGROWTH-21st standard, compared with 11.0% and 9.3%, respectively, by customized centiles. Despite low numbers of SGA infants in this study, there was a 3-fold increase in odds of SGA by INTERGROWTH-21st centiles in women who reported they usually went to sleep supine  and a nonsignificant increase in SGA by customized centiles. We postulate that the differences in aORs between INTERGROWTH-21st and customized centiles relate to the different location of the distribution of birth weight by each criteria.There is currently no international consensus on the most appropriate way to define normal birth weight; therefore, we elected to investigate 2 commonly used birth weight centiles. For the same infant, customized centiles tend to be lower than INTERGROWTH-21st centiles. This phenomenon has previously been notedStrengths of this study include that it was a prespecified analysis with objective and standardized sleep data and birth weight measurements. In the original case-control studies, sleep position data were collected blinded to the hypothesis, so any bias would be nondifferential. To our knowledge, this is the largest data set assembled with robust data on maternal going-to-sleep position and birth weight.16 Although sleep position changes several times during the night, women spend the longest duration in the position in which they first go to sleep.31 Therefore, going-to-sleep position is likely to have the greatest association with fetal blood flow and subsequent associations with birth weight.We acknowledge some limitations with the study. Only a small number of women reported supine sleeping position in late pregnancy, thus limiting power to investigate outcomes in smaller groups such as SGA and LGA. The going-to-sleep position was self-reported; however, it has been demonstrated that there is good correlation between maternal short-term recall of going-to-sleep position and going-to-sleep position recorded by video technology.The subgroup analysis of women who had going-to-sleep data at 2 points (last night and last month) suggests that the majority of women (97.8%) maintained the same going-to sleep position over the 2 periods, signifying consistency in their exposure. It is also biologically plausible that the association of decreased maternal blood flow on birth size with supine maternal position is cumulative over time. Consequently, increased duration of supine sleeping may lead to greater reduction in birth size. We were not able to investigate this question.32 and is applicable to all pregnant women.2 Public health campaigns such as those recently launched in both the United Kingdom and New Zealand to encourage women in the third trimester to settle to sleep on their side have potential to optimize birth weight.34 As the public health message to go to sleep on the side in the third trimester of pregnancy is adopted, further research into the effect of supine maternal going-to-sleep position and birth size is likely to be more difficult to undertake.Changing from a supine to a side-lying going-to-sleep position in late pregnancy is a simple intervention that can be easily adopted without known harmThis study found that supine maternal going-to-sleep position is associated with reduced birth size in late pregnancy. Women who reported going to sleep on their back had a clinically relevant and independent reduction in mean birth weight of 144 g, or an adjusted mean reduction of 10% in birth weight centile (customized or INTERGROWTH-21st). Public health campaigns to encourage women to go to sleep lying on their side have potential to increase birth size.


Low and high birth weight and rapid weight gain during infancy are associated with childhood obesity. Associations of birth and infancy body composition (BC) growth with childhood BC remain unknown in low-income countries. We aimed to investigate the associations of fat mass (FM) and fat-free mass (FFM) at birth and its accretion during early infancy with FM and FFM at the age of 4 years.In the infant Anthropometry and Body Composition (iABC) cohort, BC was assessed at six consecutive time points from birth to 6 months and at 4 years of age by air displacement plethysmography. Multiple linear regression models were used to determine the association between FM and FFM at birth and their accretion rates during infancy and FM index (FMI) and FFM index (FFMI) at 4 years in 314 children.2 higher FFMI  at 4 years while a one SD increment in FFM accretion rate from 0 to 6 months was associated with a 0.24 kg/m2 increment in FFMI  and with a 0.20 kg/m2 higher FMI at 4 years . FFM at birth did not predict FMI at 4 years. FM at birth was associated with 1.17 kg/m2 higher FMI at 4 years  whereas FM accretion from 0 to 4 months was associated with an increase in FMI of 0.30 kg/m2 . FM at birth did not predict FFMI at 4 years, and neither did FM accretion from 0 to 4 months.One kilogram higher FFM at birth was associated with a 1.07 kg/mA higher FFM in early infancy predicted higher FFMI at 4 years while a higher FM accretion during early infancy predicted higher FMI at 4 years. Follow-up studies are merited to explore associations of childhood BC with cardio-metabolic risk later in life. Its prevalence is dramatically rising2 and childhood obesity is an important risk factor for chronic disease occurrence and mortality in adulthood4.Childhood obesity is a major public health problem worldwide9 and weight gain during infancy13 are positively associated with later adiposity. However, childhood adiposity was typically assessed using body mass index (BMI) or BMI-for-age standard deviation score11. Although anthropometric measurements such as BMI and skinfold thickness are proxy indicators for body fatness, they are unable to precisely and accurately differentiate variability in fat mass (FM) and fat-free mass (FFM), and it has been suggested that BMI is suboptimal for research investigating childhood obesity15. Further, most studies on early growth and later obesity focused on weight gain16 as the main explanatory variable. Weight gain comprises the accumulation of two types of tissue (FM and FFM), which may have very different associations with later body composition and health. Some studies from high-income countries have associated rapid weight gain during infancy with FM20 and FFM19 in childhood. In contrast, the few studies conducted in low- and middle-income countries have associated birth weight and rapid infant weight gain with later lean mass23 but not with FM, indicating that greater early weight gain is broadly beneficial. It is however not known whether such associations apply to low-income countries that are undergoing nutrition transition25 and where childhood overweight is an emerging public health problem27 and co-existing with undernutrition28. Such information is crucial in order to promote healthy levels of lean tissue and also to design strategies for preventing excess fat accumulation or childhood obesity. The aim of the present study was therefore to examine the association between FM and FFM at birth and during early infancy with fat mass index (FMI) and fat-free mass index (FFMI) at 4 years of age in a study conducted in Jimma, Ethiopia. We hypothesized that birth body composition (FM and FFM) and body composition gain (FM and FFM accretion rates) during infancy are associated with body composition at 4 years differently.Numerous studies from high-income countries have shown that birth weight29. In brief, apparently healthy neonates with term birth, birth weight ≥ 1500 g, with no congenital malformations and parents living in Jimma Town in Ethiopia were enrolled within 48 h after birth at Jimma University Specialized Hospital (JUSH).We used data from the infant Anthropometry and Body Composition (iABC) cohort, a prospective birth cohort initially established to generate body composition reference data and further aimed to explore the predictors of early growth and identify short and long-term health consequences of early growth30. A wig cap was used to reduce the volume of the babies’ hair during volume measurement.Within 48 h after birth, weight and body composition were measured using PEA POD, an air displacement plethysmograph (ADP) . With the same instrument, body composition data at 1.5, 2.5, 3.5, 4.5, and 6 months were also recorded. The PEA POD equipment has been validated against deuterium dilution and the golden standard four-component method in this and other populations and found to be accurate and precise31.Childhood body composition was measured at 4 years (±3 months), using a BOD POD  with a customized seat insert for children. The BOD POD also relies on ADP methods to measure body volume and the inbuilt scale is used to measure weight32 and body mass (M), as Db = M/V. Using the body density (Db), percent fat was calculated as suggested by Lohman32 as shown below:ADP, which is a two-component method, allows us to calculate FM and FFM from measurements of total body density (Db) since FM and FFM have distinct densities. Db was calculated from body volume (V) which was predicted using the Lohman equation% fat = (C1/Db−C2) * 100, where C1 and C2 are constants based on age and sex.fm) was assumed to be constant at 0.901 g/ml, and FFM density (Dffm) was assumed to be 1.076 for male and 1.072 for female at 4 years as proposed by Fomon et al.33. Using Archimedes principle, fat percentage