Multivariate analysis showed that SI, bacterial vaginosis in the second trimester, previous preterm birth, and smoking during pregnancy were independent risk factors for preterm birth. The combination of SI and second trimester bacterial vaginosis was associated with a 60% preterm birth rate, whereas either factor alone was associated with a lower rate, suggesting a synergistic effect (p < 0.0001). Future studies are needed to investigate the effect of prohibiting SI in pregnant women with bacterial vaginosis on preterm birth.Several studies in Europe and the United States have shown that sexual intercourse (SI) during pregnancy is not associated with preterm birth. However, it is unclear whether these findings apply to pregnant Japanese women. The aim of this prospective cohort study was to elucidate the influence of SI during pregnancy on preterm birth in Japan. A total of 182 women who underwent antenatal care and delivery were included in this study. The frequency of SI was assessed using a questionnaire, and its association with preterm birth was analyzed. The results showed that SI during pregnancy was associated with a significantly higher cumulative preterm birth rate ( Preterm birth is the leading cause of child mortality worldwide, accounting for 35% of neonatal deaths and 18% of deaths in children under 5 years old . AscendiLactobacillus species (spp.) metabolize glycogen and produce lactate acid in vaginal mucosal cells. As a result, the vaginal environment becomes acidic at pH 3.5–4.0, inhibiting bacterial growth other than those of Lactobacillus spp. Thus, Lactobacillus spp. become dominant during pregnancy due to a marked increase in circulating estrogen, preventing ascending genital tract infection [Lactobacillus spp.-dominant microbiota and an overgrowth of commensal anaerobic bacteria [nfection ,7. Bactebacteria , and carbacteria . Africanbacteria . Antibiobacteria ,12,13,14Lactobacillus spp.-dominant vaginal microbiome and are less prone to bacterial vaginosis [Sexual intercourse (SI) during pregnancy has been considered a possible cause of preterm birth due to bacterial overgrowth in the birth canal, increased serum oxytocin levels, and uterine contractions induced by physical stimulation ,16,17. Oaginosis , but simThis is the first prospective cohort study to investigate the influence of SI on preterm birth in Japan, the least sexually active country. The results of this study will provide evidence for whether lifestyle advice about SI during pregnancy should vary by culture, race, and country.A single-center prospective cohort study at Kindai University Hospital was conducted on patients who underwent antenatal care and delivery from May 2018 to September 2019. This study was approved by the Ethics Review Board of Kindai University  and written consent was obtained from all subjects. All methods were performed in accordance with the relevant guidelines and regulations.The sexual intercourse (SI) frequency in the second and in the third trimester were surveyed at 30 weeks of gestation and after delivery on day 1–4 postpartum, respectively. Subjects completed the questionnaire alone in a room to protect their privacy. Answer sheets were collected in a box out of sight of health care providers.The screening was performed in the first trimester (10–12 weeks of gestation) and second (24–27 weeks of gestation). Our recent analysis of 1495 pregnant Japanese women demonstrated that a Nugent score (NS) . Based oMaternal age, parity, history of preterm birth, smoking during pregnancy, and pregnancy outcomes were extracted from the medical records.A thorough search was conducted on PubMed/MEDLINE encompassing the years from 1981 to 2022 using the terms: “sexual intercourse”, “coitus”, “sexual behavior” and “pregnancy”, and 1401 articles were extracted. A total of 46 articles, including 32 articles reported from 1981 to 2016, were reviewed in a relevant systematic review , in addip-value of 0.05. Enrollment continued throughout the enrollment period to ensure the study’s accuracy. Cumulative preterm birth rates were calculated using the Kaplan–Meier method. Univariate analysis and multivariate analysis using the Cox proportional hazards model for preterm birth risk factors was performed with EZR version1.5.5 [p value < 0.05 was considered statistically significant.The primary endpoint was to analyze whether SI during pregnancy increases preterm birth. The assumption for calculating the number of subjects was that the preterm birth rate was predicted to be 20% in the sexually active group and 5% in the control group. Assuming a ratio of 1:1 for those 2 groups, a total of 172 cases were required in order to achieve a power