Aggressive nutritional strategy, particularly enhancing early provision of energy and protein, has appeared to reduce postnatal growth failure and improve later developmental outcomes. But the amount of macronutrients required remains unclear. The aim of this study was to investigate the impact of protein and energy intakes during the first two weeks after birth on neurodevelopmental outcomes.This retrospective cohort study of very low birth weight infants born between January 2012 and December 2015 was conducted at one tertiary neonatal intensive care unit. The primary outcome was a neurodevelopmental impairment (NDI) at 2 years corrected age defined by a cerebral palsy or a 24 month Ages and Stages Questionnaires score on any of the five domains lower than 2 standard deviation below the mean score. Multivariable logistic regression analysis was used to adjust for perinatal and postnatal confounders.Among 245 (73%) infants discharged home alive, 159 (65%) had follow-up at 2 years. Infants with NDI  were more likely male gender  and experienced more patent ductus arteriosus (PDA) ligation  than control. After adjusting for confounders, first-week protein intake , second-week non-protein energy intake  and PDA ligation  had significant independent association with higher likelihood of NDI at 2 years.Providing nutrition above the optimal level may not be beneficial and may even be harmful. These results confirm the recent recommendation to decrease amino acid intakes published in the latest ESPGHAN guidelines. Over the past decade, improvements in perinatal care have resulted in increased survival rates of very low birth weight  infants, having led to a higher incidence of neurodevelopmental sequelae. Recently, a French population-based study of preterm born at 22 to 34 weeks of gestational age (GA) have shown improvements in survival at 2 years’ corrected age (CA) without neuromotor disabilities between 1997 and 2011 but these children have remained at risk of developmental delay –8. ConseThe aim of the current study was to investigate the impact of protein and energy intakes during the first two weeks after birth on neurodevelopmental outcomes at 2 years’ CA in VLBW infants.This retrospective cohort study was conducted in a 51-bed tertiary level neonatal intensive care unit (NICU) at Rennes’ University Hospital, France. All inborn and outborn VLBW infants admitted within 24 hours of life from January 2012 to December 2015 and who subsequently had neurodevelopmental assessments at 2 years’ CA in the local perinatal follow-up network were eligible. The infants who had severe congenital brain malformations or chromosomal anomalies, those who had hospital stay less than 7 days or died before follow-up and infants who were lost to follow-up were excluded. The ethics committee of the Rennes University Hospital approved the study. Written informed consent was obtained from the parents of each participating infant before their enrollment in the local perinatal follow-up network. All data were fully anonymized.The primary outcome was a neurodevelopmental impairment (NDI) at 2 years’ CA. Parents reported their child’s development using the second edition of the 24 month Ages and Stages Questionnaire (ASQ)  validateSecondary outcomes were anthropometric measurements performed at birth and 2 years’ CA. Weight, length and head circumference (HC) were recorded at birth and at 2 years’ CA. They were converted to standardized Z-scores according to Olsen curves at birth  and to WBaseline clinical data and neonatal comorbidities were retrospectively retrieved from patients' medical records. Nutritional intakes were prospectively collected from our local computerized physician order entry system.The following maternal details were obtained: singleton or multiple pregnancy, preeclampsia, clinical chorioamnionitis, antenatal steroid therapy initiated (at least two injections), and vaginal or cesarean birth. At birth, baseline clinical data included: gestational age, gender, anthropometric measurements  and surfactant replacement therapy.The presence of comorbidities associated with prematurity were collected such as mechanical ventilation duration, bronchopulmonary dysplasia defined as ventilatory or oxygen requirement at 36 weeks’ PMA, PDA confirmed by echocardiography requiring ibuprofen or surgical ligation, NEC defined as a stage 2A or more according to Bell’s modified classification, and retinopathy of prematurity (ROP) defined as a stage 2 or more according to international classification. Cerebral white matter injuries on magnetic resonance imaging at term for survivors or before death were also reported.Nutritional intakes data encompassed parenteral and enteral intakes. The daily protein, total energy, non-protein energy and fluid intakes were summed to obtain the median of daily intakes during the first and the second week after birth.Clinical pathways used in our institution during the study period indicated that parenteral nutrition should be started on the first day of life with 2.4 g/kg/d of AA, 6 g/kg/d of dextrose and 1 g/kg/d of lipids. Subsequent daily increase was 0.5 g/kg/d, 1.2 g/kg/d and 0.5 g/kg/d respectively. Targets for AA intakes were 4 g/kg/d (maximum 4.5 g/kg/d) among infants less than 1000 g at birth or 3.5 g/kg/d (maximum 4 g/kg/d) if birth weight was above 1000g. Target dextrose intake was 15.6 g/kg/d (maximum 18 g/kg/d). Target lipids intake was 3.5 g/kg/d. Early trophic feeding was started within the first day of life, with expressed or pasteurized human milk, for 5 days if the birth weight was less than 1000g or 3 days otherwise. If well tolerated, enteral nutrition was then increased with a daily volume enhancement of 20 to 25 mL/kg/d, PN being replaced gradually. Fortification of maternal or donor human milk was started when enteral intakes reached 80 mL/kg/d. Central line was removed when the infant tolerated 120 mL/kg/d enteral feeding.Patient’s characteristics are reported as numbers (with percentages) for categorical variables and as medians (with interquartile ranges) for continuous variables. Categorical variables were compared with the Chi square or Fisher’s exact test, and continuous variables were compared with a Mann-Whitney U test, as appropriate. To identify independent predictors of NDI at 2 years’ CA, multivariable logistic regression analysis were performed. In models building, nutritional intakes including protein, non-protein energy and fluid intakes were associated with all clinically relevant variables as GA, birth weight, and neonatal comorbidities. Because birth weight and birth weight Z-score were highly correlated, only birth weight was included in the multivariable models. Optimization for variable selection with stepwise method using the Akaike's Information Criterion (AIC) was applied in Model I. Because GA and birth weight are well known as independent factors of neurodevelopmental outcome and were excluded by variable selection method, Model II kept GA and Model I factors, while Model III kept GA, birth weight and Model I factors. All analyses were performed using the R  software. Statistical relevance was considered at P value <0.05.Out of a total of 336 VLBW infants assessed, 245 (73%) were discharged home alive and enrolled in the local perinatal follow-up network . Among tThe median GA was 28.4 weeks (26.9 to 29.6 weeks), the median birth weight was 1050 grams (865 to 1240 grams), 55.1% were male, and 13.1% were considered SGA according to their Z-score. The mortality rate during hospital stay was 14%. There was no statistically significant difference between included and excluded infants for the majority of the reviewed variables, including nutrient intakes. There was a longer mechanical ventilation duration (2 days (0 to 12 days) versus 1 day (0 to 6 days), P = 0.006) for excluded compared to included infants.The characteristics and morbidities of the surviving babies who were assessed at 2 years’ CA were summarized in Protein intake increased from 3.45 g/kg per day (3.06 to 3.80) in week 1 to 3.89 g/kg per day (3.53 to 4.06) in week 2. Non-protein energy intake increased from 59 kcal/kg per day (51 to 68) in week 1 to 103 kcal/kg per day (83 to 120) in week 2. No differences were observed between the two groups in the nutritional intakes on univariate analysis.Multivariable logistic regression analysis were performed to assess the independent contribution of protein and non-protein energy intakes to NDI at 2 years’ CA while controlling for birth weight, GA, gender, fluid intakes and comorbidities associated with neurodevelopmental outcomes (NEC and PDA ligation). In each of our models shown in From birth to 2 years’ CA, growth was similar between groups, except the HC delta Z-score was significantly lower (P = 0.03) in NDI group as compared to control .The objective of postnatal nutrition in VLBW infants is to achieve a postnatal growth that is similar to fetal growth and coupled with adequate long-term developmental outcomes. The correlation between early provision of protein and later outcomes has been widely documented, while the optimal maximum amount of protein still has to be determined.In this retrospective cohort study of 245 VLBW survivors, a higher first-week protein intake and a higher second-week non-protein energy intake were associated with higher odds of NDI at 2 years’ CA. Important comorbidities as NEC and PDA ligation were also associated with NDI. These findings contrast with multiple large cohort studies over the past decade that have strongly associated an increase in early protein and energy intake with an improvement of motor and cognitive scores in childhood.The strengths of this study include the primary outcome assessment method and the adherence to nutritional guidelines recommended over the study period. ASQ was used to assess development delay since is a reliable parent-completed development screening tool which previous studies have indicated high test-retest reliability, inter-observer reliability, and internal consistency . ASQ hasThe observed negative association between NDI and higher AA intakes supports the recently updated current guidelines that recommend AA intake between 2.5 g/kg per day and 3.5 g/kg per day . RegardiRelatively few studies have investigated the direct effects of neonatal nutritional intake on later neurodevelopment. Stephens et al.  were theIn contrast to above findings, Cester et al.  did not Overall these studies, evidence appeared to be insufficient to show an effect from increased early protein intake on neurodevelopment at 18 or 24 months’ CA, as confirm the most recent Cochrane systematic review . It is oStrong observed associations between neonatal comorbidities, as NEC and PDA ligation, corroborated previous observational studies ,22 who fIn addition to the limitations already described, this investigation has the potential bias inherent in observational uncontrolled study. Outcome data reported here were collected retrospectively and some data, such as the primary outcome, were provided by the parents. Even if nutrient intakes were prospectively collected from our local computerized physician order entry system, it is often reported in nutrition studies that actual intake in 24 hours period can be different from prescription.Among a single-center cohort of VLBW infants over a three-year period, a higher early protein intake and non-protein energy intake were associated with higher odds of neurodevelopmental impairment at 2 years’ corrected age. This highlights the contradictory hypothesis that greater protein intakes in early life improve neurodevelopmental outcome like previous studies. However, these results confirm the recent recommendation to decrease amino acid intakes published in the latest ESPGHAN guidelines. When the standard nutrition is below optimal, providing more nutrition may be beneficial. Nevertheless, providing nutrition above the optimal level may not be beneficial and may even be harmful. This study also confirms the strong relationship from neonatal comorbidities to early providing nutrition with an influence on later neurodevelopmental outcome. Further studies are necessary to improve our knowledge and nutritional practices in VLBW infants.S1 Dataset(XLS)Click here for additional data file.