was derived from Db, allowing FFM to be obtained by subtracting FM from body mass.Age and sex-specific equations were used to estimate FM and FFM from measurements of Db obtained from ADP. FM density /height (m)236.In order to obtain standardized outcome variables (FM and FFM) at 4 years, we calculated two indices of height-normalized body composition: the FMI, calculated as FM (kg)/height (m)37. Length at birth and during infancy was measured in a recumbent position to the nearest 0.1 cm using SECA 416 infantometer  whereas height was measured in standing position using a SECA 213 portable stadiometer  at the age of 4 years. Sex of the child, birth order, maternal age, maternal schooling and parental socioeconomic status, and breastfeeding were collected through questionnaires. Socioeconomic questions were assessed to generate a wealth index, which was classified into quintiles.The new Ballard score was used to estimate gestational ageThe scale of a bio-impedance analyser  was used to measure maternal weight to the nearest 0.1 kg whereas the SECA 213 portable stadiometer  was used to measure height to the nearest 0.1 cm. Maternal anthropometry was measured at birth and at 1.5, 2.5, 3.5, 4.5, and 6 months. Duplicate measurements were taken for length/height, and average values used during analysis.38 into exclusive breastfeeding, predominant breastfeeding , partial breastfeeding (feeding breast milk together with semi-solid or solid foods), and no breastfeeding.Breastfeeding status was assessed by questionnaire at 3.5 ± 1 months postpartum, and categorized according to the WHO classificationz-score (HAZ) were calculated based on the WHO child growth standard39 and categorized as stunted (HAZ < −2) or not stunted (HAZ ≥ −2). A detailed description of the cohort establishment, measurements, and categorizations of variables has previously been described41.Height-for-age n (%) was used for categorical variables. We generated average postnatal maternal BMI using weight and height data collected from 1.5 months to 6 months postpartum since there was a substantial number of missing weight measurements at each visit. The Stata package “Zscore06”42 was used to generate HAZ. Comparison between children followed up to 4 years and those lost to follow-up was made using two-sample t-tests and Chi-square tests. Simple and multiple linear regression models with robust standard errors were fitted. P < 0.05 was considered statistically significant.Epidata 3.1 , R version 3.3.5  and Stata 12.0  were used for data entry, calculation of tissue accretion rates and outcome analysis respectively. Mean ± SD was used to describe continuous variables while 29, a linear trend was observed for FFM during the first 6 months while FM showed a linear trend only up to 4 months. Therefore, linear mixed models were fitted to derive standardized FM accretion rates from birth to 4 months and standardized FFM accretion rates from birth to 6 months of age for boys and girls separately. Similarly, length accretion rates were derived from birth to 4 and birth to 6 months, respectively, and were used as covariates for FM and FFM accretion rates, respectively. Accretion rates were expressed as SD scores. The construction of standardized accretion rates has been described in detail elsewhere41.Body composition measurements in infancy were obtained at repeated intervals and are likely to be correlated within individuals. In order to separate the effect of each time point on body composition, we generated summary measures of body composition data based on the first 6 months. As described previously45 and included in the analysis if they changed the estimate of the main exposure variable: child sex , birth order , length at birth (continuous), standardized length accretion during infancy, maternal age (continuous), maternal education , postnatal maternal BMI (continuous), parental socio-economic status (poorest to richest), breastfeeding at 3.5 ± 1 months postpartum , age at 4 years (continuous), and child stunting at 4 years (stunted or not).Potential confounding variables were identified a priori from the literatureA series of models was developed to explore the association between FM and FFM at birth and FM and FFM accretion rates during early infancy, treated as exposures, and body composition outcomes at 4 years of age. Three separate models were fitted for FM and FFM. Model 1: FFM or FM at birth as main exposure variable adjusted for length at birth, sex of the child, birth order, and child age at 4 years. Model 2: model 1 further adjusted for maternal age, maternal education, parental socio-economic status, and maternal postnatal BMI. Model 3: model 2 with further adjustment for breast-feeding status at 3.5 months postpartum and stunting at 4 years. Similar models were considered for FM and FFM accretion rates during early infancy as main exposure variables. Model 1: contain FM or FFM accretion rate during infancy adjusted for length accretion during respective period, birth order, sex, FM or FFM at birth, and age at 4 years. Model 2: same as model 1 but additionally adjusted for maternal education, maternal age, maternal postnatal BMI, and parental socio-economic status. Model 3: same model as model 2 but additionally adjusted for breastfeeding status at 3.5 months postpartum and stunting at 4 years of age. Visual model checking was carried out using residual plots and normal probability plots. Collinearity was also assessed for each model using the variance inflation factor.Prior to examining the main exposure variables, we explored the association of birth weight with body composition at the age of 4 years by excluding body composition at birth. The association of birth weight was explored to see if we could replicate the finding observed from previous literatures.Out of 644 children recruited at birth, ten children were found to be preterm (<37 weeks) and were excluded from the study. Of the 634 remaining, 398 (62.8%) were followed up at 48 (±3) months of age, and of these, 364 91.5%) had body composition data at 4 years. Thus, a total of 314 children with complete data for all the covariates were included in models using FM or FFM at birth as main exposure variables  higher FFMI at 4 years in the fully adjusted model. However, FM at birth showed no association with FFMI in any of the models  higher FMI at 4 years. In contrast, FFM at birth did not correlate with FMI at 4 years . FM accretion during the first 4 months was not associated with FFMI at the age of 4 years  higher FMI at 4 years. FFM accretion during the first 6 months was positively correlated with a 0.20 kg/m2  higher FMI at 4 years  at 4 years compared to FMI  (result not shown).Birth weight was associated with both FMI and FFMI at 4 years of age and had a stronger association with FFMI  during pregnancy predicted FFM but not FM at 6 years of age49.We found a positive association between FFM at birth and FFMI at 4 years independent of length at birth, maternal BMI, and other potential confounders. This supports the hypothesis of “fetal programming” of later health, which may reflect the tracking of fetal FFM into the childhood period. In the same cohort, we have previously shown that FFM at birth was a positive predictor of height50, our study of a healthy population revealed that greater birth fat relates to higher level of FM at 4 years of age. This finding indicates tracking of prenatal FM to the childhood period. In the same cohort, we have previously shown that FM at birth positively predicted higher social and emotional problems at 5 years of age51, and that it did not correlate with height46 or child development47 at 2 years, or with linear growth from 1 to 5 years41. Together, these findings indicate that storing fat in prenatal life to protect against post-natal malnutrition comes at a cost to growth and cognitive development.In the current study, FM at birth showed a positive association with FMI at 4 years in all models. FM accounts for a small proportion of the total birth weight in the study population. Though fat stores are utilized to varying degrees to fund immune function and may promote survival during infant and early childhood malnutrition52.This study also showed that FFM accretion from 0 to 6 months positively predicted FFMI at the age of 4 years independent of potential confounders. Since FFMI adjusts FFM for height, this indicates that infant FFM accretion promotes childhood FFM beyond any association with linear growth. A possible explanation could be the insulin-like growth factor 1 secretion that stimulates protein accretion, which is known to contribute to the development of muscle massFurther, nutritional intake during the postnatal period is the main environmental factor associated with body composition changes during infancy. However, if the infant loses appetite due to illness or infection, low food intake results in lower FM and FFM gain in infancy and infection also costs calories. Thus, infancy FFM accretion might mediate the link between nutrition intakes during infancy with childhood FFM.53. All other things being equal, larger FFM during infancy is associated with larger FM in childhood. Thus, a baby with more FFM in infancy tends to become a child with more FFM (Table FFM accretion during the first 6 months showed a positive association with FMI. We have proposed previously that to endure a