Debates still surround using lipoproteins including Apo‐B in risk assessment, management, and prognosis of patients with coronary artery disease. During an acute ST‐segment elevation myocardial infarction, Apo‐B might help to achieve incremental prognostic information.We sought to determine the potential prognostic utility of calculated Apo‐B in a cohort of patients with STEMI undergoing primary PCI.A retrospective cohort study was conducted enrolling 2,259 patients with a diagnosis of acute STEMI who underwent primary PCI. Apo‐B was obtained using a valid equation based on initial lipid measurements. High Apo‐B was defined as a level of 65 or higher. Primary endpoint of the study was major adverse cardiovascular events (MACE).Mean age of the participants was 59.54 years and 77.9% of them were male. After a Median follow up of 15 (6.2) months, high Apo‐B was associated with MACE and the OR (95% CI) was 3.02 (1.07–8.47), p = .036. Odds ratios for prediction of MACE pertaining to LVEF, and smoking were 0.97 (p = .044), and 1.07 (p = .033), respectively. However, High Apo‐B was not able to predict suboptimal TIMI flow. Accordingly, the Odds ratio was 0.56 (0.17–1.87), p = 0.349. The power of High LDL‐C and Non‐HDLC for prediction of MACE were assessed in distinct models. Attained odds ratios were  and , respectively.Calculated Apo‐B appears to be a simple tool applicable for prediction of cardiovascular events in patients with STEMI superior to both Non‐HDLC and LDL‐C. ACC/AHAAmerican college of cardiology/American Heart AssociationACEI/ARBangiotensin converting enzyme inhibitor/ angiotensin receptor blockerApo‐BApo lipoprotein‐BBMIbody mass indexCABGcoronary artery bypass graftCADcoronary artery diseaseEASEuropean atherosclerosis societyESCEuropean society of cardiologyESRDend stage renal diseaseHDLhigh‐density lipoproteinIDLintermediate‐density lipoproteinLADleft anterior descending arteryLCXleft circumflex arteryLDL‐Clow‐density lipoproteinLVEFleft ventricle ejection fractionMACEmajor adverse cardiovascular eventsMImyocardial infarctionNon‐HDLCnon‐high density lipoprotein cholesterolORodds ratioPCIpercutaneous coronary interventionRCAright coronary arterySIHDstable ischemic heart diseaseSTEMIST‐segment elevation myocardial infarctionTGtriglycerideTIMIthrombolysis in myocardial infarctionVLDL‐Cvery low density lipoprotein1Timely primary PCI that restores coronary perfusion is the mainstay of STEMI management.Lipoprotein fractions such as VLDL‐C, IDL, and LDL‐C are comprised of structural proteins like Apo‐B. These pro‐atherogenic lipid particles contain one Apo‐B component. Apo‐B that is synthesized in the liver facilitates and amplifies cholesterol transfer in a cycle streaming from the liver to peripheral tissues.22.1We performed a thorough review of Tehran Heart Center (THC) registry for CAD. Patients with the diagnosis of STEMI  since March 2016 up to Juli 2019 were enrolled. We arranged a retrospective cohort design. All individuals with acute STEMI who underwent primary PCI or rescue PCI within 24 h since the onset of symptoms were included. Subjects in whom the initial presentation of MI was unclear or those with failed wire passage were excluded. All demographic characteristics, biochemical parameters, variables of clinical history, and physical examination were obtained from the database. Baseline Left ventricular Ejection fractions (LVEF) were used in the current study, which were determined at least 7 days post‐MI. Cardiac Troponin‐T was measured at baseline and 12 and 24 h following primary PCI denoting the extent of myocardial damage. In the current study, we applied the maximum level of Troponin‐T in analyses.All patients received the standard optimal guideline‐directed medical treatment in combination with angioplasty. Either an ACEI or ARB agent, an appropriate beta‐blocker, Aspirin (80 mg daily) and high‐dose statin were administered for all participants. Aldosterone receptor antagonist had been prescribed for those with an LVEF under 40% or diabetics. All patients received a P2Y12 inhibitor drug including clopidogrel and ticagrelor. Loading dose of clopidogrel and ticagrelor were 600 mg and 180 mg, respectively. Then maintenance dose of the former (75 mg once daily) and the latter (90 mg twice a day) were continued for at least 12 months, thereafter. Unfractionated heparin (70‐to 100‐unit /kg) was used routinely during primary PCI. The choice of using thrombus aspiration and/ or glycoprotein IIb‐IIIa inhibitors were optional depending on the opinion of the interventional cardiologist.2.2STEMI was diagnosed according to the fourth universal definition of myocardial infarction.TIMI flow grade is a surrogate measure of myocardial perfusion, which is detected via inspection of angiography movies. Operators had recorded TIMI flow of the coronary arteries before and after PCI. This visual classification also helps to determine apparent success of the procedure.Estimated Apo‐B was derived from an equation using serum concentrations of LDL‐C and natural logarithm of triglyceride (ApoB = −33.12 + 0.675*LDL‐C + 11.95*ln [TG]). Calculated Apo‐B with mentioned equation was first validated in a large‐scale Asian population with 73 047 participants. This formula appears to have an ample power in prediction of measured Apo‐B levels with a concordance correlation coefficient (95% CIs) = 0.936 (0.935–0.937).2.3Primary endpoint of the study was Major Averse Cardiovascular Events (MACE), which was a composite of all‐cause mortality, repeat revascularization by PCI or CABG, and non‐fatal MI. Secondary endpoints were suboptimal TIMI flow as well as components of MACE. Routine follow‐up of the patients were performed by regular  visits at THC clinics or phone calls at predetermined intervals.Ethics committee of Tehran University of Medical Sciences has approved the protocols of data collection in THC registry as well as the current study. Principles of declaration of Helsinki were also met in this research.2.4SD or median (Interquartile range) with respect to presence or absence of normal distribution. Categorical variables were reported by percentage. Kolmogorov–Smirnov Test and Shapiro–Wilk test were applied to determine the normality of distributions. We used t test and Mann–Whitney U test to compare the differences of continuous variables between two groups with and without normal distribution, respectively. Chi‐square test was used for comparison of categorical variables. Statistical significance was achieved for p values under .05 for all tests. All statistical analyses were performed via SPSS version 22.0 . We have displayed multivariable associations between Apo‐B and MACE. Multivariate regression analysis was also performed to evaluate the predictors of suboptimal post‐PCI TIMI flow. Kaplan–Meier graphs were recruited to illustrate the event‐free survival of Apo‐B subgroups.Continuous variables were shown as mean ± 3A total of 2259 participants were eligible for analysis in this study. Mean age of the study population was 59.54 ± 11.83 years and majority of the patients were male (77.9%). Mean LDL‐C and calculated Apo‐B levels were 103.82 ± 34.58 and 94.41 ± 25.32, respectively. Average of the Non‐HDLC was 120.43 ± 37.91. Mean LVEF of the population was 42.13 ± 9.2. The average time since early symptoms to arrival known as pain‐to‐door time was 545.26 ± 72.7 min. Statins and Aspirin were initiated and continued during follow‐up period in almost all patients. Table The association of Apo‐B as a continuous variable with MACE was determined via multivariate regression. The Odds ratio adjusted for age, sex, hypertension, LVEF, and TIMI flow was 1.002 (1.001–1.007), p = .047 per 10 units increment of Apo‐B. We categorized the estimated Apo‐B into four equal groups, Thereafter. Highest versus the lowest quartile (Q4 / Q1) was related to MACE with an Odds ratio of 1.12 (1.08–1.36). However, third versus first quartile (Q3 / Q1) as well as Q2/Q1 did not show a significant relationship with MACE. Corresponding Odds ratios were 1.16 (0.77–1.74) and 0.65 (0.41–1.03), respectively. These relations were also adjusted for age, sex, hypertension, LVEF, and TIMI flow.Table Non‐HDLC level greater than 100 mg/dl was not significantly associated with MACE. Multivariate logistic regression demonstrated that odds ratio of elevated Non‐HDLC was 1.80 (0.75–4.35), p = 0.191. Co‐variates in this regression analysis and related adjustments were performed in the same way as those in models for Apo‐B and high LDL‐C.Table Kaplan–Meier graphs also depicted event‐free survivals comparing high‐ and low Apo‐B groups Figure . A subgr4To date, Apo‐B 100 measurement has improved cardiovascular risk stratification in various conditions including acute coronary syndrome (ACS). However, Apo‐B assays are often costly and not readily available particularly in acute settings such as STEMI. Given this challenge, we recruited a previously introduced simple equation to calculate Apo‐B. Analyses demonstrated that increased baseline Apo‐B concentrations could predict the outcome of patients after primary PCI. On the contrary, the association of high LDL‐C and MACE was not confirmed even though a trend toward significance was observed. Besides, Non‐HDLC also did not show the ability to predict the outcomes. As the main finding, results suggest that calculated Apo‐B might have greater prognostic benefit than measured LDL‐C and Non‐HDLC after STEMI.There are few studies investigating the role of Apo‐B in early phase post‐STEMI. However relatively similar articles have been discussed here. In contrast with our results, a large‐scale cohort of ACS patients found no significant relationship between high Apo‐B and MACE over 12 months.Since measurement of Apo‐B is time consuming and not available as a routine test, we recruited an equation, which serves as a simple surrogate of this biomarker. Using only one baseline blood sample and the patient's conventional lipid profile, we are able to determine a modestly strong predictor of MACE in acute STEMI. We applied different cut‐off levels of Apo‐B to achieve considerable clinical and statistical significance because it was the first time for validation of prognostic utility of calculated Apo‐B in STEMI. Ultimately, we found that the lowest level (65 mg/dl), which is, defined as the goal of therapy in very high‐risk patientsThe potential privilege of Apo‐B over both LDL‐C and Non‐HDLC origins from the concept of mismatch between LDL‐C concentration and LDL‐C particle number. A meta‐analysis of 11 clinical trials of statin treatment among 17 035 patients illustrated a substantial discrepancy between gained population percentiles of LDL‐C, Non‐HDLC and Apo‐B targets.A recent case–control study with 10‐year follow‐up revealed that increased Apo‐B concentrations (> 100 mg/dl) were associated with first STEMI in asymptomatic controls. However, they declared that neither Apo‐B nor other plasma lipids did not predict MACE in patients with STEMI. These results are relatively in discordance with our findings.We found no reports about the correlation of high Apo‐B and sub‐optimal reperfusion, which is in agreement with the present analysis.The stability, synthesis, and transportation of lipoproteins are regulated via various Apo lipoprotein components. Atherogenic lipoproteins such as very low‐density lipoproteins (VLDL), intermediate‐density lipoproteins (IDL), lipoprotein (a), and LDL‐C contain one molecule of Apo‐B. Thus, serum Apo‐B represents for total number of atherogenic particles and TG‐rich lipoprotein remnants. The higher serum Apo‐B concentration, the greater circulating cholesterol content and ultimately higher risk of atherosclerotic plaque deposition.Increased TG‐rich lipoproteins, low HDL‐C and usually normal LDL‐C levels characterize lipid profile of subjects with metabolic syndrome and insulin resistance. However, frequency of atherogenic particles including small dense LDL‐C increases that tend to get oxidized.4.1Several limitations might be considered