This cohort study creates and validates an easy-to-use prediction model using only birth characteristics and describes a continuous hazard function for retinopathy of prematurity treatment. Can a prediction model be constructed for retinopathy of prematurity needing treatment by using only birth characteristics data and applying advanced statistical methods?In this cohort study of 6947 infants born at gestational age 24 to 30 weeks, the prediction model incorporating only postnatal age, gestational age, sex, and birth weight provided a predictive ability for retinopathy of prematurity needing treatment that was comparable to current models requiring postnatal data . The risk for retinopathy of prematurity needing treatment increased up to 12 weeks’ postnatal age irrespective of the infants’ gestational age.This prediction model identifying infants with a high risk for developing sight-threatening disease at an early time may improve the conditions for optimal screening. To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness.To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment.In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP  were analyzed with Poisson regression for time-varying data  to develop an individualized predictive model for ROP treatment . The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models.The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).Among 7609 infants , 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks’ GA showed high predictive ability for the model overall  by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP , OMA-ROP (Omaha-ROP), WINROP , and CO-ROP (Colorado-ROP), models requiring more complex postnatal data.This study validated an individualized prediction model for infants born at 24 to 30 weeks’ GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists. Data are registered in the Swedish National Registry for Retinopathy of Prematurity (SWEDROP). Between 2008 and 2015, only 5.7% of screened infants in Sweden were treated for ROP.3 Screening includes retinal examinations by specially trained ophthalmologists and is often stressful for the infant4; without risk prediction, some infants may not be screened and treated at the appropriate time. Individualized risk estimates would allow for optimization of timing and frequency of the screening processes from the health care and economics perspectives. Improving the timing of screening visits could avoid unnecessary examinations of low-risk infants and optimize identification of those at high risk.Retinopathy of prematurity (ROP) is a potentially blinding disease, and screening programs for detecting sight-threatening ROP needing treatment have been established worldwide.5 including poor prenatal and postnatal weight gain. For this reason, the prediction algorithm WINROP , which is based on accumulated postnatal weight gain, has been validated and broadly used.9 Similar tools based on longitudinal postnatal weight gain also have been developed.13 The objectives of this study were to create, then to internally and externally validate, and to describe the clinical implications of a prediction model for individual momentary and cumulative risks of ROP treatment based on birth characteristics alone, including infants born at GA less than 31 weeks.Risk and severity of ROP vary by prenatal and postnatal factors,14 were included as part of the Swedish Neonatal Quality Register,15 started in 2007, which has approximately 97% coverage and contains perinatal data, screening outcomes, and treatment information.3 All data are registered through standardized protocols, in most settings by a trained pediatric ophthalmologist who has performed the screening examination. A validation of 85 randomly selected infants screened in 2018 showed 100% correctly reported values for variables used in this study. This retrospective cohort study was approved by the ethics committee at Uppsala University, Uppsala, Sweden, who also waived written informed consent because all the data were deidentified.Infants born between January 1, 2007, and August 7, 2018, at GA less than 31 weeks and with completed ROP screening registered in SWEDROPIn total, data for 8784 infants born between January 1, 2007, and October 31, 2017, were retrieved from SWEDROP for the prediction model development. Of those, data for 1372 of 8784 infants (15.6%) were excluded for having GA at least 31 weeks at birth, and 126 of 8784 infants (1.4%) were excluded for missing data. This left 7286 of 8784 infants (82.9%) eligible for the model development group. Of those, 6947 of 7286 infants (95.3%) had GA 24 to 30 weeks .The group used for temporal validation consisted of infants born between November 1, 2017, and August 7, 2018, and registered in SWEDROP. Among infants born at GA 24 to 30 weeks, 308 of 323 (95.4%) were eligible and served as the validation temporal group .16 The validation European group included 329 of 354 eligible infants (92.9%) born at GA 24 to 30 weeks from Freiburg, Germany, with retrospective screening data collected between 2011 and 2017  born at GA 24 to 30 weeks from 12 US centers between 2005 and 2010 .16 The vand 2017 .1718 An SD score (SDS) of expected reference weight (birth weight SDS [BWSDS]) was calculated based on GA, sex, and birth weight for all healthy singletons born at GA at least 24 weeks between 1990 and 1999 in Sweden and registered in the Medical Birth Register .19 Hence, BWSDS was not calculated for infants born at GA less than 24 weeks because of a lack of reference for this extremely preterm population. Infants born at GA less than 24 weeks are at high risk of severe ROP requiring treatment, partly owing to a larger proportion of avascular retinal area at birth,20 and prediction models are not as useful in this cohort. Therefore, a simpler prediction model was developed for this group and is presented along with the results in eAppendix 1  in the 19 was defined as BWSDS less than −2.The estimation of GA was based on fetal ultrasonographic results. The chronological  age, postmenstrual age, and GA are defined according to the American Academy of Pediatrics’ issued policy.21 and Early Treatment for Retinopathy of Prematurity (ETROP)22 criteria for treatment were used.The prediction model was developed to estimate risk for treatment of sight-threatening ROP. The International Classification of Retinopathy of Prematurity2 trend test for ordered categorical variables, and Mann-Whitney test for continuous variables. The Jonckheere-Terpstra test was applied for identifying trends between ordered categorical and continuous variables. The crude week-specific risk of ROP treatment (number of infants with the event divided by number of infants at risk) was analyzed based on postnatal age and postmenstrual age  by GA at birth. The modeling process consisted of (1) prediction model development, (2) internal and external validation, and (3) clinical implication.23 The prediction model for ROP treatment, called DIGIROP-Birth , was developed using Poisson regression for time-varying data, from which we obtained a continuous hazard function, h(t), describing momentary risk for ROP treatment.25 From the hazard function, the survival function F(t) = 1 − S(t), were estimated. The 95% CI for F(t) was obtained via repeated sampling (1000 samples) of the model parameters from a multivariate normal distribution using a covariance matrix estimated by the Poisson regression models. Parameter estimates, SEs, and hazard ratios (HRs) with 95% CIs are presented. The predictive ability of the continuous cumulative risks was checked and was found to be similarly high after postnatal age 15 weeks .P < .10.Based on the crude risks for ROP treatment over time stratified by GA, we found that postnatal age was the most appropriate time axis. The final model for GA 24 to 30 weeks included the following: piecewise linear current postnatal age , piecewise linear continuous GA given in weeks and days , sex, piecewise linear BWSDS , postnatal age × piecewise linear GA interaction, sex × GA interaction, and postnatal age × piecewise linear BWSDS interaction. The break points for the variables were selected based on graphical review of univariable hazard functions. The final model was built by gradually expanding the models, starting only with postnatal age and further keeping interactions with 11 OMA-ROP [Omaha-ROP],12 WINROP ,7 and CO-ROP [Colorado-ROP]13) using GA, birth weight, and different weight gain variables in the algorithms, as described in more detail in eAppendix 2 in the Internal, temporal, and geographical external validations were performed. The model fit and adaptation were described by the area under the receiver operating characteristic curve (hereinafter referred to as AUC) overall, by calendar periods, and by race/ethnicity. We performed cross-validation and evaluated calibration plots; calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); and compared DIGIROP-Birth with 4 other published prediction models  developed any ROP, which regressed spontaneously in 1985 of 7609 (26.1%) and was treated in 442 of 7609 (5.8%)  per week from postnatal weeks 8 through 12. Afterward, it decreased by 30%  per week .P for interaction = .02), with HRs of 0.83  at 25 weeks and 0.50  at 27 weeks  and categorizing the probabilities based on the recommended cutoff of 0.0140, similar prediction ability was observed compared with DIGIROP-Birth , and a cutoff of 0.0083 obtained the same sensitivity (95 of 96 [99.0%] for both CHOP-ROP and DIGIROP-Birth. Specificity was 598 of 1346 (44.4%) vs 658 of 1346 (48.9%), respectively. Applying the same cutoff on the complete SWEDROP database, the model showed 97.7%  sensitivity and 59.5%  specificity. Applying a cutoff of 0.00083 for 100%  sensitivity in the cohort, a specificity of 19.0%  was obtained.Compared with OMA-ROP , a cutoff of 23 g per day in weight gain, with a corresponding cutoff of 0.0200 for DIGIROP-Birth , a sensitivity of 90 of 92 (97.8%) was obtained. Specificity was 173 of 771 (22.4%) for OMA-ROP vs 448 of 771 (58.1%) for DIGIROP-Birth.Compared with WINROP , the alarm category of WINROP score 2 or 3 provided a sensitivity of 121 of 125 (96.8%), with a corresponding cutoff of 0.0089 for DIGIROP-Birth . Specificity was 487 of 1360 (35.8%) for WINROP vs 671 of 1360 (49.3%) for DIGIROP-Birth.The specificity was 141 of 1341 (10.5%) for the CO-ROP algorithm and 642 of 1341 (47.9%) for DIGIROP-Birth. Both had a sensitivity of 122 of 124 (98.4%).2 for postnatal age and postmenstrual age at initial examination (Based on ROP treatment timing in the SWEDROP cohort (2007-2018) and the DIGIROP-Birth model, we compared the results with the current US recommendations, based on studies that are more than 20 years old,mination . The max26 based on 6947 infants born at GA 24 to 30 weeks, estimating the individual momentary and cumulative risks for ROP treatment. The model using only available data at birth but more advanced statistical methods was at least as accurate as 4 of the ROP prediction models now in use based on longitudinal weight measurements, which are not always readily available to ophthalmologists.We have created and validated the DIGIROP-Birth prediction model, available free of charge online27 found that the progression of prethreshold ROP was highly associated with postmenstrual age, similar to the finding in the CRYO-ROP (Cryotherapy for ROP) study28 15 years earlier. However, it should be emphasized that infants included in the CRYO-ROP study were born at higher GA, and no GA-specific hazard functions were studied for ROP outcome. Other Swedish studies30 have reported that lower GA at birth is associated with lower GA at treatment, but the momentary risk in relation to postnatal age and postmenstrual age was not analyzed. Recently, in a large North American cohort, the timing of ROP treatment was presented only in relation to postmenstrual age and not postnatal age.31Surprisingly, the momentary risk of ROP treatment peaked at 12 weeks’ postnatal age regardless of GA at birth, while no specific pattern was observed for postmenstrual age. This observation is particularly interesting because the ETROP study32 Hence, clinicians and parents could be alerted during this period to ensure that timely screening occurs to reduce the risk of blindness.The identification of a peak risk at 12 postnatal weeks in