given duration of undernutrition, a child with larger FFM will require larger amounts of energy and hence store larger fat stores54 have linked infant weight gain or fat accretion with higher levels of childhood adiposity, and one study in Brazil55 showed consistent results. However, a few studies from low- and middle-income countries showed opposite association23 in which weight gain associated with FFM but not with FM. Contrasting findings from previous studies conducted in high- and middle-income countries regarding the relation between infancy weight gain and body composition during childhood might be due to lack of data on early life body composition, and hence the possibility to differentiate FM and FFM. Additionally, it may be due to differences in the populations studied, while within the same population, different patterns of infant fat accretion might promote different patterns of childhood body composition56. The association between weight gain during infancy and FMI in childhood reported by other studies, might be explained by FM accretion during the postnatal period. Thus, in terms of FM accretion, both prenatal as well as postnatal period may be required to acquire higher FMI at 4 years.Postnatal FM accretion from 0 to 4 months was positively associated with FMI at 4 years. Several studies from high-income settings41. However, studies conducted in middle57- and high58- income countries have found that infancy and childhood FM is associated with markers of cardio-metabolic status in children and adolescents. Further studies from the current and similar cohorts are needed to explore if this pattern exists in children from low-income countries.This study therefore breaks new ground in explaining the possible mechanism by which early life weight gain relates to childhood fatness. In our previous analyses, postnatal FM accretion had a positive association with linear growth from 1 to 5 years59, while other studies found an association between birth weight and FFM only60. However, since birth weight is the sum of both FM and FFM, it might not be a good indicator. Thus, our study demonstrates the importance of studying infancy body composition for designing specific interventions to prevent excess fatness and maintain lean mass during childhood.Birth weight was a positive predictor of both FMI and FFMI at 4 years which is in line with some previous studies30. FM and FFM accretion during early infancy were predicted based on available data points for those children who had body composition data at birth and at one or more times in any of the follow-up visits. This is a useful approach to predict accretion rates for children with a minimum of two measurements. In addition, the outcome was also measured using ADP rather than simple anthropometry. Our findings are based on multivariate analysis with a priori identified predictors.We used repeated body composition measurements during infancy from ADP, which is an accurate and precise method to measure tissue accretionThough this study has a number of strengths, it is not free from limitations that could affect the interpretation.The body volume estimation done during the BOD POD assessment might be affected by measurement error as lung volume might be inaccurate due to improper position, uncovering of the hair or children crying. However, we minimized measurement error using the instrumentation’s pediatric protocol, covering the child’s hair with a cap, and repeating measurements when a child cried. Further, we did not collect data on pre-pregnancy weight, pregnancy weight gain, and dietary intake during pregnancy, which might all contribute to birth body composition and confound the associations. In addition, we did not assess the physical activity of children. We did not adjust the analysis for time of solid food introduction, childhood feeding pattern, or morbidity history, which might confound the current findings. However, the studied infants were urban-living, generally healthy and infants with serious medical conditions at birth were not recruited for the study but appointed for the neonatology unit at the hospital. Loss to follow-up might also affect the interpretation of the findings: in particular, the observed differences in birth order and wealth index could lead to a slight bias in estimated associations. Exclusion of children from analyses due to missing covariate information, which occurred due to many different reasons, most likely introduced a negligible bias.This study provided a more comprehensive analysis of the relation between components of weight in early infancy with childhood body composition than what was possible from weight gain alone. A higher FFM at birth and during early infancy predicted higher FFMI at 4 years. A higher FM accretion at birth and during the first 4 months predicted higher FMI at 4 years. Our findings provide support to identification and promotion of optimal maternal nutrition and infant feeding practices that help to maintain higher lean tissue and prevent excess fat storage during infancy and childhood. Further follow-up of the cohort may reveal whether these associations track into later childhood and adolescence.SUPPLEMENTAL TABLE 1


To assess the predictive value of patient characteristics, controlled ovarian stimulation and embryological parameters on the live birth outcome of single euploid frozen-warmed blastocyst transfer (FBT).This was a retrospective cohort study including 707 single FBTs after preimplantation genetic testing for aneuploidy (PGT-A) that were performed from October 1, 2015, to January 1, 2018. The effects of patient-, cycle- and embryology-related parameters on the live birth outcome after FBT were assessed.2 vs 27 (24–29.2) kg/m2, p<0.001). The percentage of blastocysts with inner cell mass (ICM) A or B was significantly higher among patients achieving a live birth, at 91.6% vs. 82.6% (p<0.001). Day-5 biopsies were also more prevalent among patients achieving a live birth, at 82.9% vs 68.1% (p<0.001). On the other hand, the mitochondrial DNA (mtDNA) levels were significantly lower among cases with a successful live birth, at 18.7 (15.45–23.68) vs 20.55 (16.43–25.22) (p = 0.001). The logistic regression analysis showed that BMI , day of trophectoderm (TE) biopsy  and number of previous miscarriages  were significantly correlated with live birth. Patients with elevated BMIs, cycles in which embryos were biopsied on day-6 and a higher number of miscarriages were at increased risks of reduced live birth rates.In the subgroup analysis based on live birth, patients who achieved a live birth had a significantly lower body mass index (BMI) than patients who did not achieve a live birth (22.7 (21.5–24.6) kg/mA high BMI, an embryo biopsy on day-6 and a high number of miscarriages negatively affect the live birth rate after single euploid FBT. Chromosomal aneuploidy is present in approximately 50% of embryos throughout preimplantation development and is a consequence of errors occurring during gametogenesis and early mitotic divisions that lead to implantation failure, spontaneous abortion, and the birth of a child with a trisomic condition . The maiAfter day 3, PGT-A of nucleated blastomeres by fluorescence in situ hybridization (FISH) failed to demonstrate an improvement in clinical outcomes . The emeThe predictive factors for live birth after IVF/ICSI treatment with eSET have long been studied. In a recent prospective observational cohort study, eSETs in 8,451 IVF/ICSI treatments in 5,699 unselected consecutive couples were analyzed, and embryo score, treatment history, number of oocytes, total dose of FSH administered, female age, infertility cause, endometrial thickness, and female height were all found to be independent predictors of live birth . HoweverIn this retrospective analysis, our aim was to determine which factors were associated with live birth rates after single euploid FBT.Data from 1,747 cycles with intent for PGT-A were collected from Bahceci Fulya IVF Center (Istanbul) from October 1, 2015, to January 1, 2018. Of these cycles, 1,397 reached the embryo biopsy stage and 978 were found to have at least one euploid embryo for FBT. The study population consisted of cycles in which women were 20–45 years of age, undergoing ICSI-PGT and employing TE biopsy using 24-chromosome NGS. The exclusion criteria were endocrine or systemic pathologies, uterine anomalies or pathologies, unilateral or bilateral hydrosalpinx, and karyotypic abnormalities . Only 707 single euploid FBT cycles were found to be eligible for inclusion in the study, as depicted in All patients provided informed consent for analysis of their identified data before undergoing IVF procedures. The study protocol was approved by the Bilim University Ethics Committee (4414529/2015-61).2 and P4 levels. When the leading follicle exceeded 13 mm in diameter, 0.25 mg of GnRH antagonist  was started daily until the day of the last trigger. When at least two follicles reached 18 mm in diameter, patients were administered 250 μg of human chorionic gonadotropin  or 0.2 mg of triptorelin , and oocyte retrieval was scheduled 35 hours after the trigger administration [COH was performed with the GnRH antagonist protocol. Recombinant FSH  and/or hMG (75–150) IU;  was administered on day 2 of the menstrual period. Starting on the sixth day of controlled ovarian stimulation, the ovarian response