in the present research. First, we have performed a retrospective cohort study, which encompasses known inherent biases. Second, phone call follow‐up might potentially affect the reliability of event records. Pain‐to‐door time was relatively prolonged in this cohort, which elevates the underlying risk and diminishes the myocardial salvage for both groups. Third, we did not have repeated measurements of lipid markers in order to determine the efficacy of statin treatment. Fourth, despite finding a significant relationship between high Apo‐B and poor STEMI outcome, we cannot strongly extrapolate the results. This caution should be considered due to several reasons including relatively broad confidence intervals, and lacking patients with other types of CAD.5The present study helped to validate the efficacy of a simple equation for estimation of Apo‐B in patients with STEMI. Clinical implications of calculated Apo‐B was shown as evidenced for measured Apo‐B previously. High Apo‐B predicted subsequent MACE following primary PCI whereas, elevated Non‐HDLC and LDL‐C failed to have a significant association.There was no relationship with any institution as well as no contracts related to industry.Hamidreza Poorhosseini and Saeed Ghodsi presented the core concept of the research. Alireza Amirzadegan, Yaser Jenab, Hassan Aghajani, Mojtaba Salarifar, Mohammad Alidoosti, Ali‐Mohammad Haji‐Zeinali performed treatment of the patients including primary PCI. Mojtaba Salarifar and Yaser Jenab supervised data entry and accomplishment of the study. Saeed Ghodsi and Zahra Hosseini extracted the data. Zahra Hosseini and Saeed Ghodsi wrote the draft and revised the manuscript Saeed Ghodsi and Mehrnaz Mohebi performed statistical analysis. Seyed‐Ali Sadre‐Bafghi, Saeed Ghodsi,and Zahra Hosseini prepared the Figures. Seyed‐Ali Sadre‐Bafghi and Saeed Ghodsi presented the tables. All authors read and approved the final manuscript.Figure S1 Subgroup analysis of the association between high Apo‐B and MACE after primary PCIClick here for additional data file.


The neuropeptide oxytocin acts as a hormone and a neuromodulator, influencing a multitude of human social behaviors, including reproduction. During childbirth and the postpartum period, it plays a key role in regulating and controlling processes that ensure a safe birth and the health of mother and child. Especially the onset of labor, the progress of labor and initial breastfeeding are mediated by oxytocin. In the maternal brain it controls the initiation of the mother–infant bond and the mother’s emotional responses towards her child. In this review we summarize the current state of knowledge about the role of oxytocin during the different aspects and mechanisms of human childbirth, combining research from human and animal studies. Physiological and psychological stress during childbirth and lactation can have negative effects on the progress of labor, breastfeeding and bonding. We discuss how maternity caregivers can support the positive effects of oxytocin and minimize the effects of stress. Furthermore, we highlight aspects of the basic neurobiological principles and connections where further research is needed to improve our understanding of the regulation and the effects of oxytocin to support maternal and infant health. Childbirth, the early phase of the postpartum period, and lactation are regulated by neuroendocrine processes, which act in a neurochemical cascade to facilitate the physiological progress of giving birth and the transition to motherhood . The pepKnowledge about sources and transport mechanisms of oxytocin in mammals mostly comes from research on rodents and other animal models, and most mechanisms have been shown to be evolutionary conserved and presumably also apply to all other mammals . Oxytocivia the hypothalamic–pituitary–adrenal (HPA) axis. Many hormones, including estrogen, progesterone, prostaglandins, corticotropin-releasing hormone (CRH), relaxin, and oxytocin act in parallel and interactive signaling pathways to initiate the onset of labor  of the Ferguson reflex, which ensures the sufficient oxytocin concentration during and after birth (see above), affects the physiological processes of mother and child. Among the many other positive aspects that are mediated by oxytocin, an elevated oxytocin concentration after birth contributes to the emergence of the mother’s positive emotions towards her baby and towards herself , 88. MatSurprisingly little is known about how midwives can support mothers during these processes and how oxytocin levels can be increased (or maintained) physiologically, although this should be one primary focus of midwifery work . For exaWe postulate that the professional support of women in the postpartum period should always have the reduction of stress-causing disturbances from intrinsic and extrinsic factors and the support of the mother–child bond (including breastfeeding) as its primary goals. Important factors that have been shown to reduce stress during birth are the birth environment, which can hinder or support physiological birth depending on the stress level exerted on the birthing woman , as wellContinuous support by a midwife has also been shown to have a positive effect on the mother’s self-determination and self-confidence . FurtherThe neuropeptide oxytocin plays a central role in securing the health and safety of mother and child during birth and beyond. It acts by endocrine and paracrine mechanisms, both in the periphery and as a neuromodulator in the central nervous system. The processes in which oxytocin is released, binds to its receptor, and affects various aspects of childbirth are finely tuned and strictly regulated, both temporally and spatially. Additionally, oxytocin influences a large bandwidth of basic biological functions of human social behavior, including recognition, trust and empathy . By lyinCP wrote the first draft of the manuscript. MW, HA, and CP edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Here, we investigate the effect of temperature on birth weight, birth weight-Z-score adjusted for gestational age, low birth weight, and preterm birth. We also explore interactions between PM2.5 and temperature.We have previously documented an inverse relationship between PM2.5 during gestation between 2012 and 2016. We used linear, logistic, and Cox regression to estimate associations between temperature during gestation and birth outcomes and explored possible modification of the temperature effect by PM2.5.We studied 123,034 singleton births in three public hospitals of Lima with temperature and PM2.5 levels. There were no statistically significant associations between temperature exposure with low birth weight.Exposure to maximum temperature in the last trimester was inversely associated with both birth weight : −28.0, −19.5] and z-score weight-for-gestational-age  with an interquartile range of 5.32 °C. There was also an increased risk of preterm birth with higher temperature (interquartile range) in the first trimester . The effect of temperature on birthweight was primarily seen at higher PMExposition to maximum temperature was associated with lower birth weight and z-score weight-for-gestational-age and higher risk of preterm birth, in accordance with much of the literature. The effects on birth weight were seen only in the third trimester. This study found that in Lima, a city without extreme seasonal temperatures , the maximum temperature during the third trimester is associated with lower birth weight and a lower z-score weight-for-gestational-age. Furthermore, this association is stronger when PM2.5 is higher. Thus, our study contributes with the evidence to show the risk of maximum temperature and high levels of PM2.5 on reproductive outcomes, even in a city with annual moderate temperatures.High temperature and PM1 Heatwave/extreme temperature is related to multiple health problems6 that can be more pronounced in vulnerable populations such as the elderly,8 infants,10 and pregnant women.11The increase in the frequency and intensity of weather events over the last 50 years is emerging evidence generating global health problems.12 where the levels of PM2.5 and PM10 are have often been found over the Peruvian permissible limit .Metropolitan Lima is the capital city of Peru, located on the central coast of the country. Lima has a warm temperate climate, with an annual mean temperature of 20 °C. In addition, Lima is one of the most polluted cities in South America,13 Low birth weight (LBW) and small for gestational age (SGA) are associated with chronic diseases in adulthood.15 Preterm birth is the major cause of death in children <5 years and is associated with an increased risk of long-term cognitive function impairments.16 In Lima, the LBW and PTB rates in 2015 were 5.4% and 6.47%, respectively.17Birth weight is a crucial health indicator with significant short- and long-term health implications.19 that could influence maternal thermoregulatory capacity, making pregnant women more vulnerable to heat stress.20 For example, extreme temperatures during pregnancy are associated with oxidative stress and systemic inflammation.22 These conditions could decrease uterine and placental–fetal blood flow, decreasing fetal growth.23During pregnancy, hormonal and physiological changes occur11 conducted a systematic review and meta-analysis using 70 studies in 27 countries. They found that higher temperature (temperatures above the 75th centile) was associated with reduction of birthweight  based on six studies, and odds of LBW  were increased (odds ratio of 1.09 (1.04–1.07) in nine studies. The odds of a preterm birth rose 1.05-fold (1.03–1.07) per 1 °C increase in temperature and 1.16-fold (1.10–1.23) during heatwaves.11Studies have shown an association between heat waves and high temperature with birth weight, LBW, and preterm birth. Chersich et al.24 considered 40 studies with data on PM2.5 and birth outcomes, and found 22 g  lower birth weight, 11% greater risk of LBW , and 12% greater risk of PTB , per 10 μg/m3 increment in ambient PM2.5. Bekkar et al.25 reached similar conclusions in a meta-analysis restricted to US studies.A large number of studies have also pointed to air pollution as a factor that is associated with pregnancy outcomes. In the most recent systematic review and meta-analysis, Ghosh et al.,24 estimate that globally 16% of all LBW babies and 36% of all PTB infants were attributable to total PM2.5, with perhaps a third contributed by ambient PM2.5, and two-thirds to household air pollution. As Chersich et al.11 point out in their review, there are no comparable figures for the risk of adverse birth outcomes attributable to heat, but clearly with climate change, if heat is indeed causally related to adverse birth outcomes, the attributable risk can only increase as temperature increases in the future.Ghosh et al.27 Wang et al.27 evaluated heatwaves on PTB and reported synergistic effects of PM2.5 and heat waves, with more PTB with a combination of high PM2.5 and heatwaves in the week before birth. Kwag et al.,26 in contrast, found that PM2.5 exposure during the first trimester (TR1) increased the risk of preterm birth among pregnant women exposed to low temperatures during TR1.However, exposure to combined effects of temperature and air pollutants on birth outcomes has been scarcely studied.2.5. We have previously published results regarding the effects of air pollution on birth outcomes in Lima, where we found that higher PM2.5 was associated with lower birth weight and more risk of being born SGA, although not significantly associated with PTB.28There are no studies related to the effect of temperature on pregnancy outcomes in Lima. The present study aimed to investigate the association between maximum temperature exposure with birth weight, birth weight-Z-score adjusted for gestational age, LBW, and PTB, across all of the gestation and by different trimesters, in the metropolitan area of Lima during the period of 