infants with GA less than 31 weeks might be clinically useful because it was recently shown that inadequate screening or treatment was identified in 11 of 17 cases with blindness from ROP (64.7%).National patient registries are valuable sources for estimation of treatment risks. Herein, the DIGIROP-Birth model was compared with a validation US group and a validation European group and showed high predictive ability and generalizability both for individuals with the same and with different reported race/ethnicity.2 was issued in 2018. The recommendations for the timing of the first examination were based on the CRYO-ROP study28 published in 1991 and the LIGHT-ROP (Light Reduction in ROP) study33 published in 1998. In those periods, fewer extremely preterm infants survived, more mature infants were treated, and treatment criteria were different from those used today. Based on the results of our study, if the initial examination was performed 1 week before the earliest observed postnatal age at ROP treatment, 14 867 of 135 061 stressful early examinations (11.0%) could be avoided (assuming 1 examination per week) compared with US recommendations.2 For GA of at least 27 weeks, with a ROP treatment incidence herein less than 1%, 14 066 of 93 052 examinations (15.1%) could have been avoided while capturing all cases of ROP treatment (100% sensitivity). Notably, reaching 100% sensitivity in such models of real-life, large data sets is accompanied by low specificity. Based on approximately as large a cohort as in our study, the updated CHOP-ROP11 model, which uses longitudinal weight data and birth data, achieved 11.2% specificity for 100% sensitivity and 36.4% specificity for 98.5% sensitivity; DIGIROP-Birth (using only readily obtained birth data) showed 19.0% specificity for 100% sensitivity and 53.8% specificity for 99.0% sensitivity.The ROP prediction models may also be used to reduce screening frequency in infants at low risk. The latest US policy statement for ROP screening26The strengths of our study include the unique and complete cohort of preterm infants born in Sweden between January 2007 and August 2018. Also, our statistical model includes 3 basic measurements . The postnatal age for ROP treatment or censoring (discontinued follow-up) is included in the hazard function estimation but is not required as an input variable. Hence, the input data are simple, facilitating their general use, even though the method is more advanced, taking into account the underlying hazard function and the important interactions that contribute to adjustment of heterogeneity, which is novel in ROP research. The DIGIROP-Birth has shown strong predictive ability in internal, temporal, and geographical external validations. If found not acceptable in future validations among a population, a subgroup-specific model designed for optimal predictions in that population might be developed using our methods. Finally, DIGIROP-Birth has been shown to be equal to or better than 4 other ROP prediction models and is accessible online.Our study has some limitations. One limitation is the use of registry retrospective data. However, the registry showed high coverage and successful validation of data for 85 randomly selected infants screened in 2018. In addition, infants born at GA less than 24 weeks could not be included in the prediction model because of the lack of a reference algorithm for birth weight, preventing BWSDS calculations. Given the small sample size, only a simple model could be developed for these infants, resulting in low predictive ability. Close monitoring of such infants is mandatory irrespective of calculated risk, making prediction models less important for this group.We created and validated the DIGIROP-Birth model, an individualized early prediction model for infants with GA 24 to 30 weeks, which estimates momentary and cumulative risks for receiving ROP treatment based on simple birth characteristics. A surprising finding was that postnatal age was the best predictive variable for the temporal risk of ROP treatment. The DIGIROP-Birth model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models that require longitudinal neonatal data, which are not always readily available to ophthalmologists.


Whereas poor maternal nutritional status before and during pregnancy is widely associated with adverse birth outcomes, studies quantifying this association in low income countries are scarce. We examined whether maternal pre-pregnancy body mass index (BMI) and weight gain during pregnancy are associated with birth outcomes in rural Malawi.We analyzed the associations between pre-pregnancy BMI and average weekly gestational weight gain (WWG) and birth outcomes . We also determined whether women with low or high pre-pregnancy BMI or women with inadequate or excessive WWG were at increased risk of adverse birth outcomes.2, of whom 5.9% were underweight (< 18.5 kg/m2), 10.9% were overweight (≥ 25 kg/m2), 71.8% had low WWG [below the lower limit of the Institute of Medicine (IOM) recommendation], and 5.2% had high WWG (above IOM recommendation). In adjusted models, pre-pregnancy BMI was not associated with duration of pregnancy (p = 0.926), but was positively associated with birth weight and HCZ . WWG was positively associated with duration of gestation (p = 0.031), birth weight (p<0.001), LAZ (p<0.001), and HCZ (p<0.001). Compared to normal weight women, underweight women were at increased risk of having stunted infants (p = 0.029). Women with low WWG were at increased risk of having infants with low birth weight (p = 0.006) and small head circumference (p = 0.024) compared to those with normal weight gain. Those with high BMI or high WWG were not at increased risk of adverse birth outcomes.The analyses included 1287 women with a mean BMI of 21.8 kg/mWWG is an important predictor of birth outcomes in rural Malawi. The high prevalence of inadequate WWG compared to low pre-pregnancy BMI highlights the need to investigate causes of inadequate weight gain in this region. The nutritional status of a woman before and during pregnancy is important for a healthy pregnancy outcome . MaternaThe effects of pre-pregnancy anthropometric status  are well documented –6. In loMaternal gestational weight gain (GWG) has also been widely studied as an independent predictor of adverse pregnancy outcomes ,12. MultThis was a prospective cohort study, nested within the International Lipid-Based Nutrient Supplements (iLiNS) Project DYAD trial in Malawi (iLiNS-DYAD-M), which was a randomised controlled trial that was carried out in Mangochi District. Mangochi district is a semi-urban, semi-rural area of southern Malawi with subsistence farming and fishing as the main sources of income. Participants were recruited between 14 and 20 gestation weeks, seen again at 32 and 36 gestation weeks, and soon after birth, to determine weight gain during pregnancy and birth outcomes.S1 Table). The intervention had a limited impact on birth outcomes  or HCZ  among infants born to underweight women and normal weight women (Table 3). However, we found that infants born to underweight women were at a greater risk of stunting  and being SGA  but no significant risk was noted for small head circumference  when compared to infants born to normal weight women (Table 4). We found no increase or decrease in risk of stunting, SGA, or small head circumference when comparing infants of overweight and normal weight women in adjusted models .The associations between low and high BMI and birth outcomes are presented in p = 0.005]; lower average infant birth weight ; LAZ ; and head circumference z-score  (Table 5). Similarly, women with low WWG were at a greater risk of having an infant with LBW, SGA and small head circumference in adjusted models , but not significantly more likely to have a stunted infant or give birth preterm  (Table 6). There were no differences in birth outcomes or risk of adverse birth outcomes among women with high WWG (above the IOM recommendations) compared to women with normal WWG.Compared to women whose WWG was normal (within IOM recommendations), women with low WWG (below the IOM recommendations) in adjusted models had a shorter average duration of pregnancy  and MMN  groups, but not among women in the LNS group . There were no significant differences in adverse birth outcomes between women with low vs higher BMI within any of the intervention groups   was strongly associated with pregnancy duration, birth weight, LAZ, and HCZ, and women who gained inadequate weight during pregnancy were at higher risk of giving birth to newborns with LBW, SGA, and small head circumference. We did not find increased risk of adverse birth outcomes among women with high pre-pregnancy BMI or WWG above IOM recommendations. These results are of public health importance as they emphasize the need for addressing proper nutrition amongst women not only during pregnancy and in the pre-pregnancy period, but also exploring other underlying factors that may influence low WWG among pregnant women in rural Malawi.We found few other studies that have reported associations between pre-pregnancy BMI and birth outcomes in developing countries. A 2011 meta-analysis of 78 studies showed increased risks of preterm birth and LBW among underweight women, however, only a handful of the studies were from developing countries . The 4 s2) increased the risk of preterm delivery [Our observation of no increased risk of adverse birth outcomes  among high pre-pregnancy BMI women is consistent with a retrospective study of Thai women . By contdelivery ,28,32. Hdelivery ,33. ThusA key finding of our study was that low average WWG is an important risk factor for adverse birth outcomes, which aligns with previous studies ,33. For We explored the associations between pre-pregnancy BMI and birth outcomes within each of the intervention groups to get a sense of whether the nutritional intervention during pregnancy helped to prevent adverse birth outcomes among women with low or high pre-pregnancy BMI. Interestingly, underweight women in the iron-folic acid and multiple micronutrient supplement groups were at greater risk of giving birth to a SGA infant than normal weight women, while there was no such association among women in the lipid-based nutrient supplement (LNS) group. LNS was the only supplement of the 3 that contained calories, protein, and essential fatty acids, which may have helped protect infants of underweight women from being SGA.One limitation of the current study is that we used BMI, a proxy for body composition, rather than the more direct methods of assessing body composition. Another limitation was that we calculated pre-pregnancy BMI from BMI at enrolment using regression modelling, rather than directly measuring pre-pregnancy BMI. The generalizability of these findings may be limited, as those included in the study were of older age, less educated, lower socio-economic status, and had a higher prevalence of primiparity compared to those excluded from the study. Additionally, the proportions with low WWG and low BMI among excluded women were slightly higher than among those included (79.9% vs 70.2% and 5.7% vs 4.1%), which may have some impact on generalizing the findings of the present study to the larger population. The strengths of this study are that it was a prospective study with a large sample size, and highly trained study staff was used to perform study protocols.Our findings support our hypothesis that low maternal WWG is an important risk factor for adverse pregnancy outcomes. These findings highlight the need for a better understanding of the reasons behind such a high prevalence of low GWG in rural Mangochi and how to improve the situation. There was a large discrepancy between the rates of pre-pregnancy underweight (5.9%) and low average WWG (71.8%), suggesting that factors other than lack of food contributes to low WWG. Therefore, programs should aim at investigating other underlying factors such as maternal infections during pregnancy that may impair appetite. Nevertheless, linear associations between pre-pregnancy BMI and birth weight and child head circumference, and increased risk of stunting among women with low pre-pregnancy BMI suggest that the importance of adequate nutrition in the pre-pregnancy period shouldn’t be overlooked.S1 Table(PDF)Click here for additional data file.