was monitored by serial transvaginal ultrasound (TV-USG) and by measuring serum Estration .The oocyte retrieval, denudation, and ICSI procedures were performed as described previously by Serdarogullari et al. . ICSI waEmbryo culture was performed in benchtop incubators  until day-6 of embryo development with daily morphological grading by Gardner and Schoolcraft . The dev®-Freeze, 90133-SO, Irvine Scientific) and vitrification warming kit . In all cases, an open carrier device  was used, and embryos were vitrified within 2 hours after trophectoderm biopsy (with a mean of 1 hour and 20 minutes) Vitrification and warming were performed as previously described [Embryo vitrification and warming procedures were achieved using a commercial vitrification kit  blastomeres  that were present in a blastocyst stage embryo and the blastocoel re-expansion ability. Only embryos that survived with fully intact morphology (100%) comprising a distinguishable inner cell mass and trophoblast were included in the study.4 concentration was also measured; if this concentration was >1.5 ng/ml, the cycle was also cancelled. Estrogen supplementation was continued at 8 mg/day, and intramuscular (IM) progesterone  supplementation at 50 mg/day was started as previously described [Endometrial preparation for ET involved hormone replacement therapy. Briefly, each woman was administered oral estrogen  according to an incremental regime: 4 mg/day on days 1–4, 6 mg/day on days 5–8, and 8 mg/day on days 9–12. TV-USG was performed on day 13 to measure endometrial thickness, and if endometrial thickness was <7 mm, the cycle was cancelled. The serum Pescribed . The embTM (Thermo Fisher Scientific). Sequencing steps were subsequently performed in a PGM sequencing machine using a 318 chip or in a S5 TM XL sequencer (Thermo Fisher Scientific) using a 530 chip. Data analysis was performed using version 5.4 of the Ion Reporter software (Thermo Fisher Scientific). Embryos were diagnosed as euploid, aneuploid or chaotic abnormal.The NGS platform  used in this study has previously been validated and published elsewhere , 22. WhoFor the calculations of the mtDNA ratios, an optimized algorithm was applied that used the output dataset obtained from the NGS analysis, which comprised a mixture of mtDNA reads and nuclear DNA (nDNA) reads. To calculate the relative mtDNA copy number score in embryos, the numbers of reads after filtering were mapped to the mitochondrial genome and were divided by the number of reads that mapped to the nuclear genome as previously described and called mitoscore .The serum human chorionic gonadotrophin (β-hCG) level was measured 12 days after embryo transfer and regarded as positive if it was more than 5 IU. The clinical pregnancy rate per embryo transfer was determined by dividing the number of embryo transfers having a gestational sac observed by means of ultrasound over the number of embryo transfers. The live birth rate per embryo transfer was defined as the number of deliveries divided by the number of embryo transfers. The miscarriage rate was calculated by dividing the number of pregnancies with a gestational sac that could not reach delivery by the total number of pregnancies with a gestational sac.All statistical analyses were performed with SPSS for Windows software package version 20 . A p-value of p≤0.05 was considered to indicate statistical significance for all statistical tests. Continuous quantitative variables investigated in the study were reported as the median (quartile 1-quartile 3).A chi-square test was used to analyze the proportions of β-hCG positivity, clinical pregnancy, live birth and miscarriage rates in maternal age groups.Distributions of continuous parameters were tested with the Kolmogorov-Smirnov test to determine whether each variable followed a normal distribution. 707 patients were then divided into two groups of outcomes of live birth; whether a patient has had a live birth (n = 403) or not (n = 304). Since the continuous variables were not found to follow a normal distribution, a nonparametric equivalent test, namely, the independent-samples median test, was used to compare the medians of two groups of live birth outcomes with respect to the patient characteristics and cycle parameters. Differences in euploid hatching embryo characteristics in ICM score, trophectoderm score and day of embryo biopsied groups are compared between patients who have and haven’t had a live birth by using chi-square test. At the same time, the differences in the median scores of mitoscore among patients who had and didn’t have a live birth are compared by using nonparametric independent samples median test.2 and P4 levels on trigger day, endometrial thickness, E2 and P4 levels 6 days before the FBT cycle, mitoscore, ICM score, trophectoderm score and day of embryo biopsy were used as factors and covariates in the binary logistic regression model. Odds ratios and corresponding 95% confidence intervals are reported for each significant variable to analyze the effect of each parameter.Finally, a binary logistic regression model was performed to evaluate the factors affecting the live birth outcome. In performing the binary logistic regression analysis, the forward stepwise procedure and likelihood ratio statistics were used as the criteria for removing the variables from the model. Maternal age, paternal age, BMI, infertility diagnose, number of previous attempts, number of previous miscarriages, duration of stimulation, total gonadotropin dosage used, EDuring the study period, a total of 707 single euploid FBT cycles employing NGS were included. Overall, the clinical outcomes in this study were as follows: positive β-hCG rate: 71% (502/707); clinical pregnancy rate: 67.2% (475/707); live birth rate: 57% (403/707); and miscarriage rate: 15.2% (72/475). 2 vs 22.7 (21.5–24.6) kg/m2, p<0.001). In all cycles, sperm count, controlled ovarian stimulation parameters, number of oocytes retrieved, number of mature oocytes (MII), and number and rate of fertilized oocytes with two pronuclei (2PN) were not significantly different between groups. Trigger day E2 level was significantly higher in Group I than in Group II (1428 (713–2237) pg/mL vs (1050 (658–2129) pg/mL, p = 0.003). Regarding FBT cycle parameters, neither endometrial thickness nor E2 or P4 levels on the day of progesterone initiation were significantly different between the two groups , whereas Group II consisted of cycles that did not (n = 304). Regarding patient characteristics , there were no significant differences between the two groups. BMI was found to be significantly higher in Group II than in Group I (27 (24–29.2) kg/mo groups .The embryo development characteristics are presented in 2 and P4, number of COCs, number of M2 oocytes, fertilization rate or endometrial thickness, showed any effects on the live birth rate.In the present study, patient characteristics, ovarian stimulation variables, embryo development characteristics and variables associated with FBT cycles were also used to identify possible factors that could impact the live birth outcome. When all the parameters were assessed together to identify which covariates and factors affected the live birth outcome, BMI, number of previous miscarriages and day of TE biopsy were found to be significant. To evaluate the level of the effect of each of these parameters on the live birth outcome, the odds ratio was used . The negThis study aimed to evaluate and determine which factors affect live birth outcomes after single euploid FBT cycles. Our findings indicate that BMI, day of TE biopsy and number of previous miscarriages are significantly associated with the live birth rate per transfer.Increasing maternal age is related to decreasing success in both spontaneous and IVF/ICSI-mediated conception . MaternaData on the potential effects of elevated BMI on fertility treatment outcomes are conflicting. Multiple studies have reported no significant adverse effects of elevated BMI on IVF outcomes –32; howeAccording to the logistic regression analysis, TE score and ICM score were not associated with a live birth in the current study setting with euploid blastocysts. Morphological evaluation of blastocysts has been widely used for fresh and frozen-warmed ET. Although blastocyst grading systems are the most commonly used method for embryo selection, the relationships between each blastocyst morphology parameter, such as the degree of expansion, ICM score or TE score, and the IVF/ICSI outcome are not well defined. Several studies have reported that TE score has a stronger predictive power than ICM score in the estimation of outcome after blastocyst transfer –51, whilThere is an ongoing debate on the implantation potential of slow-growing embryos. Whether the poorer reproductive potential is due to the pace of embryo development or is a result of asynchronization between the embryo and the endometrium is still poorly understood. The meta-analysis reported in 2010 included 15 controlled studies comprising 2,502 frozen-warmed transfers involving blastocysts that were cryopreserved on either day-5 or day-6 and found no differences in the ongoing pregnancy or live birth rates after the transfer of day-5 frozen blastocysts versus that of day-6 blastocysts with the same morphological quality on the day of cryopreservation . Yang etThe cause of miscarriage is multifactorial, with