2012 to 2016. We also explore possible interactions with PM2.5 with pregnancy outcomes in Lima, Peru, from 2012 to 2016. The pregnant women were identified by birth records from Lima hospitals, with exposure to heat and PM2.5 ascertained retrospectively before the birth.This study investigates the association of high temperature and PM29 This city has a subtropical climate, high humidity, and low rainfall. The average annual temperature is 20 °C with an average maximum and minimum temperature of 25 °C and 17.9 °C, respectively. These conditions give it a pleasant climate without excessive tropical heat in the summer months (29 °C) or extreme cold in winter (14 °C).Metropolitan Lima is the capital of Peru, located on the country’s central coast at 150 m above sea level with an approximate population of 9,174,855 inhabitants.29Lima comprises 43 districts, which were the basis for assigning exposure to women residents in these districts. From the total population, 28.5% are women of childbearing age, and 2.13% are pregnant women.We obtained data on live births records from the Perinatal Information System (SIP 2000) from one large public hospital  and two exclusive maternal care facilities . All three are located in the central area of Lima and receive patients from all Lima districts; 26 % of births from Lima occur at the sites included here. The data covers January 2012 to December 2016 and includes information on mothers and their babies. We excluded multiple births , malformations based on clinical practice guidelines (n = 855), mothers residing in other provinces (466), duplicate records , stillbirths , outliers .2.5 estimators . Our final population sample included 123,034 live newborns of singleton births.In addition, we excluded missing data from the district of residence (n = 150), mother’s age (n = 69), and missing PMOur objective was to study adverse birth outcomes, including lower weight at birth (continuous), birthweight among full-term births (≥37 weeks), and weight-by-gestational age (z-score), as well as LBW (dichotomous) and PTBs (dichotomous). We did not study stillbirths in this study because they will be the subject of another paper.https://intergrowth21.tghn.org/).Birth weight, expressed in grams, was defined as the first weight of the baby obtained from a calibrated scale by trained staff in each of the three hospitals selected for the study. LBW was defined as birth weight less than 2,500 g at 37–42 gestational weeks. PTB was defined by delivery with <37 weeks of gestation. We also studied the birth weight-Z-score adjusted for gestational age (WAZ), determined from INTERGROWTH tables (Tmax) estimated at 0.1° gridded spatial resolution from PISCO . This database was provided by SENAMHI  (https://www.gob.pe/senamhi). These data were constructed from interpolated data from 684 air temperature monitors throughout the country and remote-sensed data.30 We used population-weighted data to derive a daily maximum temperature for Lima as a whole. For each birth, we calculated average temperature across Lima by trimester and entire pregnancy using the date of last menstrual period (LMP) to 13 weeks of gestation for the first trimester, from 14 to 26 weeks for the second trimester and, from 27 weeks to birth for the third trimester.We used daily maximum temperature , and ground measurements to predict daily PM2.5 at a 1 km2 spatial resolution; the model had an R-square of 0.70 when compared to ground measurements. From this model, we obtained daily PM2.5 data by district (n = 43) assigned to each pregnant woman according to her district of residence, averaging across all 1 km2 grids in the district for each day. On every 16th day throughout the study period, we could not to estimate PM2.5 due to lack of satellite coverage, and we averaged across nonmissing data for those days.To evaluate PM2.5 in four districts (4% of Lima’s population) due to the altitude and the lack of ground monitors there. Besides, we did not want to extrapolate our altitude effect from our predictive model out to very high altitudes. Overall, we had PM2.5 estimates for 91% of the days in our study period. When we were missing a day in calculating an average over gestation or over a trimester, we calculated the average ignoring the missing data.We were unable to estimate PMThere were no comparable data for other pollutants such as nitrogen dioxide or ozone, where only spare ground monitoring data were available, without a model to estimate daily exposure.32 Mother’s age was defined as age at delivery . Parity was categorized as childless, 1–2, or and, >2 births). Prenatal care was dichotomized as with medical control (≥1) versus without medical control. We also included a variable for the presence of any medical complications during pregnancy, such as preeclampsia and urinary infection. The percentage of poverty was defined as the households within a district with a self-reported family income below what is needed for sustenance, food, clothing, or shelter by the Peruvian Census.33 We dichotomized poverty into districts above and below the median poverty level. Smoking was not considered since the rate is very low (<1%) in pregnant women in Peru34 and data are not recorded in the database. Because warm days are often more polluted, PM2.5 was included as a covariate in birth outcome models, averaged over gestation or by trimester.Gestational age at delivery was determined by the LMP. According to Capurro’s methodology, the values missing (n = 105) in the SIP database were replaced by the gestational age determined by physical examination.2.5 by district and population-average temperature for the entire pregnancy by trimester. We performed analysis for each pregnancy outcome across all gestation periods, and during each trimester, in separate models.Data were collected in an Excel spreadsheet and analyzed using Stata software version 14.0 . We calculated the population-weighted average of pollutant PMWe used multiple linear regression to explore the association between maximum temperature exposures during pregnancy with birth weight as a continuous variable for all births as well as restricted to full-term infants. We also studied the WAZ using a multiple linear regression model. Logistic regression analysis was used to determine the relationship of temperature with LBW.2.5, averaged entire gestation, or according to trimester, as well as time invariant covariates (see below).We used a Cox proportional hazards model to estimate the hazard ratio for PTB by temperature. The time variable days of gestation up to 37 weeks, at which point observations were censored, as no PTBs could occur after that point. In the Cox analysis, each PTB was compared, regarding temperature exposure, to all other non-PTB births up to the time of the PTB event. While it would have been possible to study PTBs as yes/no events across all births via logistic regression, we felt that time-to-event provided increased information and chose a Cox model. We included in the Cox model the time-varying variables temperature and PMP value < 0.1 were included as candidate covariates, and those that retained statistical significance at P < 0.05 were included in the final model. Final models for continuous birthweight and z-score included covariates for maternal age, parity, gestational age, preeclampsia, prenatal care, poverty, for LBW the same variables minus poverty and final models for PTB included mother’s age, preeclampsia, prenatal care, parity, and urinary infection as time-invariant covariate.Based on the known determinants that influence birth weight, we included maternal age , poverty (no and yes), prenatal care (control and no control), parity , preeclampsia (no and yes), urinary infection (no and yes) initially in all regression models. Variables that by themselves attained a We evaluated multicollinearity between the variables included in the regression models using the variance inflation factor (VIF).As an additional analysis of the average maximum temperature as a linear term, we analyzed quartiles according to all gestation and specific time windows. For the entire pregnancy, the quartiles were: Q1st: 17.65–22.63 °C; Q2nd: 22.64– 23.76 °C: Q3rd: 23.77–24.86 °C, and Q4th: 24.87–29.04 °C. Quartiles were similar for each trimester. The interquartile temperature range (IQR) for the entire pregnancy was 2.23 °C and for trimesters: 5.43 °C, 5.32 °C, and 5.23 °C, respectively, with more variation for IQRs by trimester due to the smaller sample sizes used for calculations. For the analysis, we considered an IQR of 5.32 for all trimesters.2.5 as a continuous variable in all models, and we also explored the interaction temperature-PM2.5 using a dichotomous PM2.5 level above or below the median (≥18.86 µg/m3 vs. <18.86 µg/m3) and continuous temperature, during the exposure window . We tested the interaction in the total population and also ran separate models below and above the median.For adjustment by air pollution, we included PMThe protocol was approved by the Ethics Review Committee of Cayetano Heredia University (SIDISI code 101546).The present study included 123,034 pregnant women. Of these, 70% were aged 25 to 34 years, 84% had a partner, 12% had high education, 7% had more than two children, and 74% had prenatal care. Among all pregnancies, 8,897 (7.16%) were PTB and, among those with full-term births, 2,074 (1.78%) were LBW  in birth weight per increase an IQR (5.32 °C) of maximum temperature in the third trimester. Evaluated by quartiles, there was a monotonic decrease in birthweight with higher quartiles of temperature. The highest quartile of temperature (>26.0 °C) was associated with the largest reduction in birth weight . In contrast, we observed a positive relationship between temperature and birthweight in the first trimester .We evaluated the relationship between birth weight and temperature Table , with reAnalyzing the weight z-score by age, we found a significant inverse relationship during all gestation, more marked in third trimester of pregnancy  and a monotonic inverse relationship by quartiles during the third trimester. Again, in contrast, there was a positive trend in z-score during the first trimester.When we restricted the analysis to full-term babies, we found a similar pattern to the estimations observed in the total population, meaning a decrease of 25 g in the third trimester per temperature IQR, and, in contrast, an increase of 18 g in birth weight per IQR of temperature in the first trimester Table . For PTBNo significant associations Table  were obs2.5 of the effect of temperature on birth outcomes by including an interaction term for the continuous variable temperature and PM2.5 and stratifying our analyses of temperature and birth outcomes by high and low PM2.5. (Table 2.5 was observed for birth weight in the entire pregnancy (P = 0.03) and third trimester (P = 0.002), with the effect of temperature on birthweight stronger with higher PM2.5. Similar patterns were observed for weight-for-age z-score and full-term infants. For LBW, we found a significant increased risk with higher PM2.5, but only in the third trimester.We explored modification by PM5. Table . A signi2.5 with birth weight and PTB. Our results showed an inverse association between temperature and birth weight and weight-for-age z-score, more pronounced in the third trimester but no association with LBW. We found an association between higher temperature and PTB, but in contrast to birth weight, this association was seen in the first and second trimesters but not the third.This study is focused on evaluating the relationship between maternal exposure to maximum temperature and PM11 The effect of maximum temperature on birth weight during the last trimester could be explained by the faster growth of the fetus in this period, which might be a time of increased susceptibility. Exposure to high temperatures could decrease uterine blood flow and restricting the fetal growth.21Our results are consistent with most studies