To determine the concentration of alpha-tocopherol in umbilical cord serumof full-term and preterm newborns, in order to assess the nutritional statusof both groups in relation to the vitamin and its possible correlation withintrauterine growth.st. Thealpha-tocopherol levels ofumbilical cord serum were analyzed by High Performance LiquidChromatography. A cross-sectional observational study conducted with 140 newborns, of which64 were preterm and 76 were full-term. They did not have any malformations,they came from healthy mothers, who were nonsmokers, and delivered a singlebaby. Intrauterine growth was evaluated by weight-to-gestational age atbirth, using Intergrowth-21 The mean concentration of alpha-tocopherol in umbilical cord serum forpreterm and full-term infants was 263.3±129.5 and 247.0±147.6 µg/dL(p=0.494). In the preterm group, 23% were small for gestational age, whereasin the full-term group, this percentage was only 7% (p=0.017). Low levels ofvitamin E were found in 95.3% of preterm infants and 92.1% of full-terminfants. There was no correlation between alpha-tocopherol levels and weightto gestational age Z score (p=0.951). No association was found between alpha-tocopherol levels and weight togestational age at birth. Intrauterine growth restriction was more frequentin preterm infants and most infants had low levels of vitamin E at the timeof delivery. This can result in lowserum and tissue levels of Vitamin E at birth, especially in prematurenewborns.2and E2,Low serum levels of alpha-tocopherol are associated with the development of edemas,thrombocytosis, and hemolytic anemia, which can result in spinocerebellardegeneration.st,which is currently the most suitable tool for assessing intrauterine growth, byproviding up-to-date growth curves for preterm and full-term newborns.,Intrauterine growth restriction (IUGR) is one of the main causes of neonatalmorbidity and mortality, and has possible repercussions in adulthood, especiallywith regard to cardiovascular diseases.,,,However, despite the possible role of alpha-tocopherol in aiding the intrauterinedevelopment of fetuses, there are still few studies that evaluate this relationship,and consider weight and gestational age at birth. There are reports that full-termnewborns with appropriate weight for gestational age (AGA) present higher levels ofalpha-tocopherol than infants that are small or large for their gestationalage.Thus, considering that premature newborns represent an at-risk group for lowalpha-tocopherol serum levels and IUGR at birth, this study aimed to determine theconcentration of alpha-tocopherol in the umbilical cord serum of full-term andpreterm newborns in order to evaluate the nutritional status of both groups withregard to this vitamin and its possible correlation with intrauterinedevelopment.The study was comprised of 140 newborns, including 64 preterm infants (< 37 weeks)and 76 full-term infants (≥ 37 weeks), who were cared for at two public maternitywards in Rio Grande do Norte: Ana Bezerra University Hospital, located in the cityof Santa Cruz, and Januário Cicco Maternity School, located in Natal, from 2013 to2015. The inclusion criteria were healthy mothers , who were non-smokers, and delivered one baby withoutmalformations.The study was observational with a cross-sectional character for convenience. Birthweight, length at birth, and gestational age at birth were consulted in thepatients’ medical records. To complement the research and characterize thepopulation, data on maternal age, family income, type of delivery and parity werecollected using forms.The nursing staff at the maternity wards collected 5 mL of umbilical cord blood atthe time of the delivery, in dry polyethylene plastic tubes wrapped in laminatedpaper (to protect against luminosity), and transported in refrigerated containersuntil they reached the lab. In the laboratory, the blood was centrifuged for 10minutes (500 xg) to separate the serum, which was cooled until the levels ofalpha-tocopherol were determined..To extract the alpha-tocopherol serum, we used the adapted method proposed by Ortegaetal® 100 Column RP-18 (5 µm). For data processing, we used the LCsolution® software .The mobile phase used in HPLC was 100% methanol with a 1 mL/min flow.Alpha-tocopherol level was monitored at a wavelength of 292 nm. The analysis tookplace in the LC-20 chromatograph at Shimadzu, and was coupled to the SPD-20AShimadzu UV-VIS detector and the C18 LiChrospherThe alpha-tocopherol was identified and quantified in the samples by comparing theretention time and the peak area obtained by the previous application of thetocopherol level standard. The concentration of the standard was confirmed by thespecific extinction coefficient for alpha-tocopherol  inabsolute ethanol.st.st software to calculate the percentile andZ score. Newborns were classified as small for their gestational age (SGA) when thepercentile was <10, AGA when the percentile was 10 to 90, and large forgestational age (GIG) when the percentile was >90.,Intrauterine growth was evaluated using the anthropometric indices of birth weightand length at birth by gestational age, using the new growth curves ofintergrowth-21The continuous variables were verified to be normal using the Kolmogorov-Smirnovtest. Pearson’s correlation was used to verify the correlation between the levels ofalpha-tocopherol and the Z score of weight for gestational age, since the datapresented normal distribution. The chi-square test was used to ascertain thedifferences in the categorical variables between the preterm and full-term groups,and the Student’s t-test was used to evaluate the average differences inalpha-tocopherol and maternal age between the groups. The data were analyzed inStatistical Package for the Social Sciences(SPSS), version 7.0 . All differences were considered significant when p<0.05.The study was approved by the Research Ethics Committee of the Federal University ofRio Grande do Norte (CAAE 07416912.8.0000.5537), and all of the new mothersvoluntarily signed the free and informed consent form before starting thecollections.A total of 140 newborns participated in the research - 64 were preterm and 76 werefull-term. Weight and length at birth were different between groups, andintrauterine growth restriction was observed in 23% (n=15) of preterm births and in7% (n=5) of full-term births (p=0.017) .There was no significant difference in the levels of alpha-tocopherol in theumbilical cord between the preterm and full-term groups (p=0.493) . The maj=0.005; p=0.951).Considering the SGA, AGA and LGA groups, the average levels of alpha-tocopherolfound were, respectively, 243.4, 258.0 and 239.1 µg/dL.There was no correlation between the levels of alpha-tocopherol and the Z-score ofthe weight to gestational age at birth  (n=28) had low income (<0.5 minimum wage per capita), while in thefull-term group, this result was found in only 8%  . In the Preterm newborns had a higher frequency of SGA babies, compared to those born atterm. The findings were similar to those found in the literature, in which most SGAnewborns are premature.Thus, when the child is born prematurely, it does not gain part of the weight itwould have during the third trimester, which makes it smaller in relation tofull-term newborns.A study conducted in Nepal with more than 25,000 women concluded that there is a riskof death that is 12 times higher for premature newborns. When considered prematureSGA, the risk increased to 16 times.,SGA newborns may also present lower concentrations of alpha-tocopherol in theumbilical cord serum. A study developed in Algeria identified that full-term AGAnewborns presented concentrations of alpha-tocopherol in the umbilical cord(528.5µg/dL) that were larger than the SGA newborns (201.7 µg/dL).,,,However, in a study that observed full-term infants separately from preterm infants,there were statistical differences in the level of alpha-tocopherol between the AGAand SGA full-term newborns, but not between the SGA and LGA preterm newborns,,,,,,,,However, in the present study, the serum levels of alpha-tocopherol in the umbilicalcord were similar among newborns. In relation to preterm births, the values are inagreement with those found in the literature (between 224.8 and 330.0µg/dL),Among the newborns, only nine (6.4%) presented satisfactory levels of the vitamin. Ofthese, three (2.1%) were premature. Most of the authors report high percentages ofnewborns with low levels of alpha-tocopherol at birth. A study that adopted 500µg/dL as a cutoff point found low levels of the vitamin in 77.4% of preterminfants.,,Low serum levels of alpha-tocopherol in newborns are worrisome, since they havebecome associated with the development of edemas, thrombocytosis, hemolytic anemia,and muscular degeneration, which compromises the nervous system and themyocardium.,Despite the alleged role of alpha-tocopherol in improving fetal development throughthe increase in blood supply and, consequently, of nutrients for the fetus duringpregnancy,It is worth noting that in this study, family income, parity, and type of deliveryshowed statistical differences between the groups. Only 8% (n=6) of the families ofthe full-term children were low income, against 44% (n=28) of the families in thepreterm group. Low family income can lead to decreased access to medications andmedical care, unsatisfactory housing conditions, stressful family contexts, amongother factors that may contribute to premature birth.Thus, because of the implications of growth restriction and vitamin E deficiency innewborns, it is essential to study the factors that may be leading to theseconditions and the evolution of the nutritional status of these children in thepostpartum period, especially when they come from pregnant women with a morevulnerable clinical and socioeconomic profile. Lowlevels of alpha-tocopherol serum,if persistent, can lead to vitamin E deficiency, bringing serious repercussions tothe child’s health, including changes in long-term cognitive development.It was concluded that preterm infants had higher proportions of IUGR and that,regardless of gestational age, more than 92% of the subjects had low levels ofvitamin E at birth. Nodifferences were found between full-term and preterm newborns,nor was there a correlation between intrauterine growth and alpha-tocopherollevels.