genetic, anatomical, infectious, immunological and endocrine causes. In our retrospective study, we included patients with RM, although there have been no randomized trials evaluating the efficacy of PGT-A in RM. An intent-to-treat analysis comparing PGT-A to expectant management reported that the clinical outcomes including live birth and clinical miscarriage rates, were similar between RM patients undergoing PGT-A and those receiving expectant management . HoweverThe mtDNA ratio has been suggested to be a biomarker of embryonic competence and viability. Initial studies reported that an increased mtDNA copy number is related to aneuploidy and a decreased embryo implantation potential , 26. HowFET is an essential part of IVF/ICSI. In a retrospective analysis, the factors that affected the live birth outcome after FET which included cleavage stage embryos, were top-quality embryo characteristics, maternal age, endometrial preparation protocol, number of embryos transferred and BMI . In our This study has limitations. The first is its retrospective design; therefore, a certain risk of bias was inevitable. Second, this study did not observe other clinical outcomes, such as the miscarriage rate. Third, the present study only evaluated the vitrified blastocyst, with a certain blastocoel expansion, after embryo warming. Finally, the study is restricted in a certain ethnic patient population and the data are related to the clinical and lab practices of one unit and the conclusions may reflect the end results of these practices.In conclusion, BMI, day of TE biopsy and number of miscarriages are the independent variables that affect the live birth outcomes of single euploid FBTs.


Very preterm  and/or very low birth weight  children often have cognitive and mathematic difficulties. It is unknown whether VP/VLBW children’s frequent mathematic problems significantly add to the burden of negative life-course consequences over and above effects of more general cognitive deficits. Our aim was to determine whether negative consequences of VP/VLBW versus healthy term birth on adult wealth are mediated by mathematic abilities in childhood, or rather explained by more general cognitive abilities.z-standardized.193 VP/VLBW and 217 healthy term comparison participants were studied prospectively from birth to adulthood as part of a geographically defined study in Bavaria (South Germany). Mathematic and general cognitive abilities were assessed at 8 years with standardized tests; wealth information was assessed at 26 years with a structured interview and summarized into a comprehensive index score. All scores were n = 193, 52.3% male) had lower mathematic and general cognitive abilities than healthy term comparison children . At 26 years, VP/VLBW had accumulated significantly lower overall wealth than term born comparison adults (-0.57 (1.08) versus -0.01 (1.00), mean difference 0.56 [0.36–0.77], p < .001). Structural equation modeling confirmed that VP/VLBW birth  and childhood IQ  both directly predicted adult wealth, but math did not . Analyses were controlled for small-for-gestational-age (SGA) birth, child sex, and family socioeconomic status.At 8 years, VP/VLBW (This longitudinal study from birth to adulthood shows that VP/VLBW survivors’ general cognitive rather than specific mathematic problems explain their diminished life-course success. These findings are important in order to design effective interventions at school age that reduce the burden of prematurity for those individuals who were born at highest neonatal risk. Very preterm  and very low birth weight  children have a highly increased risk for academic underachievement, in particular in mathematics , which hPopulation studies have shown that early arithmetic abilities predict long-term academic achievement –13 and pIn addition to life-course studies of normal population samples, recent research on VP/VLBW individuals followed from childhood into adulthood has found that neurodevelopmental and academic problems continue after adolescence, and decreased economic success has also been noted –26. ScanData were collected as part of the prospective Bavarian Longitudinal Study (BLS) , a geogrOf 70,600 children born in South Bavaria during a 15-month period in 1985/86, 682 were VP (<32 weeks gestation) or VLBW infants , or both. Of these, 411 were eligible for longitudinal follow-up, 14 had severe disability and were unable to be interviewed, and 193/397 (49%) participated at both 8 and 26 years and had complete datasets. The BLS VP/VLBW participants did not differ from adults who dropped out in terms of gestational age, birth weight, duration of hospitalization, sex, maternal age, parental marital status, and childhood cognitive scores, but they had fewer prenatal complications and were more often of higher SES .Healthy term infants who were born in the same obstetric hospitals during the same period were recruited as comparisons. Of an initial sample of 916 children alive at 6 years, 350 were randomly selected within the stratification variables sex and family SES to be comparable to the VP/VLBW sample. Of these, 308 were eligible for longitudinal follow-up assessments, and 217 (70%) participated at both 8 and 26 years. The comparison participants assessed at the 26 year follow-up did not differ from those lost to follow-up in terms of neonatal characteristics but they more often had higher SES, older mothers and higher childhood cognitive scores .Details of peri- and neonatal data have been described elsewhere  and are th percentile for their respective GA according to the national standard weight charts (1985–1986) [Gestational age (GA) was determined from maternal reports of the last menstrual period and serial ultrasounds during pregnancy. Birth weight was documented in the birth records. Infants were classified as small for gestational age (SGA) if they weighed less than the sex specific 1085–1986) .Information was obtained by standardized interviews within the first 10 days of life. Family SES was computed as a weighted composite score derived from the occupation of the self-identified head of each family together with the highest educational qualification held by either parent . The sumAt age 8 years, children were administered a comprehensive mathematic test , 38. TesInformation on occupational success and wealth was obtained using a range of interviews and questionnaires. Critical items were selected from these assessments including no own income, unemployment, social benefits, part time work, frequent job changes, not living independently, low educational qualifications, failure to honor financial obligations, impoverishment, as well as restrictions in occupation and economic self-sufficiency. Items were summarized into a comprehensive wealth index score  that wasData was analyzed with SPSS 24 and Amos 24. We used structural equation modeling (SEM) to answer our research question, whether negative consequences of VP/VLBW versus healthy term birth on adult wealth were mediated by mathematic abilities in childhood or rather explained by more general cognitive abilities. All analyses were adjusted for child sex, SGA birth, and family socio-economic status at birth.χ2 = 7.55, p = .374, CFI = .999, and RMSEA = .014. Structural equation modeling  showed tThis prospective 26 year longitudinal study shows that VP/VLBW birth and childhood IQ both independently and directly predict adult wealth, but childhood math does not seem to add to the predictive effects of these two major influences. Previous findings have documented the specific importance of childhood math for adult wealth in moderately and late preterm individuals . In contRecently, studies have started exploring the neural mechanisms underlying math performance in young adults born preterm and reported altered fronto-parietal activity , 46 wherAlthough recent studies have shown that delivery at any gestation other than full term may represent a risk for adverse neurocognitive outcomes , 51, theNo matter whether their functional deficits are global or specific, many VP/VLBW individuals require continuous educational support across various areas of development in order to succeed in school and in life. Most VP/VLBW children have multiple and complex learning difficulties  and atteThis is the first longitudinal study testing independent effects of childhood IQ and math on adults’ wealth using a large, prospectively defined, whole-population sample of VP/VLBW and term comparison individuals born in the same obstetric hospitals at the same time. In total, 58% of the eligible VP/VLBW and term comparisons recruited at birth had complete data at both age 8 and 26 years, however, the dropout was not random as low SES families were less likely to continue participation. As a result, our findings may not generalize to cohorts of preterm children from high social risk backgrounds. However, social factors are a major reason for dropout in most longitudinal studies , 67, andIn conclusion, our results show that VP/VLBW survivors’ general cognitive problems rather than specific mathematic deficits explain their diminished life-course success. These findings can help inform the design of follow-up and intervention services to reduce the burden of prematurity for those individuals that were born at highest neonatal risk.S1 Table(DOCX)Click here for additional data file.