in the literature which found that higher temperatures were associated with lower birth weight.36 and improving the growth of the fetus. Furthermore, infants whose mothers were exposed to peak sunshine during their first trimester were born significantly heavier than their counterparts with such exposure. Sunshine during early gestation might increase the level of insulin-like growth factor (IGF-1), facilitating prenatal growth.37In contrast, we found an increase in birth weight associated with temperature in the first trimester. There is some evidence that heat stress could cause a greater degree of hypoxemia in immature placental tissue, triggering the expression of vascular endothelial growth factor (VEGF) as a response. This activation can promote branching angiogenesis, reversing the placental hypoxia status,Regarding LBW, most studies have shown an independent association with temperature, while we did not.38 Heat stress could activate the fetal hypothalamic-pituitary-adrenal axis, prompting the placental release of estriol, prostaglandins which could induce labor onset.38We found a slightly increased risk of PTB per IQR increase in temperature, primarily during the first trimester. Several studies have reported that exposure to high-temperature changes increases the risk of premature birth.2.5, our results showed that the negative effect of temperature on the birth weight (as well as low birthweight) was primarily seen at higher values of PM2.5, particularly in the third trimester. At the same time, the positive effect of temperature in the first trimester was also slightly accentuated by higher PM2.5. In contrast, when we analyzed the interaction between PM2.5 and temperature for PTB, we found that the risk of PTB was higher during low exposure to PM2.5, but the effects were not strong. The most significant fetal growth occurs during the third trimester when the fetus is vulnerable to any harmful stimulus. Concerning PTB, we have no explanations for the reverse finding of increased risk of PTB due to heat when PM2.5 levels are low.Evaluating a modifying effect by PM30 These data were constructed using interpolation techniques that included temperature data from fixed monitoring, satellite data, and geographical features, supplementing available data from two ground monitors. In addition, we used the perinatal records of three large public hospitals located in the city center, which receive pregnant women from all the districts in Lima. One limitation of our data is that our exposure estimates were restricted to PM2.5. We had very limited data on other pollutants, while our data on daily PM2.5 were complete both temporally and spatially for the entire study period. Another limitation of this study is the lack of data related to the women’s occupation and occupation location. However, this would not be expected to change temperature exposure greatly, as the temperature is distributed relatively uniformly across Lima. Also, we were missing data for some possible confounders such as maternal body mass index, education and nutritional status, conditions that may affect the development of the fetus.39 However, it is not clear that these variables would be related to temperature, required to act as confounders. Finally, it is possible that the approximately 25% of births in Lima studied here are not representative of all births in Lima; however, we believe the underlying mechanisms of the effect of heat on birth outcomes are likely to be shared among all births in Lima.One strength of our study is temperature data estimated from an extensive new government database (PISCO).2.5 could enhance the effect of temperature on birth weight.Maternal exposure to high ambient temperature was associated with reduced birth weight during the third trimester of pregnancy and a slight risk of PTB in the first two trimesters. Our findings suggest that maternal exposure to high concentrations of PMThe authors thank to the Ministry of Health (MoH), the hospital directives and SENAMHI for providing the data for the analysis.The authors declare that they have no conflicts of interest with regard to the content of this report.


Preterm birth is the leading cause of perinatal morbidity and mortality in the U.S. and disparities among racial and ethnic groups persist. While etiologies of preterm birth have not been fully elucidated, it is probable that environmental and social factors play a role.2.5) or ozone (O3) and neighborhood socioeconomic factors that increase the risk of preterm birth.We hypothesized that there is an interactive association between exposure to fine particulate matter  data to assess census tract-level socioeconomic factors in California urban counties.We conducted a retrospective study using geocoded birth certificate data between 2007 and 2011, daily ambient air quality data on PM2.5 and O3 and preterm birth that varied by gestational exposure period. In mixed-effects models, we found an increase in the risk of preterm birth for a one-unit change in PM2.5 averaged across the entire pregnancy  and O3 during 3-months pre-pregnancy . Interaction between census tract-level factors and air pollutants showed an increase in the risk of preterm birth among mothers living in higher socioeconomic areas, though, a fixed cohort bias sensitivity analysis showed these associations were not significant.Our study found a small positive association between maternal exposures to PMThese findings substantiate previous studies that showed associations between air pollution and preterm birth, even as pollution levels have decreased. This study has important implications for policy decisions and may help inform research on potential mechanisms of preterm birth. Approximately 10% of all infants born in California are preterm . It remaWhile the pathophysiology of preterm birth is still being investigated, it is probable that a combination of genetic, social, and environmental factors contribute . Since p2.5), is associated with preterm birth and adverse birth outcomes , whereas we found the association between O3 and preterm birth to be highest in the 3-month pre-pregnancy period for every 1-unit (ppb) increase in O3 . For early preterm birth (<32 weeks), we found the highest risk associated with O3 during the third trimester pregnancy period  and no significant association for PM2.5 during any period.Table rth Fig. . We saw 3 and preterm birth with AORs ranging between 1.03 and 4.48 across the different exposure periods. Births conceived in the summer (June–August) compared to other seasons had stronger associations between PM2.5 and preterm birth with AORs ranging between 1.06 and 1.41 across the different exposure periods. Overall, the remaining seasons of conception had associations that were less consistent and sometimes in opposite directions with each pollutant.Associations between pollutants and preterm birth differed by the season of conception Table . Births 2.5 during the whole pregnancy had increased risk of total preterm birth per 1-unit μg/m3 , high public assistance, high supplemental security income (SSI) and high poverty . In addition, we also performed a fixed cohort sensitivity analysis that showed a reversal of the PM2.5 findings. This analysis showed no significant association between PM2.5 and preterm birth. For O3, we found the highest association for preterm birth was in the third trimester pregnancy period  and early preterm birth (<32 weeks). Increased risk of early preterm birth was associated with high PM2.5 during the third trimester and high O3 over the whole pregnancy. This heightened risk of PM2.5 with early preterm birth during the third trimester was corroborated by our fixed cohort sensitivity analysis and has been shown in other studies. It may be due to the shortened third trimester period indicating possible overlap with the third trimester exposure period or may be due to the lower power in the subset data [3 exposure averaged over the entire pregnancy does not provide as much explanatory information is given seasonal variation of O3 throughout the year suggesting that another process may be underlying this finding.Interestingly, we found mothers exposed to higher levels of Oset data . However2.5. This finding is supported by the increased odds of preterm birth for mothers with high levels of exposure to PM2.5 during the second and third trimester given that peak PM2.5 is seen during the winter months and this would correlate with a summer season of conception. For O3, we saw the greatest association with those individuals who were conceived in the spring, also correlating with increased sunlight exposure [Furthermore, we observed different associations with exposures to air pollutants when analyzed by the season of conception, which has also been seen in other studies. Results from these prior studies have been mixed with some showing increased odds of preterm birth for those conceived in autumn and others showing an increased odds of preterm birth for those conceived in summer . Our resexposure . However2.5 (third trimester and entire pregnancy exposure periods) and preterm birth in areas with high inequality (as measured by the GINI index) compared to areas of low inequality. Interestingly, we saw even more consistent effect modification of several census tract socioeconomic factors for the O3 exposure group. For the 3-month pre-pregnancy period, we saw positive associations for total preterm birth in mothers who lived in census tracts with a high percent of total assistance, a high percent of poverty, and a high GINI index. Given the positive association between O3 during the 3 months pre-pregnancy and preterm birth, this analysis may suggest that individuals with these markers of social deprivation are more vulnerable to the adverse effects of air pollution. In addition, we saw larger associations for almost all census tract-level factors and maternal exposure to O3 during the whole pregnancy for total preterm birth. Interestingly, when examining early preterm birth, we observed a higher risk of early preterm birth associated with higher exposure to O3 and higher levels of SES; however, the results should be taken in the context of the multiple comparisons of our secondary analyses. It is unclear what is driving this increase and it is possible that this finding was due to chance. We believe the further analysis is warranted.Previous studies have suggested that neighborhood deprivation can modify the relationship between air pollution and preterm birth , 51, 52.2.5 and O3, result in higher levels of reactive oxygen species and increased markers of oxidative stress that may lead to adverse birth outcomes [These and previous epidemiological findings indicate that a deeper mechanistic understanding of the associations between exposures to air pollutants and preterm birth would be useful. Studies that have explored mechanistic underpinnings suggest that exposures to air pollutants, including PMoutcomes . Anotheroutcomes . The autoutcomes . AlthougStrengths of our study include the large sample size and distribution of regions across the state of California, use of an innovative air quality model, and detailed individual-level covariates such as maternal cigarette use, pre-pregnancy BMI, and maternal comorbidities such as diabetes and hypertension that allowed us to evaluate the impact of these factors.2.5) emissions from heavy-duty diesel vehicles that may have influenced the reduction in air pollution and could partially explain the decrease in preterm birth seen over our study period [Our study had several limitations. Misclassification bias could have occurred when assigning air pollution exposure estimates. We used maternal residence at delivery as a proxy for the residential location for the entire pregnancy and pre-pregnancy period. However, it is possible that individuals moved during these times, previous research has shown that residential mobility is unlikely to have substantially affected the associations we observed , 56. In y period , 48. LasOur study adds to the growing body of literature on the interactive impacts of socioeconomic factors and exposures to air pollution on preterm birth. Our findings are consistent with previous work on the associations between exposures to air pollution and preterm birth in California, with detailed air pollution exposure data and a large study population. It is notable that these associations with preterm birth persist even as the levels of these pollutants have recently decreased in California compared to earlier studies. These findings provide further evidence for the need for reproductive justice policies that can mitigate the impact exposures to air pollution have on the physical environment of under-resourced and low-income communities who have a higher burden of preterm birth.SupFigure 1SupFigure 2SupTable 1SupTable 2SupTable 3SupTable 4SupTable 5SupTable 6