Preterm birth is the leading cause of neonatal mortality and significant health consequences to the newborn, families, and communities and tens of emotional and economic costs. Therefore, the aim of this study was to assess the magnitude of singleton preterm birth and associated factors in Shire Suhul General Hospital, Northern Ethiopia. P values ≤ 0.25 and <0.05 for each model, respectively. Institutional based cross-sectional study was conducted among systematically selected 325 postnatal mothers in Shire Suhul General Hospital, Northern Ethiopia, from January to March 2018. The data were collected through both face-to-face interview and chart review by using pretested semistructured questionnaires. SPSS version 20 was employed to enter and analyze the data. Both bivariate and multivariate logistic regression models were run to identify factors associated with singleton preterm birth at the level of The magnitude of singleton preterm birth in Suhul Hospital was 16.9%. Smoking cigarette/drinking alcohol during pregnancy , previous abortion , hemoglobin level < 11gm/dl , visible physical neonatal congenital anomaly  , and history of giving low birth weight baby  were the factors statistically associated with singleton preterm birth. The magnitude of preterm birth in this study was higher than the average prevalence of preterm birth reported in Ethiopia. Smoking cigarette/drinking alcohol during pregnancy, mothers who had previous abortion, low maternal hemoglobin level, presence of visible physical congenital anomalies of newborn baby, and history of bearing low birth weight baby were found to have statistically significant association with singleton preterm birth. Supplement of daily iron with folic acid  for all pregnant mothers with good adherence monitoring and giving attention to preconceptional health care service to avoid any cigarette smoking/alcohol drinking and risk detection were set as recommendations. The World Health Organization (WHO) defines preterm birth as a baby born too early or before 37 complete weeks of gestation from the first day of the last normal menstrual period (LNMP). Birth too soon is categorized as extremely preterm (less than 28 weeks), very preterm (28-32 weeks), and moderate to late preterm (32weeks to 36 weeks and 6 days). Preterm birth may happen spontaneously or is initiated by clinicians for different medical or nonmedical reasons and mothers deliver either single or multiple neonates. Globally, around 1 million children die each year due to complications of preterm birth and 60% of them occur in Africa and South Asia. Generally, the average rate of preterm birth in lower income countries and higher income countries is 12% and 9%, respectively . Similarly, mothers who had a history of abortion were nearly 2.4 times more likely to give preterm baby than their counterparts .Mothers whose most recent hemoglobin level was <11 gm/dl were 2.4 times more risky for preterm birth as compared to those whose hemoglobin level was ≥ 11gm/dl . Finally mothers who gave neonates with physical congenital defect and who had history of delivering low birth weight baby including the most recent birth were statistically significant with singleton premature birth compared to their counterparts  and , respectively  see .This study revealed that the prevalence of preterm birth was 16.9%. This finding is in line with those studies conducted in India 18.01% , NigeriaThis finding is higher than the average rate of preterm birth in lower income countries reported by WHO 12% , Brazil On the other side, the magnitude of preterm birth in this study was much lower than the study carried out in India 25.6% , IndonesMothers who smoked cigarette/drank alcohol during the most recent pregnancy experienced preterm birth more than those who never smoked/drank . This finding was consistent with that of the study conducted in China, Australia, and Jimma –21. ThisMothers whose most recent hemoglobin levels <11gm/dl were nearly 2.5 times more likely to experience preterm birth compared to those ≥11gm/dl . This figure is in line with WHO 2013 report and the studies carried out in India, Indonesia, Malawi, and Debre Markos , 30, 32.Visible physical neonatal congenital anomalies in the most recent baby increased odds of the preterm birth occurrence compared to normal babies with . This finding was consistent with that of the study conducted in the United States of America, Palestine, and Jimma , 18, 19.The study was conducted with a small sample size, only in one institution, and used maternal charts as additional data source which could result in overreporting and difficulty in inferring the entire society. Additionally, we failed to assess hypertension disorders during pregnancy separately as preeclampsia, eclampsia, gestational hypertension, and superimposed preeclampsia. Finally, the study design was cross-sectional, which did not show the causality of the limitations of this study.The magnitude of preterm birth in this study was higher than the average prevalence of preterm birth reported in Ethiopia. Substance intake during pregnancy, previous abortion, low maternal hemoglobin level, the presence of visible physical congenital anomalies of newborn baby, and history of bearing low birth weight baby had statistically significant association with preterm birth. Supplement of daily iron with folic acid  for all pregnant mothers with good adherence monitoring and giving attention to preconceptional health care service to avoid cigarette/alcohol intake, and risk detection were set as recommendations.


Spontaneous vaginal birth rates are decreasing worldwide, while cesarean delivery, instrumental births, and medical birth interventions are increasing. Emerging evidence suggests that birth interventions may have an effect on children's health. Therefore, the aim of our study was to examine the association between operative and medical birth interventions on the child's health during the first 28 days and up to 5 years of age.In New South Wales , population‐linked data sets were analyzed, including data on maternal characteristics, child characteristics, mode of birth, interventions during labor and birth, and adverse health outcomes of the children  registered with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification codes. Logistic regression analyses were performed for each adverse health outcome.CI 2.26‐3.07).Our analyses included 491 590 women and their children; of those 38% experienced a spontaneous vaginal birth. Infants who experienced an instrumental birth after induction or augmentation had the highest risk of jaundice, adjusted odds ratio (aOR) 2.75  compared with spontaneous vaginal birth. Children born by cesarean delivery were particularly at statistically significantly increased risk for infections, eczema, and metabolic disorder, compared with spontaneous vaginal birth. Children born by emergency cesarean delivery showed the highest association for metabolic disorder, aOR 2.63 (95% Children born by spontaneous vaginal birth had fewer short‐ and longer‐term health problems, compared with those born after birth interventions. Children's health was followed until August 31, 2013. The NSW Centre for Health Record Linkage utilized probabilistic data linkage techniques to merge data of the following data sets: Record Linkage from the Perinatal Data Collection (PDC), Admitted Patient Data Collection, Register of Congenital Conditions, NSW Registry of Birth Deaths and Marriages, the Australian Bureau of Statistics—Socio‐Economic Indexes for Areas. Probabilistic record linkage software assigns a “linkage weight” to pairs of records.The study was approved by the Ethics Committee of the NSW Population and Health Services Research Committee (HREC/10/CIPHS/96). The ethics privacy statement outlines that consent is waived due to the size of the data set, retrospective nature of the data, and the inherent difficulties in obtaining consent.2.1Data were routinely collected from women who gave birth or had subsequent births in either a public or private hospital in NSW, Australia. Data of nulliparous and multiparous women were selected if they were low‐risk pregnant women according to the guideline of the National Institute for Health and Care Excellence on intrapartum care and in alignment with methodology previously utilized on this and other linked data sets.Women or children with missing data on either mode of birth, maternal age, parity, gestational age, or birthweight were also excluded from the analyses since these variables have a potential effect on children's health. If missing data on other variables occurred, that is, country of birth, socioeconomic status, and infant gender, these variables were indicated as system missing in the linked data file and subsequently excluded from the logistic regression models.2.2Mode of birth and birth interventions were collected from the PDC file and included: spontaneous vaginal birth, instrumental birth, elective cesarean delivery, and an emergency cesarean . Medical birth interventions included induction or augmentation of labor with oxytocin, prostaglandin, and/or artificial rupture of membranes.The short‐term follow‐up data of infants during the first 28 days and of children up to 5 years of age included admissions to public and private hospitals located in NSW (Admitted Patient Data Collection file). The children were followed from the date of birth until their fifth birthday to identify any adverse health outcomes which occurred during this time period. The classifying diagnoses and reasons with accompanying hospital visit dates were registered with ICD‐10‐AM‐codes. Short‐term adverse health outcomes included jaundice, feeding problems, and hypothermia and often are part of the adaptation of the infant to being outside the uterus.Potential confounders of either women or children characteristics were selected from several data files. Women's characteristics were extracted from the PDC and NSW Registry of Birth Deaths and Marriages files and included, for example, age and country of birth. From the Socio‐Economic Indexes for Areas file, the socioeconomic status of women were collected and were based on area indices of income and education using women's postal codes and defined as low (10‐30 percentiles), medium (40‐60 percentiles) or high (≥70 percentiles). Pharmacological pain medication during labor and birth , and anesthesia  were extracted from the PDC file.Children's characteristics were extracted from the PDC and Admitted Patient Data Collection files and included gender, gestational age, birthweight, small‐for‐gestational age, large‐for‐gestational age, and birth trauma .2.3A retrospective analysis of prospectively collected linked data was performed. Baseline characteristics of the women and children were reported using descriptive statistics. Statistical differences in baseline characteristics in women and children in the different mode of birth and birth interventions groupings  were calculated with chi‐square tests.P‐value of .01 was defined as significant and all statistical analyses were performed with SPSS Statistics 23.0 .Univariate and multivariate logistic regression analyses were performed to examine the association between the exposure variable and each child outcome. Spontaneous vaginal birth without induction or augmentation of labor was used as the reference group. The logistic regression models were adjusted for maternal characteristics , birth characteristics (pain medication during birth), and child characteristics . Crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI) were reported. For all analyses, a 3The total population linked data set contained the antenatal, birth, and postnatal details of 669 880 women and 1 097 762 births which occurred in public or private hospitals during the study period 2000‐2008 with a follow‐up until age 5 years. A total 548 815 births (50%) were excluded due to medical or obstetric risk factors  or substance abuse in pregnancy . We excluded 54 254 (4.9%) children with congenital abnormalities. After applying all other exclusion criteria, mortality was recorded for 1638 (0.1%) children during the study period. There were 653 stillbirths, 353 cases of neonatal mortality, and 632 of childhood mortality. The risk of neonatal mortality was similar across the different mode of births. Finally, 1465 cases were excluded due to missing data on either