Based on data obtained from pregnant women who participated in the Mothers and Children’s Environmental Health (MOCEH) study in South Korea, we aimed to determine whether maternal intake of fruits and vegetables or vitamin C is associated with fetal and infant growth.A total of 1138 Korean pregnant women at 12–28 weeks gestation with their infants were recruited as study participants for the MOCEH. Intake of fruits and vegetables or vitamin C during pregnancy was assessed by a 1-day 24-h recall method. Fetal biometry was determined by ultrasonography at late pregnancy. Infant weight and length were measured at birth and 6 months.A multiple regression analysis after adjusting for covariates showed that maternal intake of fruits and vegetables was positively associated with the biparietal diameter of the fetus and infant’s weight from birth to 6 months. Also, maternal vitamin C intake was positively associated with the abdominal circumference of the fetus and infant birth length. In addition, there was a significant inverse relationship between consumption of fruits and vegetables (below the median compared to above the median of ≥519 g/d) and the risk of low growth (<25th percentile) of biparietal diameter (odds ratio (OR): 2.220; 95% confidence interval (CI): 1.153–4.274) and birth weight . A significant inverse relationship also existed between vitamin C consumption (below vs above the estimated average requirement (EAR) of ≥85 mg/d) and the risk of low growth (<25th percentile) of birth weight , weight from birth to 6 months , and length at birth .An increased intake of fruits and vegetables or vitamin C at mid-pregnancy is associated with increased fetal growth and infant growth up to 6 months of age. Vitamin C, also known as ascorbic acid, acts as an antioxidant by scavenging reactive oxygen and nitrogen species in an aqueous environment  and playThe increased consumption of fruit and vegetables, an excellent source of vitamin C, during pregnancy has been shown to be positively associated with birth weight , 7. In cn = 239)   and the data then analyzed by a generalized linear model test, after controlling for confounding factors. The adjusted odds ratios (ORs)  for the prevalence of low growth (<25th percentile) in infants of mothers with low fruit and vegetable/vitamin C intake levels were calculated by logistic regression analysis. Variables that were considered to be confounding factors  were included as covariates. These covariates included maternal age (years), pre-pregnancy BMI  for the Korean Dietary Reference Intake. The average fruit and vegetable consumption of the pregnant women was 594.4 ± 365.4 g/d. Gestational age at the time of ultrasound measurement, fetal biparietal diameter, abdominal circumference, and femur length were 36.4 ± 2.5 weeks, and 8.9 ± 0.1, 32.1 ± 2.5, and 6.9 ± 0.5 cm, respectively. Gestational age at delivery was 39.1 ± 1.1 weeks, birth weight was 3.3 ± 0.4 kg, and birth length was 50.5 ± 2.5 cm. The general characteristics did not differ significantly between the included and excluded subjects (data not shown).r = 0.727, P < 0.0001) with vitamin C intake. Also, maternal fruit and vegetable (P < 0.05) and vitamin C (P < 0.05) intakes were both negatively correlated with urinary MDA levels at mid-pregnancy, respectively.According to the correlation analysis Table , maternaP = 0.0511) at late pregnancy. A general linear model adjusted for covariates revealed that biparietal diameter was higher in fetuses whose mothers had a fruit and vegetable consumption above the median value (≥519 g/d) than in fetuses of mothers with a lower fruit and vegetable intake (p = 0.0245). Similar analyses for vitamin C intake during pregnancy showed a significant result in the abdominal circumference. Maternal vitamin C intake was positively associated with abdominal circumference  at late pregnancy. Abdominal circumference in fetuses of mothers with intakes of vitamin C above the EAR (≥85 mg/d) was significantly higher compared to fetuses of mothers with intakes below the EAR (P = 0.0234). After controlling for confounding factors in the multiple logistic regression analysis, a significant inverse relationship was noted between fruit and vegetable consumption and the risk of low biparietal diameter (<25th percentile). Compared with fetuses whose mothers had a fruit and vegetable consumption above the median value (≥519 g/d), those of mothers with a lower fruit and vegetable intake had a higher risk  of low biparietal diameter (<25th percentile) at late pregnancy  with infant birth weight and length (data not shown). Based on the multiple regression analysis . Birth weight in neonates born to mothers who consumed above the median fruit and vegetable value (≥519 g/d) was significantly higher than those born to mothers who consumed below the median value (P = 0.0024); these results were also observed in mixed models analysis for birth to 6 months (P = 0.0077). Maternal vitamin C intake was positively associated with infant birth length . Birth weight (P = 0.0400) and length (P = 0.0010) in neonates born to mothers who consumed above the EAR (≥85 mg/d) of vitamin C were significantly higher than in neonates born to mothers who consumed below the EAR (P = 0.0010). After adjusting for covariates, a significant negative relationship was observed between maternal fruit and vegetable consumption and low infant weight at birth (<25th percentile) [OR (95% CI) for below the median compared to above the median (≥519 g/d): 1.434 (1.001–2.256)]. There was also a significant negative correlation between the vitamin C consumption and low weight at birth (<25th percentile) [OR (95% CI) for below the EAR compared to above the EAR (≥85 mg/d): 1.470 (1.011–2.139)]. A similar trend was revealed between vitamin C intake and low weight from birth to 6 months (<25th percentile) [OR (95% CI) for below the EAR compared to above the EAR (≥85 mg/d): 1.520 (1.066–2.165)] and low length at birth (<25th percentile) [OR (95% CI) for below the EAR compared to above the EAR (≥85 mg/d): 1.579 (1.104–2.258)].Fetal biometric measurements, such as biparietal diameter, abdominal circumference, and femur length, were positively correlated  of biparietal diameter and weight at birth. In line with this result, there was a significant inverse relationship between consumption of vitamin C (an abundant nutrient in fruit and vegetables) and the risk of low (<25th percentile) weight at birth, weight from birth to 6 months, and length at birth. Prior research has demonstrated that the vitamin C contained in fruit and vegetables may contribute to both, placental functions and optimal immune system functioning , which aAlong with maternal vitamin consumption, we investigated maternal oxidative stress (MDA level), considering that it might be increased under normal pregnancy environments and cause adverse birth outcomes. Although the correlation coefficient value is very low, the maternal fruit and vegetable, and vitamin C intakes were negatively correlated with the oxidant marker (MDA) levels at mid-pregnancy, in agreement with the literature . This faAnother possibility is that vitamin C, an essential cofactor for two key enzymes (lysyl and prolyl hydroxylase) in collagen biosynthesis, is beneficial for cartilage and bone development . Some exDuring normal prenatal development, fetal vitamin C concentrations in plasma are higher than maternal levels. One study demonstrated an approximately two-fold higher vitamin C level in newborns at birth than in their mothers , implyinThe main vitamin C sources were fruits (40.3%) and vegetables (46.5%) (data not shown), but the correlation between fruit and vegetable/vitamin C with fetal and infant growth was partly inconsistent. Notably, in the biparietal diameter, a significant inverse relationship between fruit and vegetable intake and a low growth rate (<25th percentile) was observed, whereas mothers with a relatively lower vitamin C intake did not have a higher risk of low biparietal diameter. It may be that fruits and vegetables have played a role in other ways, such as provide unexpected bioactive components that are not vitamin C. The high number of bioactive components are found in fruits and vegetables, such as vitamins, minerals, phytosterols, phenolic compounds , carotenOur study had some limitations. First, we did not measure plasma vitamin C concentrations, which are considered to