Closely spaced births have been reported all over the world especially in developing countries, and they have been correlated with poor maternal and infant health. Enhancing optimal birth interval is one of the key strategies to promote the health status of mothers and their children. However, factors affecting short birth intervals have not been identified in the study area and region. This study was aimed to assess determinants of short birth interval practice among reproductive women in Farta woreda, Ethiopia, 2019.Community based unmatched case-control study design was conducted from February to March 2019. The sample size of 303 (101 case and 202 controls) was included by using multistage sampling and then study participants were selected by simple random sampling technique. The data was collected by structured and pre-tested face-to-face interviewer-administered questionnaires from the selected respondents. The collected data were entered with Epi-Data version 4.2 and analyzed by using SPSS version 23 software. Bivariate and multivariate analyses were used to examine the association. Odds ratios, 95% CI, and P-value <0.05 were used to determine the statistical association.Women who had no formal education , had not a history of antenatal care follow up ), did not use modern contraceptives before getting the latest pregnancy ) and duration of breastfeeding less than 24 months ) were significantly associated with short birth interval.Maternal education, duration of breastfeeding, contraceptive utilization, and antenatal follow-up were identified as the predictor variables of short birth interval practice. Therefore, providing health information for reproductive-age women about the benefit of contraceptive utilization, breastfeeding practice and antenatal care follow up to minimize problems resulting from the short birth intervals. A short birth interval is an interval between two consecutive births of less than 33 months . After a live birth, the world health organization recommended intervals before attempting the next birth is at least 33 months to reduce the risk of adverse maternal, perinatal, and infant outcomes . And othClosely spaced births have been reported all over the world, and they have been correlated with poor maternal and infant health . In the Fertility is an essential component of population dynamics that influences the size and structure of a population . FertiliBirth spacing practices vary greatly throughout the world . Women iThe study showed that the proportion of short birth interval and median birth interval in Ethiopia was 45.7%  and 34.5Short birth intervals have been associated with adverse health outcomes, including infant, child, and maternal mortality . Women wDifferent studies regarding determinant factors of short birth interval revealed that maternal age –25, mateMaternal and child complication associated with short birth interval practice has a significant negative impact on socio-cultural and health of the mothers and their children. However, factors affecting short birth interval practice have not been identified and there was scarce studies conducted in the study area at the community level. Therefore, this study aimed to assess the determinant factors of the short birth interval among reproductive-age women who gave birth in the last one year in rural and urban kebeles in Farta, South Gondar Zone, Ethiopia.This study was conducted from February 30 to March 30, 2019, rural and urban kebeles in Farta woreda, South Gondar, Northwestern Ethiopia. Farta woreda is located 590 kilometers North West of the capital city of Ethiopia, Addis Ababa.Community based unmatched case-control study design was employed.Reproductive age women (15–49 years) residing in the study area who experienced at least two consecutive births and the last delivery occurred within the past one year before the data collection.Reproductive age women residing in selected kebeles in the study area who experienced at least two consecutive deliveries and the last delivery occurred within the past one year before the data collection.Reproductive-age women who have short birth intervals between the latest two consecutive births.Reproductive-age women who have optimal births interval between the latest two consecutive births.Controls. All women who gave alive birth within the last one year and have at least two consecutive births with a birth intervals of 33 and 59 months between the latest two successive live births.Cases. All women who gave birth within the last one year and have at least two consecutive alive births with a birth interval of fewer than 33 months between the latest two successive live births.Exclusion criteria for both cases and controls. Mothers who had a history of abortion between the last two consecutive births and participants who severed ill.1:2 allocation ratio of cases to controls were assumed. An additional nonresponse rate of 10% and design effect of 2 was considered. Based on the assumptions, the final sample size was determined to be 303 (101 cases and 202 controls).The sample size was determined by using the double population proportion formula for an unmatched case-control study using Open EPI-info version 7 software by taking of contraceptive utilization from the previous study was chosen as an independent variable, since it gives a maximum sample size. The proportion of mothers who did not utilize contraceptives among controls was 33.3% and a minimum detectable OR was considered to be 3.01 . AccordiA multistage sampling technique was used to select study participants. All kebeles  were first stratified into 1 urban and 32 rural kebeles. Then 1 urban kebele and 10 rural kebeles were selected by simple random sampling methods to get the representative sample size. Then, the sampling frame was prepared from the health extension workers’ registration book (family folders) having household identification numbers. Using respective household identification numbers, frames of households containing study subjects defined as cases and controls were prepared to form each selected kebeles. Then, the proportional allocation technique was employed to determine the study participants from each kebele both for cases and controls. Finally, reproductive-age women who had at least two consecutive births and whose latest birth within the past one year before the data collection. The study participants were selected using a simple random sampling technique from the existing sampling frame by lottery method. The participant who was not present at the time of data collection; three revisits were made to interview the woman. In the case of more than one eligible participant in the household, the lottery method was used to select only one participant .Short birth interval practice.Socio-demographic variables . Obstetrics and reproductive health-related variables .When the duration between two consecutive births is less than 33 months .When the duration between two successive births is 33 to 59 months .When the duration between two successive births is greater than 59 months .Birth to birth interval = birth-to-pregnancy interval(24 months) plus nine months of pregnancy (24+9 = 33 months) [ months) .The data were collected by using face-to-face interview-administered, pretested, and structured questionnaires. After reviewing previous literature, the questionnaire was first developed in English and translated to the local language (Amharic) then back to English by language experts to keep its consistency. Five health extension workers who were familiar with the local language and customs were recruited as data collectors and two-degree midwives were assigned as supervisors. The training was given for data collectors and supervisors for two days on data collection procedures, interview techniques, and confidentiality of the information obtained from the respondents. Overall supervision made by the investigators.Data quality was ensured during data collection, entry, and analysis. Before conducting the main study, a pretest was carried out on 5% of the sample size outside of the selected kebeles and necessary modifications had been made. The principal investigator and supervisor conducted day-to-day on-site supervision during the whole period of data collection. At the end of each day, the questionnaires were reviewed, checked for completeness and accuracy by the supervisor and investigator. Then, corrective discussions were undertaken by the research team members.After coding, the data were entered into Epi-Data version 4.2 and then exported to SPSS version 23 software for analysis. Bivariate analysis was executed to examine the crude association of predictors with short birth intervals. Finally, variables having p-values ≤0.2 on bivariate analysis were selected as candidates for multivariable analysis. Odds Ratio and 95% CI and P-values less than 0.05 were used to determine the statistical significance of the tests. Finally, the results were presented in texts and tables.After approval, ethical clearance was obtained from the Institutional Review Board (IRB) of Medicine and Health Sciences, Bahir Dar University. A permission letter was obtained from the Farta woreda health office before starting data collection. At the beginning of the data collection, written informed consent was obtained from each respondent after a thorough explanation of the purpose and the procedures of the study. Respondents were also informed that all the data obtained from them were kept confidential and anonymous. To ensure confidentiality, the names of respondents were replaced by code numbers.This study was carried out with a total of 303 child-bearing age women who had at least two consecutive births with a response rate of (99%). The mean age of the respondents was 33.5 (SD±5.5) and 33.9 (SD ± 5.5) years among cases and controls, respectively. Among the respondents, 99% were Amhara in ethnicity. About 97% of the cases and 95.0% of the controls were married. Regarding educational status, 73 (73.0%) of the cases and 58% of controls did not attend formal education. Concerning religion, 98.0% cases and 98.5% of controls were Orthodox Christian followers. Eighty-four percent of the cases’ husbands and 85.0% of the controls husbands’ occupation were farming .The mean duration of the birth interval was 25.36 with SD ± 4.37 and 44.86 ± 7.83 months among cases and controls, respectively. Fifty percent of the cases and ninety-four (47.0%) controls were reported to have three up to four alive children. Eight percent of the cases and nine percent of the controls had a history of stillbirth before the preceding birth.Thirty-two percent of the case and 43.5% of the controls gave birth in health institutions for their preceding child. A majority (73.0%) of the cases breastfed for less than 24 months, while one hundred twenty (60.0%) of the controls breastfed for 24 months or above. Seventy percent of the cases and one hundred seventy-nine (89.5%) of the controls utilized modern contraceptive methods after the delivery of the preceding child but before they got pregnant for the last child. Fifty-seven (57.0%) of cases and seventy-one (35.5%) of controls did not have antenatal care visits during their latest pregnancy .First bi-variable logistic regression was conducted among twenty-one variables only eleven variables with p-values of 0.2 or less were included in the multivariable logistic regression. These variables were: educational level of mothers, husbands’ educational level, age at first pregnancy, number of living children, sex of the preceding child, the status of the preceding child, latest pregnancy plan, ANC in preceding pregnancy, place of previous delivery, contraceptive use between preceding birth and latest pregnancy and duration of breastfeeding.As can be depicted from multivariable backward stepwise logistic regression mothers who did not have formal education, did not have modern contraceptive methods before getting pregnant for the latest child, breastfed for the preceding child less than 24 months, and mothers who have no antenatal care follow up in preceding pregnancy were found to be significantly associated with short birth intervalMothers with no formal education were about 2 times ), more likely to have short birth intervals as compared to those who attended formal education. The odds of having a short birth interval were higher among mothers who did not use modern contraceptive methods before getting pregnant for the last child ) than those who had a history of using modern contraceptives. Mothers who breastfed for the preceding child for less than 24 months were 3 times more likely to have short interbirth intervals than their counterparts of mothers who breastfed for 24 months or more ). The odds of having a short birth interval were higher for mothers who hadn’t a history of antenatal care follow-up in preceding pregnancy than those who didn’t have ) .Short birth interval is critical for many Sub-Saharan African countries including Ethiopia, where perinatal mortality and fertility remain high. However, birth spacing was affected by different factors. Thus, this community-based case-control study identified factors influencing short birth interval practice among childbearing age mothers.In this study, the odds of having a short interbirth interval were higher among mothers who did not have formal education as compared to participants who attended formal education. This finding was similar to studies conducted in Arba Minch, Pakistan, Mekele, Ethiopian DHS 2011, and Iran , 35. ThiWomen who did not have a history of modern contraceptive utilization before they got pregnant for their latest child were more likely to experience short birth intervals than women who had a history of contraceptive utilization. This was similar to studies done in Arba Minch, southern Ethiopia, Lemo district, Manipur, and Mekele , 32, 36 Women who breastfed the preceding child for less than 24 months were more likely to have short interbirth intervals than participants who breastfed for 24 months and above. This finding was similar to the studies done from Arba Minch, southern Ethiopia, Manipur, Nigeria, Mekele , 31. ThiWomen who had a history of antenatal care follow-up were more likely to have optimal birth interval practice than women who didn’t attend antenatal care follow-up during the preceding pregnancy. This might be due to women with a history of ANC follow up might get information from health care providers about family planning and the bad outcomes of short birth interval practice.Community-based study design.Since the study participants include within one year after birth memory bias might be introduced and this study focuses on a Quantitative approach Which could not address the “why” questions in detail.In this study educational status of the mother, contraceptive utilization, duration of breastfeeding and antenatal care follows up in preceding pregnancy were determinant factors for short birth interval practice. Special attention should be given to the women by giving health information about the benefits of contraceptive utilization, the benefit of breastfeeding for birth spacing, family planning counseling during antenatal care follow-up at the community level as well as encouraging women for education.


BACKGROUND: The purpose of this study was to analyze the characteristics of the physical growth of twins in childhood and to present growth charts of Japanese twins.METHODS: The subjects consisted of 2029 pairs of normally developed Japanese twins. Growth data were obtained by mailed or hand-distributed questionnaires. Factors that affect body weight and height/length at selected ages were analyzed by stepwise regression analysis. Selected percentiles o body weight, height/length, and body mass index were calculated according to sex, and growth curves were drawn using a spline function. The size deficit of the twins compared to the standards for the general population of Japan was calculated.RESULTS: Gestational age, parity, zygosity, and birth order affected physical growth in varying degrees, although the overall effects themselves were small and mostly disappeared by one year of age. Growth charts of the twins present growth at selected percentiles from birth to 6 years of age according to sex. The size deficit of the twins was largest at birth: more than 20% for weight and approximately 6% for length compared to the 50th percentile of the standard for the general population of Japan. These deficits decreased rapidly in the first 6 to 12 months, and were found to be as low as 0-2% at 4 to 6 years of age.CONCLUSION: Growth charts specifically for twins are needed, at least for the first 1 to 3 years of age but not beyond the age of 6 years. There have been many studies on the physical growth of twins in childhood in Western countries,4-10 including Wilson’s detailed summary of the features of twin growth.11In Japan, as in other developed countries, the rate of multiple births has been increasing since 1975. The higher twinning rates in Japan since 1987 have been attributed to both the higher proportion of mothers treated with ovulation-inducing hormones and to the increasing use of in vitro fertilization.3,12-14 Because there are no growth standards for twins in Japan, the physical growth of twins in childhood must be evaluated using the standards for the general population15 — that is, standards for singletons. As a result, many twins are regarded as having poor growth, especially when they are very young, and this causes both the twins and their parents much embarrassment and concern. In general in Japan, pediatricians and public health nurses, the professional advisors for the growth of children, do not have adequate information to answer questions that the parents of twins ask about their children’s growth. Moreover, many factors that affect body size after birth, such as the perinatal medical system, body size at birth, and the body size of the mother, differ significantly between Japan and Western countries. To resolve these shortcomings in appropriate data, it is essential to obtain objective growth data based on a large sample of Japanese twins.It is well known that the growth patterns of twins in utero and in childhood are very different from those of singletons.6,9 and comparing the similarity of the twins within a pair by zygosity.5,8,10 The present study deals with twins as individuals. The purpose of this study is to analyze the characteristics of twins’ physical growth from birth to 6 years of age and to present growth charts of normally developed Japanese twins in comparison with those of the general population. This comparison between twin and singleton standards may also be useful in growth studies of Caucasians.There are two dimensions to estimating the growth of twins: comparing individual twins versus singletons,3 To cover the gap between vital statistics and hospital data, the authors have been constructing a twin database that would contribute to overall health care for families with multiples. The database is larger and less biased than hospital data and its information is more detailed than the vital statistics, especially as to zygosity. In addition, the authors made much of afterbirth data, which neither vital statistics nor hospital data adequately supply. The basic characteristics of this database are described in detail elsewhere . The present data were drawn from this database and were obtained by questionnaire.In Japan only two main sources of data about multiple births have been established, and the gap between them is wide. First, vital statistics may be available without access to information on specific individuals. Second, data from hospitals have been used in the field of obstetrics, mainly in managing high-risk pregnancies. Although this method is relatively easy to use, it may allow large selection biases to occur.The subjects of this study were 2029 mothers and their 4058 twin children, who were recruited from among two different groups. The first group of subjects consisted of 937 mothers and their 1874 twins who belonged to various associations for parents of multiples throughout Japan . The second group of subjects consisted of 1092 mothers and their 2184 twins living in the Tokyo metropolitan area; all of the twins in this group had applied to (though not necessarily enrolled in) the secondary education school attached to the faculty of education of the University of Tokyo between 1982 and 2003 (school applicants group). In the maternal associations group the twins were born between 1986 and 2002, and in the school applicants group the twins were born between 1968 and 1991. At the time data were collected, in 2002-2003, the twins in the maternal associations group ranged in age from 0 to 15 years , and the twins in the school applicants group were all 11 or 12 years old.Data were collected through mailed or hand-delivered questionnaires, which had nearly the same format between the two groups. The questions asked about family structure; obstetrical findings on the mothers; the twins’ physical growth, zygosity, motor, language, and mental development; the twins’ and parents’ medical histories; and any behavioral problems the twins had had. In the school applicants group, one parent of each twin, usually the mother, participated in a medical interview by two or three interviewers, including, from 1988 on, one of the present authors (Ooki), in which their responses to the questionnaire were checked carefully.Detailed obstetrical records on the mothers in the school applicants group were also obtained from the “Maternal and Child Health Handbook”, which the Ministry of Health, Labor and Welfare of Japan provide to all pregnant women. No complete information on chorionisity was obtained.15 and 2000. The growth data of children based on mass examinations are usually recorded in this Handbook. The authors of the present study advised the mothers to refer to these records when completing the questionnaire. Growth data were assigned to the appropriate age groups on the basis of days since birth, which was calculated as the date at mass examination minus the child’s birthday. For example, if the subject’s age was 73 days, his or her data were assigned to the 2- to 3-month-old group. The data from the Handbook were accepted without modification; therefore, the method and accuracy of those measurements could not be ascertained.In Japan, the health examination system after birth differs according to life stage. This has made it difficult to obtain continuous growth data on children before and after 6 years of age. Until 6 years of age, children receive a health examination administered by the Ministry of Health, Labor and Welfare based on age, which is counted as real weeks, months, or years after birth. The “Maternal and Child Health Handbook” presents the growth standards of weight and height/recumbent length and developmental milestones every 10 years, e.g., 1980, 1990,Although this method seemed to be an effective way to collect large amounts of growth data on twins after birth, it did not produce