maternal characteristics  or child characteristics . The final study cohort consisted of 491 590 healthy pregnant women and their children.P ≤ .001, Table The majority of the women were Australian born (69%) and had a mean age of 29 (SD 4) years. Fifty‐five percent of the women were nulliparous. About 38% had a spontaneous vaginal birth, 28% had a vaginal birth with induction or augmentation, 4% had an instrumental birth without induction or augmentation, and 8% had an instrumental birth with induction or augmentation. Eleven percent of these women had an elective cesarean delivery, 4% had an emergency cesarean, and 7% had an emergency cesarean delivery after induction or augmentation of labor Table . Overall3.1P = .07). Infants born by instrumental vaginal birth after induction or augmentation showed the highest association of jaundice . Significantly higher odds of hypothermia were observed for infants born by all the specified cesarean groups compared with those born by spontaneous vaginal delivery . Compared with children born by spontaneous vaginal birth, children born by cesarean delivery had higher odds of longer‐term adverse health outcomes. Birth by elective cesarean delivery aOR 2.49 (95% CI 2.19‐2.82), an emergency cesarean aOR 2.63 (95% CI 2.26‐3.07), and emergency cesarean delivery after induction aOR 2.41 (95% CI 2.11‐2.76) was associated with increased odds of metabolic disorder.Diagnosed respiratory infections had the highest prevalence of any of the medical conditions during the 5‐year follow‐up period, 14%. The lowest prevalence was observed for gastrointestinal disorders, 0.5%. Other bacterial infections, sepsis, otitis, cystitis, or urethritis, were reported in 8% of the children in the study. There was no evidence to suggest an association between mode of birth and the odds of asthma. Metabolic disorder was reported in 1% of children and 3% were diagnosed with eczema. Compared with children born after spontaneous vaginal birth without induction or augmentation, all other groups had higher odds of respiratory infections, metabolic disorder, and eczema  or vaginal birth (n = 21) and found a higher global measure of DNA methylation if the infant was born by cesarean delivery. While there was a nonsignificant difference between vaginal birth and cesarean delivery at 3‐5 days postpartum, the pattern did not alter in the infants born vaginally but significantly decreased in infants born by cesarean delivery.The EPIIC hypothesis postulated by some of the authors in this paper, proposes that nonphysiological interventions during the intrapartum period, and specifically the use of synthetic oxytocin, epidural analgesia, and cesarean delivery, may interrupt the normal stress of being born.An alternative theory, the Extended Hygiene Hypothesis suggests that in utero, during a vaginal birth, and following skin‐to‐skin contact and breastfeeding, the infant needs to gather a community of microbes that come from the mother and the surrounding environment.Despite this, there is a global awareness that cesarean delivery rates are too high. Currently, the emphasis is on labor induction to address this issue, as in, for example, a recently reported randomized controlled trial on routine induction of labor at 39 weeks in nulliparous women.Our study had several strengths and limitations. To our knowledge, this is the first study that has provided an overview of associations between all possible birth interventions and a wide range of adverse child health outcomes within a large population of healthy pregnant women and their children. In our analyses, we adjusted for a range of confounders, including maternal characteristics, birth characteristics, and child characteristics. However, our associations could still be affected by unmeasured confounding, such as maternal body mass index, antibiotic use during pregnancy or administered during childhood until the age of 5, breast or artificial feeding, paternal characteristics, and familial environmental and genetic factors. Moreover, we were unable to control for confounding by indication since the underlying reasons for the provided medical and operative birth interventions were unknown.Further research is required to confirm or refute the findings from this study. Research ideally would include other population‐based data registries, including a longer follow‐up period for a wider range of adverse child health outcomes, particularly those that are found more commonly beyond 5 years of age . More research is also needed to explain some of the potential mechanisms at play, including epigenetic and microbiome research.By analyzing linked population data, we obtained insight into the association of medical and operative birth interventions and short‐ and longer‐term child health outcomes. These results support the “Too little too late, too much too soon debate” in maternal care, in which Miller et al5Children born by spontaneous vaginal birth had fewer short‐ and longer‐term health problems, compared with those born after birth interventions. This suggests that when examining labor interventions, researchers need to pay attention to use of exogenous oxytocin and to instrumental and operative birth, and that follow‐up should be continued into the longer term. Click here for additional data file.


Over 12% of women in the United States have reduced fertility and/or fecundity. Environmental factors, such as temperature, and socioeconomic factors have been implicated in reducing female fecundity. The purpose of this study is to investigate the effect of environmental factors coupled with socioeconomic factors on birth rate at the country-level. We use birth rate as a proxy for female fecundity. This will enable us to identify the most important factors affecting female fecundity.182 countries, we constructed a regression model of the effects of environmental and socioeconomic factors on birth rate at the country-level. Our model assesses the role of temperature, Gross Domestic Product (GDP) per capita, fine air particulate matter (PM 2.5), and prevalence of male and female Body Mass Index (BMI) > = 25 (age-standardized) on birth rate per country. Because many of these factors are inter-dependent, we include all possible two-way interaction terms to assess the role of individual factors and interactions between multiple factors in the model.Using country-specific data from In the full regression model, we found that GDP per capita along with 5 interaction terms were significant after adjusting for multiple testing. Female BMI was only nominally significant. GDP per capita was independently associated with birth rate . Prevalence of BMI > = 25 age-standardized in males and females were also significant when interacting with air pollution or GDP on female fecundity (birth rate). Temperature did not affect birth rate either independently or as an interaction unless BMI was removed from the model.A country’s economic wealth was the most significant factor in predicting birth rate in a statistical model that includes environmental and socioeconomic variables. This is important for future studies investigating environmental factors involved in increasing or decreasing female fecundity. This reveals an incomplete understanding regarding the relationship between seasonal temperature variation and female fertility/fecundity later in life.Over 12% of women in the United States have reduced fertility and/or fecundity . Other f in life –9. This  in life , New Zea in life  and NYC  in life  and RomaOther factors are known to affect female fecundity and birth rate. High socioeconomic status (SES), which is related to income, is inversely correlated with fertility and birth rate , 14. HigThe purpose of this study is to investigate the relationship between environmental factors and socioeconomic factors on female fecundity as measured using birth rate. We aim to measure this at the country-level to simultaneously assess the effects of multiple socioeconomic and environmental factors from around the world on female fecundity . We will also include interactions between the various inter-dependent factors to reveal the strongest global determinants in female fecundity.We assembled a country-specific dataset on birth rate and other socioeconomic and environmental factors using data integrated from publically available data sources. For female fecundity, we used country-specific birth rate per 1,000 population as a proxy. To obtain birth rate data, we used data collected and maintained by the Central Intelligence Agency (CIA) . For envTable 1 to illustrate the variance across datasets. Determining the number of independent countries in the world is complex. There are 193 countries that are recognized as such by the United Nations (UN) with 2 countries–Vatican City and Palestine–having ‘permanent observer’ status at the UN [195 recognized independent countries [We included the total number of countries included in each dataset in t the UN . In addit the UN . Accordiountries . We usedountries .S1 Dataset). This dataset captures 93.3% (182/195) of the independent states from around the world. Thirteen recognized independent countries by the CIA are missing from these analysis [Clearly, some datasets contained many more country names (sometimes including non-independent states), especially the birth rate dataset and the Gross Domestic Product (GDP) dataset with 226 and 264 countries respectively. The GDP dataset also included assessments of regions that were given their own country codes, but were in fact groupings of other countries already included in the dataset. Therefore, we decided to integrate these datasets together, understanding that we would have at most only 185 countries captured in the integrated dataset because the air pollution dataset did not contain data from the all 195 independent countries. Whenever possible, we utilized the ISO Alpha-3 standard country codes to map across datasets. In some cases, this was not possible and we used the country names to map across datasets. However, different datasets used different nomenclatures for country-names. The birth rate and temperature datasets contained country names without corresponding ISO Alpha-3 codes. All records were manually reviewed to ensure that harmonization was accurate. Overall, our dataset contained information on six variables: birth rate, average air pollution, and average country temperature, GDP from 2016, BMI for males and BMI for females from 182 countries , including environmental factors: temperature and air pollution, socio-economic: GDP per capita and lifestyle: prevalence of BMI> = 25 (age-standardized) for males and females per country. We also included in this model pairwise interaction terms due to the inherent interdependency of these variables. A total of 16 terms were included in the model, including the intercept term, 5 covariates, and 10 interaction terms. We report the raw p-values, and also the Bonferroni-adjusted p-values (adjusted for 16 tests).We also constructed a linear regression model excluding the two BMI factors. We again modeled birth rate as the outcome variable, and the following set of dependent variables: annual temperature, GDP, and fine air particulates (PM 2.5). In addition three pairwise interaction terms were included in the model . This model is the same as the one described in section 2.2 except that we removed the male and female BMI terms and their corresponding interaction terms. Interestingly, female BMI exhibited a different pattern. In countries with lower fecundity , the prevalence of females with BMI> = 25 (age-standardized) was positively correlated with fecundity. However, when a country’s fecundity passed a certain threshold (around 20) then the prevalence of females with BMI > = 25 (age-standardized) became inversely correlated  had higher air pollution and were warmer overall . This is an important consideration for analyses that demonstrate the effect of temperature on fecundity and was part of our motivation to include all factors into our global analysis of factors affecting female fecundity.We investigated the relationship between fecundity (birth rate) and two environmental factors–temperature and air pollution–and also socio-economic factors–GDP, male and female BMI. We found that the prevalence of males with BMI > = 25 (age-standardized) was inversely correlated with fecundity across all countries . Asia, South America and Africa have high temperatures and in general high fecundity (birth rate). However, these countries are also poorer (low GDP) and are exposed to higher air pollution levels . These countries also have lower prevalence of BMI > = 25 (age-standardized) for females and males. , which could be driven by the type of work they engage in .The global variation in birth rate and its correlated factors can also be observed from the maps , positively correlated with temperature , slightly positively correlated with air pollution  and negatively correlated with male and female BMI . Interestingly, male BMI was more strongly correlated with birth rate then female BMI. However, this is likely due to the interaction between GDP, pollution and BMI among males . Hence our regression model (described in section 3.2) includes additional interaction terms to determine the most important factors.Many of the factors that are involved in fecundity are also correlated or anti-correlated with each other. Therefore, regression models that include interaction terms are important to capture this source of variation. Our comprehensive model of environmental and socioeconomic factors and their role on female fecundity (birth rate) included average temperature per country from 1961–1990, GDP per capita, average air pollution (PM 2.5) and prevalence of BMI > = 25 (age-standardized) for males and females. We also included 10 pairwise interaction terms in the model. We report nominal p-values and also Bonferroni adjusted p-values (adjusting for 16 tests–one test for each factor included in the model). The model results are shown in Table 2). After adjusting for multiple testing, GDP per capita was still significantly negatively correlated with birth rate (p<0.001). Five interaction terms were also significant.Both female BMI and GDP per capita were nominally significant  in the model for birth rate. Although prevalence of female BMI > = 25 was not significant after adjusting for multiple testing .Significant interaction terms included an interaction between male and female BMI > = 25 (age-standardized); GDP and BMI ; and air pollution and BMI. The air pollution (PM 2.5) term was not associated with birth rate in the full model , but only interactions between air pollution and BMI. Overall, prevalence of female BMI > = 25 (age-standardized) was nominally significant in determining birth rate independently and also via indirect mechanisms ; whereas, prevalence of male BMI > = 25 (age-standardized) was not independently associated with birth rate. This indicates that the strong anti-correlation between prevalence of male BMI > = 25 (age-standardized) and female fecundity is through correlation with other variables . Temperature and the interaction term for temperature and GDP were significant. Importantly, GDP was not significant in this model, but only the interaction between GDP and temperature.The model result for our linear regression model constructed without the two BMI terms is shown in 2.38 X 10−4 (Table 3). None of the air pollution terms in this model were significant.Without BMI in the model, temperature and the interaction of temperature and GDP were significantly associated with birth rate. Importantly temperature was positive associated with fecundity . The interaction between temperature and GDP was significant with adjusted p-value = Table 2). Air pollution (PM 2.5) and BMI were also important contributory factors (as interaction terms) in predicting fecundity (birth rate). However, temperature did not affect birth rate either independently or as an interaction unless the BMI terms were removed from the model .In this study, we constructed a country-level model of factors involved in fecundity (birth rate) using data from 182 countries across the world. A high-level global analysis was performed to look at factors correlated with birth rate on the global scale to identify the most important factors in female fecundity or birth rate. We modeled interactions between multiple factors because of the high-degree of interdependency among factors. Overall, we found that a country’s economic wealth  was the most significant in predicting fecundity in a full model that includes male and female BMI (Table 2), but was significant in the model without BMI (Table 3). Studies in insects have shown that temperature and the size of the female were both important in determining fecundity indicating that temperature was not the only variable of importance [Many studies have pointed to the role of temperature on female fecundity. Some studies point to an in-direct mechanism, through impairment of the male’s fertility. Spermatogenesis in males is impaired when temperature increases resulting in impaired fertility . This suportance . Studiesportance  indicati In the model without BMI, temperature was a significant factor even after adjusting for multiple testing (p = 0.009). Temperature is highly correlated with many other variables that are important in fecundity, which was the rationale for constructing this global model. In addition, the significant interaction terms point to the importance of capturing the inherent inter-dependency among a number of these variables  in  demonstrate the importance of other factors  and their interactions with environmental factors (BMI and air pollution) on female fertility and birth rate on a global scale. This is important because many of these factors correlate with temperature indicating that earlier work seeking to demonstrate a relationship between perinatal exposure of females to high temperatures decreases female fertility later in life may be capturing an environmental exposure that is coupled with temperature, but not temperature itself [Significant factors in the full model . However, in a full model that includes male and female BMI, the GDP of the country was the most significant variable along with interactions between air pollution, BMI and GDP (Table 2). Some of these findings could be related to our inability to assess the pregnancy loss rate across countries.Importantly, our analysis focuses on birth rate, which is a measure of fecundity. We are not able to assess the number of pregnancies lost in various countries and how variance in pregnancy loss  affects a country’s birth rate. Pregnancy loss is very difficult to capture in many countries due to lack of reporting. Even outcomes such as preterm birth and still birth (which are easier to capture then pregnancy loss) are still difficult to capture globally . This isThere are several limitations to this study. First, we perform a global analysis investigating each country equally. However, not all countries are the same size. We use statistics such as birth rate per 1,000 population and GDP per capita, which should help to address some of these issues. However, there are some fundamental differences between large and small countries that are not fully addressed by our methods. Therefore, this remains a limitation of our approach. We only investigated variables that have been reported to impact female fecundity and that had data available at the country-level for the majority of countries included in our study. Therefore, not every factor implicated in female fecundity was included in our model. The major factors  were included.not include BMI pointing to other mechanisms underlying the temperature to fecundity relationship.In conclusion, we constructed a global model of female fecundity using data from 182 countries. Our model captured known environmental and socioeconomic factors that have been implicated in reducing or increasing female fecundity. We included at the country-level measures of average annual temperature, average air pollution, GDP per capita and prevalence of BMI > = 25 for males and females (age-standardized). We also included interaction terms to capture the inherent inter-dependency among many of these factors. We found that GDP per capita was independently associated with fecundity (birth rate). In addition, air pollution (PM 2.5), and BMI were important contributory factors as interaction terms. BMI was found in significant interactions with GDP and air pollution. Annual temperature was only significant in the model that did This study only includes publically available data. No patient-level data was used only aggregate statistics therefore no consent was required to conduct this study.S1 DatasetAll data included in the global fertility model for 182 countries is provided in this file.(CSV)Click here for additional data file.


Background: Infants are currently stabilized at birth with initial low FiO2 which increases the risk of hypoxia and suppression of breathing in the first minutes after birth. We hypothesized that initiating stabilization at birth with a high O2 concentration, followed by titration, would improve breathing effort when compared to a low O2 concentration, followed by titration.Methods: In a bi-center randomized controlled trial, infants <30 weeks gestation were stabilized at birth with an initial O2 concentration of 30 or 100%, followed by oxygen titration. Primary outcome was minute volume of spontaneous breathing. We also assessed tidal volumes, mean inspiratory flow rate (MIFR) and respiratory rate with a respiratory function monitor in the first 5 min after birth, and evaluated the duration of mask ventilation in the first 10 min after birth. Pulse oximetry was used to measure heart rate and SpO2 values in the first 10 min. Hypoxemia was defined as SpO2 < 25th percentile and hyperoxemia as SpO2 >95%. 8-iso-prostaglandin F2α (8iPGF2α) was measured to assess oxidative stress in cord blood and 1 and 24 h after birth.Results: Fifty-two infants were randomized and recordings were obtained in 44 infants . Minute volumes were significantly higher in the 100% O2-group (146.34 ± 112.68 mL/kg/min) compared to the 30% O2-group (74.43 ± 52.19 mL/kg/min), p = 0.014. Tidal volumes and MIFR were significantly higher in the 100% O2-group, while the duration of mask ventilation given was significantly shorter. Oxygenation in the first 5 min after birth was significantly higher in infants in the 100% O2-group [85 (64–93)%] compared to the 30% O2-group [58 (46–67)%], p < 0.001. The duration of hypoxemia was significantly shorter in the 100% O2-group, while the duration of hyperoxemia was not different between groups. There was no difference in oxidative stress marker 8iPGF2α between the groups.Conclusion: Initiating stabilization of preterm infants at birth with 100% O2 led to higher breathing effort, improved oxygenation, and a shorter duration of mask ventilation as compared to 30% O2, without increasing the risk for hyperoxia or oxidative stress.Clinical Trial Registration: This study was registered in www.trialregister.nl, with registration number NTR6878. In the fetus, spontaneous breathing movements enable small volumes of liquid to move in and out of the airways. During apnea, the glottis is predominantly closed, restraining the efflux of lung liquid which is essential for normal lung growth and development by maintaining the lung in a distended state –3. AfterWhile most preterm infants need respiratory support at birth because of their low muscle strength and structural and biochemical immaturity of the lung, support is mainly provided non-invasively instead of invasively to reduce the risk of lung and brain injury. However, successful application of non-invasive respiratory support requires an open upper airway in order for air to enter the trachea and aerate the lung. A closed glottis during apnea hampers the effectiveness of non-invasively applied positive pressure ventilation. This has been demonstrated by both animal  and humaOne of the factors influencing breathing activity is oxygenation. Hypoxia is a potent inhibitor of fetal breathing movements before birth and this inhibitory effect persists for days-weeks after birth . As hypo2) is required because the surface area for gas exchange is suboptimal. However, the 2015 versions of the international resuscitation guidelines recommend that resuscitation of very and extremely preterm infants should commence with a low FiO2 in order to reduce the risk of hyperoxia  at 5 min after birth is associated with a higher risk of mortality and the development of intraventricular hemorrhage . We hypothesized that initiating resuscitation of preterm infants at birth with a high FiO2 will increase