be a more objective means to assess vitamin C status than dietary vitamin C intake reports alone, due to the limited amounts of samples for other measurements . Second, the maternal dietary intake data from a single 24-h recall may not be sufficient to determine typical daily intake, due to a probable and considerable intra-individual variability in food and nutritional intake. However, the well-trained dietitians applied standard protocols to assist the subjects’ recollection of their daily diet and thereby minimize any potential bias. Regarding intra-individual variability of nutrient intake, as part of the 4th Korean National Health and Nutrition Examination Survey in 2009 , the intThe strengths of our study include the sample size and the research strategy, considering the strictly-controlled prospective birth cohort design of the MOCEH study in Korea. Also, this research collected reliable data from medical records. Furthermore, an adjustment for crucial confounders having the potential to affect the correlation between maternal vitamin C intake and birth outcomes of newborns were considered, in detail, for more precise analysis.Fetal growth is an important determinant of health and disease throughout a human’s lifetime. Interestingly, a prospective birth cohort study in Brazil noted a positive association of birth length with blood pressure at 11 years of age, whereas birth weight and blood pressure were not associated . It exemIn conclusion, an increased intake of dietary vitamin C, which is abundant in fruit and vegetables, at mid-pregnancy is associated with increased fetal growth and infant growth up to 6 months of age.


Background: Preterm infants are at increased risk for hypertension in adolescence. Microcirculatory dysfunction has been identified as an underlying cause for cardiovascular disease. Our goal was to document the development of the cutaneous microcirculation in preterm infants during the first weeks of life and to compare it to the situation in term infants at birth.Methods: In 20 preterm infants, microcirculatory parameters were obtained prospectively by Sidestream Dark Field (SDF) Imaging at the upper inner arm once a week until discharge or 37 weeks of gestational age. A single microcirculatory measurement was obtained in 30 term infants during the first 3 days of life. Videos were blinded and analyzed with the AVA software.Results: Microcirculatory parameters in preterm infants differ significantly from term infants with a lower vessel surface (VS), a lower percentage of large and medium but higher percentage of small vessels, a higher Functional Vessel Density (FVD), and a higher Microcirculatory Flow Index (MFI). In multivariable linear regression models we could demonstrate a statistically significant association between the dependent microcirculatory variables  and gestational age as independent predictor variable while adjusting for postnatal days of life. Looking at the longitudinal follow-up data of preterm infants by means of a multivariable mixed-effects linear regression model adjusting for clinical variables, there is a significant decrease in FVD with increasing postnatal age, however no other significant changes in microcirculatory parameters over time. Accordingly, comparing the microcirculatory parameters of near term former preterm infants with term born neonates, we could still find significant differences with a higher FVD, lower VS and differences in vessel diameters in the former premature group.Conclusion: Infants born prematurely exhibit distinct microcirculatory alterations compared to term neonates with gestational age at birth being associated with microvascular parameters. Interestingly, this premature vascular phenotype persists even close to corrected term age. In view of the known increased cardiovascular risk of former preterm infants, our observations might have important clinical impact. The factors governing the development of the microvascular network in preterm infants and the contribution of microcirculatory changes observed here to vascular pathology in later life need to be further investigated. Microcirculatory dysfunction has been linked to the risk of vascular pathology in cardiovascular disease and infection –4. PreviIn a prior study, we have obtained skin microcirculation images from former preterm infants at age 10–15 years and found significant differences to age matched term children. In the former preterm infants, small vessels were stiffer and the intima media thickness of the carotic artery was increased as marker for beginning arteriosclerosis . PrematuThe aim of the present study was to (i) compare the microcirculatory parameters of term and preterm infants of various gestational ages, (ii) to assess possible associations between microcirculatory parameters and gestational age, (iii) to longitudinally observe the development of the microcirculatory network in preterm infants after birth, and (iv) to compare microcirculatory parameters of former preterm infants near term age to term infants after birth. A better knowledge of potential differences in the microcirculation between term and preterm infants, as well as the postnatal development of the microcirculation in the preterm population might contribute to our understanding of the pathogenesis of cardiovascular pathology.Between Sept 2010 and Feb 2012, we prospectively included healthy term neonates  after birth on our maternity ward and preterm infants  upon admission on our neonatal intensive care unit. Exclusion criteria were significant congenital malformations, newborn infection, and dark skin pigmentation due to technical limitations in visualizing the microcirculation with SDF imaging in this population.The study was approved by the ethical advisory board of the medical faculty and written parental consent was obtained prior to patient recruitment.in vivo image of perfused vessels in the skin can be obtained and subsequently analyzed for different microcirculatory parameters  using the SDF Imaging technology. SDF Imaging is a non-invasive photometric technique, which allows visualizing the microcirculation at the bedside –17. It crameters . The micrameters , 19–22.The cohort of healthy term newborns was assessed once between the 2nd and 3rd day of life, whereas in every premature newborn, the microcirculation was assessed once a week until discharge or maximum until 37 weeks of gestation. Due to movement of the infants, it was very difficult to obtain 5 videos per infant as suggested by international consensus guidelines . TherefoAfter completion of all recordings, video sequences were chosen according to pre-defined and internationally accepted quality criteria  . SequencFunctional Vessel Density (FVD) accounts for the cumulative length of all vessels per field of view in mm/mm2. In the AVA program this parameter is also defined as total vessel density (TVD).diameter distribution is defined as the percentage of total vessel length of small (<10 μm), medium (10–20 μm) and large vessels (>20–100 μm).The Vessel Surface (VS) stands for the percentage of the image area, which is covered by vessels and therefore combines the parameters diameter distribution and vessel length.Microcirculatory Flow Index (MFI) is quantified by attributing different flow qualities to small, medium and large vessels in each quadrant of the image. Flow qualities were defined as 0 = no flow, 1 = intermittent, 2 = sluggish, 3 = continuous , and 4 = hyperdynamic flow (mic flow . The MFIHeterogeneity index of the MFI (HI) is a measure to account for blood flow heterogeneity calculated by substracting the minimum MFI from the maximum MFI and dividing it by the mean MFI  were involved in obtaining video sequences, blinding, and analysis. Both were trained together beforehand by an experienced researcher (A.P-S) until they were consistent in achieving high quality SDF recordings and analyzing only images fulfilling the quality criteria described above. Both examiners analyzed 10 exemplary video sequences, with the goal to achieve reproducible data. In general, our approach was to minimize any additional adjustments and only correct for clear artifacts such as dander or hair. In order to control for a potential rater-bias resulting from manual correction of the automated analysis and to assess the comparability between both investigators, the percentage of manually corrected vessels of the total