perfect longitudinal data, and there were certain differences in the number of subjects in each age group.16 that was used widely in Japan and that, in the present study, was completed by the mothers in both groups. The zygosity types were monozygotic, unclassified, and dizygotic, according to the similarity score, which was calculated by using five questions regarding the physical similarity and confusion of identity between the twins. The accuracy in classifying their twins was nearly 98%, although about 10% of pairs were unclassified.16 The accuracy was a trade-off according to the percentage of unclassified pairs.The zygosity of the twins was determined primarily by a questionnaire3 The twins in the present study were classified as 1159 monozygotic, consisting of 557 male-male and 602 female-female pairs; 675 dizygotic, consisting of 170 male-male, 174 female-female, 163 male-female, and 168 female-male pairs; and 195 unclassified, consisting of 106 male-male and 89 female-female pairs. As zygosity testing is very rare in Japan, this is the largest sample to date for a study on growth data of twins in Japan that includes both correct age and specified zygosity.For the school applicants group, zygosity was diagnosed also by the use of many genetic markers for those twin pairs who were actually admitted to the school.Twin Research, mentioned above). Birth complications of mothers or twins, such as placenta previa, placental abruption, coiling of the umbilical cord, neonatal asphyxia, growth-discordant twins, and twin-to-twin transfusion syndrome, were observed to varying degrees. None of these were grounds for exclusion from the study. In general, it was very difficult to set clear and consistent inclusion/exclusion criteria, as more than 10% of the present subjects had at least one of the complications mentioned above. Moreover, no subjects showed apparent retardation of physical growth at the time of data collection. The preliminary analyses are summarized as follows. (1) The twins in the maternal associations group had one-week shorter gestations than the twins in the school applicants group. (2) Body size parameters at birth, namely weight, length, chest circumference, and head circumference were slightly smaller in the maternal associations group. Nevertheless, both birth weight itself according to gestational weeks and the percentage difference in relative birth weight within pairs were nearly the same compared to the birth weight norms of the general twin population in Japan.17 (3) The two groups were very similar to each other in body weight and height from birth through 6 years of age, as shown in Before the data of the two groups were combined, weight and height in both groups were examined in detail. The results are described elsewhere , whereas after birth the standards are presented according to sex alone. In the case of twins, at least two additional factors that are not relevant to singletons might also be considered: the birth order of the twins and their zygosity (monozygotic or dizygotic).Birth complications were not grounds for exclusion from the following analysis. Usually, the growth standards of singletons First, the factors that affected the body weight and height/length of twins at selected ages were confirmed by stepwise regression analysis, with a threshold significance level of 0.05. The variables considered were sex, birth order of the twins, gestational weeks, maternal and paternal age upon the birth of the twins, parity, zygosity, presentation, the birth year of the twins, and the group to which the subjects belonged. For qualitative variables, the following codes were used: sex, female 0, male 1; birth order, first-born 1, second-born 0; zygosity, monozygotic 0, dizygotic 1; presentation, non-vertex 0, vertex 1; group, maternal associations group 1, school applicants group 0. The numbers of subjects on whom data were missing as to parity, presentation, zygosity, gestational age, maternal age, and paternal age were 4, 446, 390, 52, 36, and 8, respectively. There were no missing data for sex, birth order, or birth year of the twins.2) at each age were calculated, and growth curves were drawn by means of a spline function. Body mass index (BMI) is mathematically equal to the Kaup index, which has been widely used in Japan as an index for the physique or obesity of a child younger than 6 years. Though several problems were pointed out regarding BMI as an indicator of child obesity, this index has become a world standard.18Growth charts were developed from the results of the regression analysis. The selected percentiles  of body weight (kg), height/length (cm), and body mass index  in 1990.The mothers in the maternal associations group all cooperated voluntarily in this research, mainly through their associations. Informed consent concerning the statistical analysis of the data in the school applicants group was obtained from each twin and his or her parents in writing as part of the application process.The results of the stepwise regression analysis are shown in 2) of gestational weeks rapidly decreased with age, while the effect of sex did not. Physical growth from birth to 3 years of age was calculated according to sex and gestational weeks. The results are shown in 3, growth charts after birth were calculated separately for males and females without taking gestational periods into consideration, following the system used to calculate standards for singletons.20The coefficient of determination (RThe 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentile curves of weight and height/length from birth to 1 year of age are presented in The size deficits of twins in weight and height/length from birth to 6 years of age are presented in There are no growth charts for twin children in Japan despite the rapid increase in multiple births and the increasing need to provide appropriate information to parents and nursing staff. Most studies reported so far regarding the physical growth of twins after birth in Japan had very small samples and therefore only roughly classified age after birth. The present data are the largest twin sample in Japan to provide accurate age after birth and information on zygosity.21-23 Nevertheless, in the present study those effects were small and mostly disappeared at an early age, as shown in 3 Moreover, the growth standards of the general population do not correct the effects of gestational periods to reflect the actual conditions of physical growth.20 To estimate the difference between the general population and twins, the present data should be treated in the same way. Therefore, in this study the growth charts for the twins were differentiated only by sex.The effects of parity, birth order, and zygosity in twins on their birth weight and length, irrespective of gestational age, have been extensively reported.11 It was very difficult to determine when or whether twins fully catch up to singletons, as the present study did not use a complete birth cohort containing singletons. Since it is found here that most of the size deficit of twins compared to the general population is gone by 6 years of age, there is no practical necessity for specific growth charts for twins after that age.Compared with the general population, the twins’ size deficit was greatest at birth but decreased dramatically in the first 6 to 12 months, reaching as little as approximately 2%, around 1 kg for weight and 1 cm for height, by 6 years of age. This finding was consistent with the data reported by Wilson.The limitations of the present study were as follows. First, the data were obtained from retrospective records, and the methods of measurement were not necessarily consistent. Nevertheless, the data on physical growth did not reveal a large difference between the maternal associations group and the school applicants group, as shown in 15 The clinical use of 3rd percentiles and 97th percentiles of this growth charts as indicators of growth retardation is not necessarily appropriate.The second limitation was that these data were semi-longitudinal rather than cross-sectional. Specifically, data on the same individual were used according to the recorded times. For example, some twins provided almost longitudinal data. On the other hand, others provided only birth weight. Additionally, the number of subjects in each age group varied considerably, as shown in 3Third, as all data were derived from normally developed twins, the norm for the early days after birth may have been overestimated. It is difficult to specify the direct effects of these selection biases. However, compared with the hospital data, which usually include many high-risk subjects, the present data seem to reflect more closely the physical growth features of the general twin population.15 were used in the present study, the difference between twins and singletons was smaller according to the growth standards presented in 2000. Given this trend, it is difficult to achieve a meaningful comparison of twin growth and singleton growth. Body weight and height after school entrance in both groups of subjects were not analyzed, because the present data did not accommodate the much larger secular trends at this life stage.Fourth, as the birth years of the present subjects ranged from 1968 to 2002, a period of 35 years, yearly trends in physical growth may also be considered. Fortunately, no birth-year effects were observed in the present study, as mentioned in the results of the stepwise regression analysis. According to the physical growth standards of the general population, birth weight in Japan began to decline after 1975, with the result that body size is smaller until several years after birth. The reduction in infant body size has been attributed to other factors, too, such as lifestyle changes. Although the growth standards presented by the Ministry of Health and Welfare in 199015Fifth, physiological body weight loss after birth was not assessed because of a lack of appropriate data. Such weight loss was presented as to the growth standards in the general population.24 For the present data, no special corrections were performed. Some unexpected selection biases or confounding may have occurred. These effects would be estimated by comparing the data to less biased, more representative, and nationwide data on twins.Finally, the merits and demerits of combining the data of the two subject groups should be discussed. One reason why we combined the data was that the groups were of similar size. Preliminary analysis showed that the body size parameters of the twins at birth were slightly lower in the maternal associations group, whereas physical growth after birth was nearly identical between the groups. Moreover, it is not always the case that growth charts are developed based on only one group of subjects. Usually, complicated methods of weighting measurements and modifying those measurements according to the number of subjects and so on are part of the development of growth charts; see, for example, “2000 CDC Growth Charts: United States”.Although selection bias should be quite low in a population-based study, it is almost impossible to conduct this type of twin study in Japan at the present time. Nevertheless, it is extremely important to present objective growth charts for infant twins using the best available methods. Moreover, there exists much less information on the physical growth of higher-order multiples such as triplets. The growth charts developed in the present study will be more useful than those of the general population to estimate the growth of higher-order multiples.In conclusion, the present study reveals the physical growth characteristics of twins in Japan and shows the need for early-childhood growth charts for twins, though the present data also suggest that such charts are not necessary for twins after 6 years of age. The present charts are the first objective ones for twins in Japan, and will be especially useful for child and maternal health.