breathing effort.We aimed to evaluate the effect of reducing hypoxemia on breathing effort of preterm infants at birth by using an initial high vs. low FiO0/7 and 296/7 weeks were included. Infants with congenital abnormalities or conditions that might have an adverse effect on breathing effort or ventilation were excluded. Infants were randomized for resuscitation with an initial FiO2 of 0.3 (30% O2-group) or 1.0 (100% O2-group) using Castor EDC , an electronic data capture system. Allocation was stratified by gestational age (240/7-266/7 weeks and 270/7-296/7 weeks), using variable block sizes  and the Amsterdam University Medical Centre (Amsterdam UMC), both located in the Netherlands. Preterm infants with a gestational age between 242 setting, FiO2 was titrated following SpO2 target ranges recommended by our local guidelines on stabilization after birth, which are based on the target ranges described by Dawson et al.  or a Giraffe Star System . Respiratory function monitoring (RFM) data were recorded during stabilization in the first 5 min after birth to assess respiratory effort, and RFM data were collected of the first 10 min after birth to assess duration of positive pressure ventilation and oxygenation. Blinding of data analysis was performed to increase validity of outcomes, without interfering with clinical practice by blinding the oxygen blender or changing the caregiver responsible for oxygen titration.After the initial FiOn et al. . When Spprotocol . At birt2 and heart rate were measured using either a Masimo SET pulse oximeter  or NellcorTM pulse oximeter ; the probe was placed around the right wrist or hand of the infant. Data on oxygenation and heart rates were extracted using a Philips Intellivue MP30 monitor . The FiO2 was measured using a portable oxygen analyzer AX300-I . The signals were digitized at 200 Hz using the NewLifeBox-R physiological recording system  and all signals were recorded by the NewLifeBox Neo-RSD computer system  supported by Polybench physiological software . Pulmochart software  was used to analyze primary and secondary outcomes.The RFM was used to measure inflation pressures, flow and tidal volumes. This was used to calculate minute volume, mean inspiratory flow rate (MIFR), and the total ventilation time. Gas flow in and out of the facemask or endotracheal tube was measured using a small variable resistance anemometer, which also measured airway pressure . The flow signal was integrated to provide inspired and expired tidal volumes in real time, with the difference in volume providing the degree of leak from either the facemask or endotracheal tube. SpO2 values in the first 10 min and determining the amount of time that infants were considered to be hypoxemic  or hypeThe level of oxidative stress was assessed by measuring the level of 8-iso-prostaglandin F2α (8iPGF2α) at birth by using cord blood, and 1 and 24 h after birth using blood samples of the infant. A detailed description of sampling and the rationale for this marker are presented in the study protocol . The sam2 was switched from 0.21 to 1.0, in the first minute after FiO2 was increased (from 134 to 240 mL/kg/min). However, since we investigate a FiO2 of 0.3 instead of 0.21 in the lower oxygen arm, we expected half of the effect (40% relative increase) in respiratory drive than reported by van Vonderen et al.  and time were taken in consideration. Other study parameters and basic characteristics were explored to test for differences between the study groups. Demographical data and data on clinical outcomes are shown for all infants who were randomized, including infants for whom the primary or secondary outcomes could not be assessed. In addition, these data are also shown separately for the group of infants in whom primary and secondary outcomes could be assessed. Data are presented as mean ± SD for parametric data, median (IQR) for non-parametric data and n (%) for categorical data. P < 0.05 were considered significant.Statistical analysis was performed with SPSS software version 23.0 . Although allocation was stratified by gestational age, outcomes are analyzed and presented for both treatment groups as a whole, because of the relatively small sample size. Differences in parameters of breathing effort in the first 5 min after birth between the study groups were tested with a Student's 2. Six of these infants were excluded from analysis for outcomes on breathing effort and oxygenation due to failure to record physiological parameters with the RFM and pulse oximetry. One infant was excluded from the complete analysis because no respiratory support was needed and one infant because deferred consent was not obtained  vs. FiO2 0.48 (0.33–0.53), p < 0.001), as was the average FiO2 in the first 10 min after birth (FiO2 0.69 (0.41–0.88) vs. FiO2 0.45 (0.33–0.64), p = 0.020). Over the first 5 min after birth, total exposure to O2 (measured as AUC of FiO2 vs. time) was significantly higher in the 100% O2-group (AUC0−5 559.2 (346.6–745.2)%·min vs. 346.3 (260.9–450.9)%·min, p = 0.002, but when assessed over the first 10 min after birth it was not different between groups (AUC0−10 1011.3 (784.0–1191.7)%·min vs. 844.1 (741.0–1006.7)%·min, p = 0.178). This was because FiO2 was rapidly reduced in the 100% O2-group, whereas at the same time FiO2 levels in the 30% O2-group were increasing  compared with 30% . Although there was a trend toward a higher incidence of breaths with a tidal volume >4 mL/kg , the incidence of recruitment breaths (>8 mL/kg) did not differ between study groups  s vs. 108.3 (46.4–205.1) s, p = 0.021]. While Apgar scores at 1 min after birth were not significantly different between the study groups , infants in the 100% O2-group showed significantly higher Apgar score at 5 min after birth , as a result of higher scores on breathing and tone.The duration of mask ventilation was significantly shorter in the 100% O2-group . In addition, there was a trend toward a higher heart rate in the 100% O2-group . In addition, the duration of hypoxemia [SpO2 < 25th percentile of reference ranges described by Dawson et al. (2-group (2 > 95%) did not significantly differ between the study groups.The average oxygen saturation in the first 5 min after birth was significantly higher in infants in the 100% OO2-group . Infantse groups . A SpO2 n et al. ] was sig(2-group . HoweverCord blood from 32/44 (73%) infants could be obtained to analyze the level of 8iPGF2α at baseline. At 1 h after birth, blood samples of a total of 27/44 (61%) infants were obtained and analyzed, and at 24 h after birth, again blood samples of 25/44 (57%) infants were obtained and analyzed. The level of 8iPGF2α did not differ between the study groups over time, neither did the level of 8iPGF2α differ at the specific time points analyzed .2-group. There were no differences between the study groups with regard to intubation, incidence of IVH ≥ grade III or death before hospital discharge  was increased over the first 5 min, it was less during the second 5 min in the 100% O2-group, resulting in no difference between groups after 10 min. The improved oxygenation and breathing effort were also reflected by a shorter duration of mask ventilation in the 100% O2-group. These results indicate that initiating stabilization at birth with a high FiO2 followed by careful titration to avoid hyperoxia, is a better option for stimulating breathing and decreasing the need for positive pressure ventilation in very and extremely preterm infants.In this bi-center, single blinded, randomized controlled trial, the effect of initiating resuscitation with an FiO2 during stabilization of preterm infants at birth, none of these trials have evaluated breathing effort  and shorter periods of hypoxemia than infants in the 30% O2-group. Apart from the initial FiO2, our intent was to manage all infants with the same respiratory support strategy, but the 100% O2-group required less intermittent positive pressure ventilation than the 30% O2-group. As such, we consider that the higher initial partial pressure gradient for oxygen is likely to be the major contributor to the improved oxygenation in the 100% O2-group. While the total O2 exposure (AUC of FiO2 vs. time) was increased over the first 5 min after birth, it was not different between groups when measured over the first 10 min after birth. This is because the FiO2 was reduced between 2 and 6 min after birth in the 100% O2 group, whereas over the same time period, the FiO2 increased in the 30% O2 group (2 levels were decreasing in the 100% O2 group (between 2 and 6 min after birth) indicates that the O2 exchange capacity of the lung markedly increased over this time. This finding supports our contention that higher partial pressure gradients for oxygen  should be used initially, when the lung is partially aerated and the surface area for gas exchange is low, and that the FiO2 can be rapidly titrated down as the lung aerates and the potential for oxygen exchange increases. Indeed, as lung aeration and the increase in gas exchange surface area occurs in an exponential manner, presumably the decrease in FiO2 can follow a similar function.Infants in the 100% OO2 group . The fin2 (<0.3) results in significantly lower SpO2 values compared to a high FiO2 (>0.9) (2 titration protocols (both increasing and decreasing) between studies are likely to be a major confounding factor. FiO2 titration steps have ranged between 0.1 and 0.79, with step durations ranging between 10 s to every 5 min. There is also much heterogeneity in timepoints at which outcomes were assessed, with measurement start times ranging from at birth to 2 min after birth, whereas measurement end times ranging from 5 to 30 min after birth. Probably just as important is the prevention of hyperoxia and the tissue damage caused by increased oxygen free radicals. In our study, we found no difference in the duration of hyperoxemia or in the level of oxidative stress (assessed by measuring 8iPGF2α levels) between infants initially receiving either 30% or 100% O2. However, a previous study found that oxidative stress markers (advanced oxidative protein products AOPP and 8iPGF2α) were increased at 2 and/or 12 h after birth in infants initially receiving a high (FiO2 1.0) vs. low (FiO2 0.21) FiO2   , 20, 23,2 (>0.9) , 21, 22.O trial) . Again, 2-group .Improving oxygenation in the first 5 min after birth has gained increased attention, as it has become clear that persistent hypoxemia at >5 min after birth is associated with an increased risk of intraventricular hemorrhage and mortality . As hypo2 during resuscitation of preterm infants at birth showed no difference in clinical outcomes, including mortality, neurodevelopmental impairment and other key preterm morbidities (2 levels used for high (ranging from 0.6 to 1.0) and low (0.21–0.5) FiO2 study groups and SpO2 targets. In our study, we aimed to provide knowledge on one of the factors that could contribute to improve breathing effort at birth. It was shown that oxygen is a major contributing factor, in addition to other factors that have previously been shown to increase breathing effort, such as tactile stimulation and caffeine administration in the delivery room  or the level of 8-iso-prostaglandin F2α, measured at 1 and 24 h after birth. The results suggest that oxygenation might be an important determinant in stimulating breathing and decreasing the need for positive pressure ventilation in preterm infants at birth.In this randomized controlled trial, we have demonstrated significantly higher breathing effort when resuscitation was initiated with an OThe datasets generated for this study are available on request to the corresponding author.The ethical committees of the LUMC and Amsterdam UMC approved the study protocol. Informed parental consent was obtained antenatally when possible. In case of an emergency situation  or when obtaining antenatal consent was inappropriate , consent was asked retrospectively.JD, EL, MG, SH, and AP made substantial contributions to conception and design of the study. JD, TM, EL, EM, JH, RL AK, and AP recruited and included infants in the study and obtained data. Data was analyzed and interpreted by JD, TM, MG, AP, and SH. The first version of the manuscript was drafted by JD, AP, and SH. All authors are acknowledged for their critical revision of the manuscript and approval of the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.