vessel length was evaluated.p-value < 0.05 was considered as statistically significant.For each time point, the mean of 3 video scans per child was used for statistical analysis. Descriptive statistical analyses were performed with GraphPadPrism 7.0 . Regression models were fitted using STATA software version 15.1 . A In detail, we used the following statistical tests:The single microcirculatory measurements in 30 term infants were compared to the first microcirculatory measurements in 20 preterm infants. Furthermore, the single measurement of term infants was compared to the last microcirculatory measurement in the preterm group at a mean corrected age of 34.3 weeks of gestation.In order to assess a possible association between microcirculatory parameters at the first measurement and gestational age at birth, a linear regression model was fitted adjusting for postnatal days of life, as measurements took place at different time-points. To take into account further clinical variables, we ran a second linear regression model additionally adjusting for heart rate, blood pressure and oxygen saturation all of which were shown to significantly differ between groups. Body temperature could not be included into the model as there was no data on body temperature for the term infants.To take into account the longitudinal time component, the data of 17 preterm infants obtained in consecutive weeks 2, 3, 4, and 5 of life was analyzed with a mixed-effects linear regression model with postnatal days of life and gestational age at birth as independent variables. In a second model, we additionally adjusted for clinical parameters such as heart rate, blood pressure, oxygen saturation, and body temperature.To assess variability in the microcirculatory parameters  between the three video sequences evaluated per time point, we calculated the CV by dividing the standard deviation of the three original data points by the mean.Results of the comparison between term and preterm infants (first measurement only) are shown in p = 0.001), i.e., with every unit increase in gestational age vessel surface is increasing . Further clinical parameters such as hematocrit, hemoglobin and body temperature could not be taken into account, as those parameters were not routinely determined for term infants.To take into account other clinically relevant parameters that could have an influence on the microcirculation we ran a second linear regression model. When adjusting for mean arterial blood pressure, heart rate and oxygen saturation, the linear association between gestational age, vessel surface, and MFI failed to be statistically significant, but remained significant for all vessel diameter distributions  there was no statistically significant time-dependent variation in relation to days of life adjusting for gestational age at birth . To takeFinally, we wanted to assess whether the differences between term and preterm infants observed in the initial microcirculatory measurements level out when prematurely born infants grow older and reach near term age. This data could be obtained in 15 preterm infants in the last week on the neonatal intensive care unit. The data of 5 children was excluded as the last measurement on our ward took place before an adjusted gestational age of 32 weeks due to transfer to other wards. Due to the design of our scientific question, both groups differ in gestational age at birth and day of life at measurement .Comparing the microcirculatory parameters between both groups, significant differences could be shown . SpecifiOur results show distinct differences in the postnatal cutaneous microcirculation of preterm and term infants affecting FVD, diameter distribution, VS, and MFI. Significant differences in the cutaneous microcirculatory parameters persist even at a near term age compared to term infants soon after birth.FVD is one of the most validated parameters in the microcirculation, and a reduction in FVD was found in a range of diseases including mild to severe sepsis, patent ductus arteriosus, hypotension, and anemia , 27, 28.Intriguingly, VS was significantly lower in preterm infants and we could show decreasing VS with decreasing gestational age. At the first glance, this seems to be in contrast to the higher FVD found in preterm children; however, it can be explained by the observed differences in the distribution of vessel diameters between preterm and term infants. As the VS is the coverage of vessels in an observed area, it is directly related to the diameter distribution, and a higher percentage of small vessels directly results in a lower VS. In our study, preterm infants were shown to have a significantly higher percentage of small vessels compared to term infants. As capillaries are the major site for nutrient and oxygen exchange , it is tAnother interesting aspect of our data is that the MFI is decreasing in apparently healthy infants with rising gestational age. This is not what we would have expected as a lower MFI usually indicates a microcirculatory dysfunction. However, this finding is supported by another study that also showed a large number of low MFI values in their collective in apparently healthy children . WhetherOne might argue that our findings rely on the cutaneous microcirculation and are thus only indirect parameters for mechanisms taking place inside the body, and it can be discussed whether it would be more adequate to measure the microcirculation in more central organs. However, there is increasing evidence that the cutaneous microcirculation is affected in various diseases and can be used to evidence microcirculatory alterations in different cardiovascular risk groups  , 37, 38.Our results might have far reaching clinical consequences. The finding of little postnatal “evolution” of the microcirculatory parameters in the first weeks of postnatal life together with evidence for persisting alterations in adolescence point at fundamental alterations in vascular development associated with prematurity. In this regard, it was suggested that the increased cardiovascular risk of adults born prematurely is a reflection of Barker's fetal origin of disease hypothesis in the sense that preterm neonates like growth-restricted newborns, do not reach their genetic potential for vessel growth, leading to affected development of the microcirculation . The exaThere were some limitations to our study. Due to the strict exclusion criteria and the time consuming methods and analyses, our study population was rather small and random errors cannot be ruled out. It would be very interesting to analyze the microcirculation directly and later after birth both, in term and preterm infants, but this remains a challenge in our clinical setting as healthy newborns are soon discharged. Another concern to the validity of our results could be the differences in clinical parameters between the two study groups as well as a possible influence by mechanical ventilation, the presence of a hemodynamically significant PDA and hypercapnia , 40. In Our results suggest that the cutaneous microcirculation between term and preterm infants differs after birth and that differences remain present until near term gestational age. Key findings are a higher FVD, a higher percentage of small diameter vessels and a lower VS in preterm infants, which results in a distinct premature microvascular phenotype. Long-term differences might present an important risk factor and contribute to the higher incidence in cardiovascular diseases of adults born prematurely. Therefore, these observations should be followed-up in a larger trial.This study was carried out in accordance with the recommendations of the institutional review board of the Ludwig-Maximilians-University Munich. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the institutional review board of the Ludwigs-Maximilians-University Munich.AP-S, AG, and CN conceived and planned the trial and the measurements. AG carried out the measurements for term infants and analyzed the microcirculatory videos and clinical data for the term infants. AP-S, AG, OG-B, and CN contributed to the interpretation of the results. AP-S performed the statistical analyses and took the lead in writing the manuscript. CN and OG-B revised the manuscript. All authors provided critical feedback and helped shape the investigations, analyses, and the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.