An increasing number of extremely premature infants survive the neonatal period and beyond. Little is known about the maturation of the preterm infant’s metabolome and its relation to the development of morbidities. Using 1H-NMR, we investigated the serum metabolic profile of 87 infants born at a gestational age (GA) <28 weeks [mean GA (SD) 25.4 (1.4) weeks] in samples longitudinally collected from birth to term equivalent age. The infant metabolome was analyzed in relation to GA, postnatal age, nutrition, and preterm morbidities. At postnatal day 1, low GA correlated with high levels of 3-hydroxyisobutyrate, acetate, acetoacetate, acetone, formate, glucose, and valine. Nearly all quantified metabolites displayed postnatal concentration changes. For example, the two phospholipid-related metabolites myo-inositol and ethanolamine displayed a similar decline from birth over the first weeks of life, irrespectively of GA. The proportion of enteral/parenteral energy intake in the first 28 days significantly correlated with mean levels of 52% of the analyzed metabolites. Low enteral energy intake was associated with high serum levels of 3-hydroxyisobutyrate, creatinine, glucose, glycerol, histidine, lactate, leucine, lysine, methionine, ornithine, phenylalanine, proline, threonine, and uridine. There were also significant correlations between high enteral intake and high serum levels of isoleucine and tyrosine. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) outcomes were not significantly associated with metabolite levels in the neonatal period after correcting for multiple testing. In conclusion, the serum metabolome of extremely premature infants changes substantially in the neonatal period, largely driven by the gradual transfer from total parenteral nutrition to full enteral feeding. Further studies are needed to disentangle the intricate relationships between the metabolome, nutritional management, GA, and the development of preterm morbidities. Advances in obstetrics and perinatal care over the last decades have dramatically improved the survival of infants born preterm. Despite improved survival, the prevalence of morbidities among extremely preterm infants (born <28 weeks of gestation) remains high, particularly among infants born at the lowest gestational ages (GAs) . MorbidiMetabolomics allows for the detection and quantification of an array of low molecular weight compounds derived from cellular metabolism or exogenous sources and has the potential to provide detailed insights into disease etiology and progression . MetabolThe neonatal period of extremely preterm infants involves the gradual transfer from total or partial parenteral nutrition (PN) to full enteral nutrition (EN). Human milk is always the firsthand choice of enteral feed for preterm infants. In Sweden, all extremely preterm infants receive exclusively human milk, mother’s own milk if available, otherwise, donor human milk, from the day of birth until usually 34 weeks postmenstrual age. Thereafter, a preterm formula may be introduced. Feeding tolerance is strongly linked to the GA at birth, and the most immature infants require the longest time to reach full enteral feeding. Therefore, an infant’s metabolic profile depends on the GA and the postnatal age . FurtherBronchopulmonary dysplasia and ROP are multifactorial diseases with certain common elements but also with distinct pathogenesis. ROP is a neurovascular disease characterized by dysregulated retinal vascularization that can lead to retinal detachment and permanent visual loss if not timely diagnosed and treated. The prevalence of ROP is higher in infants with low GA and low weight at birth . BPD steHere, we assessed the serum metabolic profiles of extremely preterm infants from birth to term equivalent age and analyzed the metabolome in regards to GA, postnatal age, nutrition, and morbidities.ClinicalTrials.gov Identifier: NCT02760472). The Donna Mega trial is a single-center, randomized open-label trial designed to determine the effect of parenterally administered lipids with or without n–3 long-chain polyunsaturated fatty acids (LC-PUFAs) on growth and morbidity outcomes in infants born extremely preterm. Infants were randomly assigned an olive oil-based lipid parenteral emulsion  or a mixed-oil emulsion high in n–3 LC-PUFAs . The results of the primary outcomes of the trial have been previously published  1, 7, 14, and 28, and at postmenstrual age (PMA) 32, 36, and 40 weeks. The blood was allowed to clot at 4°C for a minimum of 45 min and a maximum of 2 h before centrifugation at room temperature at 1500 1H NMR analysis have been published (Serum samples (50 μl) were prepared and then analyzed on an Oxford 800 MHz magnet equipped with an Avance III HD console and 3 mm TCI cryoprobe (Bruker BioSpin). Details of sample processing and the ublished . Tentatiublished . In totaThe Donna Mega trial was approved by the Regional Ethical Review Board, Gothenburg (Dnr 303-11). Informed signed consent for all participants included in the study was obtained from their parents or legal guardians.U-test was used to compare continuous variables with non-normal distribution, and Spearman’s rank test was applied to assess correlations between variables.Mann–Whitney The area under the curve (AUC) for metabolites for PND 1–28 was calculated using the trapezoidal rule. The AUC was divided by the total number of days to yield a daily mean value. Only infants who had a complete sample series during their first 4 weeks of life  were included in this sub-analysis. In instances where no NMR signal could be detected and a peak intergraded, the minimum value/2 was imputed. Six out of 15593 (0.04%) values were imputed using this method.For clustering, the NMR signal of each metabolite was first standardized with a standard deviation of 1 centered at 0. Then, the scaled values from all 503 samples were used to create the Euclidean distance matrix for dendrogram generation. Dendrograms showing metabolite levels in heatmaps have been clustered using the Ward2 algorithm, an implementation of Ward’s minimum variance method implemented as “Ward.D2” in R package pheatmap . SpearmaStatistical analyses were performed using IBM SPSS Statistics version 27  and R-Statistics Software .1H NMR metabolomics was available from 87 out of 90 infants enrolled in the Donna Mega trial , 25–26 weeks GA (n = 36), and 27 weeks GA (n = 18). There was apparent clustering both according to sampling time and GA at birth. Overall, samples from the two lower GA groups (<25 and 25–26 weeks) clustered together and showed larger variability in metabolite levels between time points than samples from the group of infants with the highest GA (27 weeks). Samples collected at PND 1 and PND7 in the two lower GA groups formed a cluster defined by high levels of acetone, creatinine, and phenylalanine. Furthermore, PND 1 samples from GA <27 weeks infants displayed high 3-hydroxyisobutyrate, ethanolamine, and myoinositol levels, among other metabolites. At PMW 40, samples from all three GA groups clustered together, indicating a transient change in the metabolome in infants born at the lowest GAs occurring in the neonatal period.Thirty-one serum metabolites could be unambiguously annotated and quantified in all samples . To overAt PND 1, levels of 7 (23%) of the analyzed metabolites were significantly correlated with GA at birth . NotablyNext, we explored relationships between the infant metabolome, growth, and nutritional parameters by correlating data collected the first 28 postnatal days . About hn = 69). Isoleucine and tyrosine displayed positive correlations with % enteral energy intake, whereas many other (14/31) metabolites were negatively associated, including glycerol, threonine, and creatinine  PND 1–28 with mean metabolite levels. Only infants with complete metabolic profiles from PND 1 to PND 28 were included  and infants who developed severe ROP  (n = 36) or did develop BPD (n = 32), but none remained significant after false discovery rate correction  . Howeverrrection .We longitudinally followed the serum metabolome of extremely preterm infants from birth to term equivalent age. Our results show that the metabolome of the infants undergoes substantial composition changes during the early perinatal period, strongly influenced by the feeding regime, and moreover, relates to GA at birth.The levels of seven serum metabolites on PND 1 significantly correlated with GA at birth . Valine has previously been shown to be the amino acid with the most considerable concentration difference between extremely preterm and full-term infants, demonstrating a GA dependence . Apart fSerum myo-inositol and ethanolamine followed a similar decline after birth to reach plateau levels around PND 28. Both of these metabolites are essential components of membrane phospholipids. A postnatal decrease in myo-inositol is known to occur in preterm infants , and attWe correlated infant serum metabolites with growth parameters and nutritional data collected over the first 4 weeks of infant life. Choline, a compound involved in one-carbon metabolism and phospholipid synthesis, correlated positively with enteral nutrition. Choline is not present in PN solutions, and we previously reported that high parenteral intake is associated with lower infant serum choline . SomewhaDetailed analysis of the relationship between nutrition and metabolites revealed that a majority of the analyzed amino acids in serum were negatively correlated with enteral energy intake . This finding is expected and in line with previous reports showing an increase in infant blood amino acids after parenteral administration of amino acids . Furtherper se in the 1st weeks of life is a known risk factor for ROP (Previous efforts have been made to detect disturbances in metabolic pathways relating to ROP and BPD development. However, the results of these studies have not been conclusive; for studies on ROP, differences likely relate to clinical characteristics of the subjects, timing of sample collection, and analysis platform . In an a for ROP . Metabol for ROP , and the for ROP . As no mThere are limitations to our study. Serum samples used in this study were subjected to one or a few freeze-thaw cycles before analysis, which is a known factor to impact the metabolome . HoweverWe provide a comprehensive view of the evolution of the serum metabolome of extremely preterm infants from birth to term equivalent age. There was large interindividual variability in the metabolome that was partly explained by the GA at birth and by the amount of enteral and parenteral nutrition the infant received. The results from our and other studies imply that there is not a single metabolic biomarker that could satisfactorily distinguish those infants who are at the highest risk to develop ROP or BPD. Instead, enhanced diagnosis of ROP and BPD must likely rely on integrative and multiparameter biosignatures that encompass the complexity of these diseases.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by The Regional Ethical Review Board, Gothenburg. Written informed consent to participate in this study was provided by the participants’ parents or legal guardians.AN, GH, and AH contributed to the conception of the research. AP and DM contributed to the data acquisition. AN, AT, and DM contributed to the analysis of the data. AN drafted the manuscript. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, read and approved the final manuscript, contributed to the design of the research, and contributed to the interpretation of the data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.