of 80% for detecting a difference in proportion of 0.15 between the 2 groups at a 2-sided ion1.5.5 . Other sp = 0.018, p < 0.0001, 182 of the 205 eligible women completed the questionnaire on sexual intercourse (SI) during pregnancy. Patients at an increased risk of sexually transmitted diseases were not included. In total, 63 (34%) patients had SI at least once during pregnancy and 35 (19%) of those patients had SI after 28 weeks’ gestation. Pregnant women who had SI during pregnancy had a significantly higher cumulative preterm birth rate than those who did not . Previous history of preterm birth and smoking during pregnancy were significantly associated with an increased preterm birth rate   and those without bacterial vaginosis (NS ≤ 6) in the first trimester A. In thectively) C,D. Matectively) E,F. ScreCox proportional hazards regression analysis was performed in order to evaluate risk factors for preterm birth. In univariate analysis, SI, bacterial vaginosis in the second trimester, previous preterm birth, and smoking during pregnancy were significantly associated with preterm birth. They were independent risk factors in multivariate analysis .p < 0.0001), indicating a synergistic effect  rate was 86 97–35)%. The SI rate tended to be lower in East Asia, and the 34% observed in this study was the lowest. There were two trends in the change in the SI rate during pregnancy: four studies showed a decrease from the first to the second trimester ,31,33,35%. The SIp value < 0.05 shown in Sexual intercourse (SI) during pregnancy has not been associated with preterm birth in previous studies ,19,20,44Bacterial vaginosis has been considered a preterm birth risk ,46, and Further investigation is required to elucidate how SI leads to preterm birth in pregnant women with bacterial vaginosis. One possible mechanism is that SI pushes vaginal bacteria into the cervix. Inflammatory cytokines and prostaglandins in the vaginal secretions of women with bacterial vaginosis are significantly higher than in healthy women , resultiThe results of this study suggest that the treatment of bacterial vaginosis in pregnant women could be effective in preventing preterm birth. Our previous retrospective cohort study showed that an improvement in bacterial vaginosis with metronidazole tended to reduce preterm birth. However, in the overall population, metronidazole did not reduce preterm birth because of drug resistance . ClinicaFurther research is needed in order to include the strategies suggested by the present study in clinical practice. Firstly, the number of sexually active patients with bacterial vaginosis was small n = 8,  because The present study is the first to show the SI rate and frequency for pregnant Japanese women, which is extremely low compared to studies in other countries. This study also demonstrated that SI was associated with an increased risk of preterm birth. The exploratory analysis indicated the markedly increased risk of preterm birth when SI was combined with bacterial vaginosis, suggesting that treatment including lifestyle advice prohibiting SI for pregnant women with bacterial vaginosis may be beneficial. Further studies are necessary to investigate the reproducibility of the results in this study with larger sample sizes and to elucidate the effect of SI prohibition for pregnant women with bacterial vaginosis on preterm birth in randomized intervention trials.


Birth asphyxia is of significant concern because it impacts newborn health from low to severe levels. In Thailand, birth asphyxia remains a leading cause of delayed developmental health in children under 5 years old. The study aimed to determine the maternal, fetal and health service factors contributing to birth asphyxia.A case–control design was conducted on a sample of 4256 intrapartum chart records. The samples were selected based on their Apgar scores in the first minute of life. A low Apgar score (≤ 7) was chosen for the case group (852) and a high Apgar score (> 7) for the control group (3408). In addition, a systematic random technique was performed to select 23 hospitals, including university, advanced and secondary, in eight health administration areas in Thailand for evaluating the intrapartum care service. Data analysis was conducted using SPSS statistical software.The odds of birth asphyxia increases in the university and advanced hospitals but the university hospitals had the highest quality of care. The advanced and secondary hospitals had average nurse work-hours per week of more than 40 h. Multivariable logistic regression analysis found that intrapartum care services and maternal–fetal factors contributed to birth asphyxia. The odd of birth asphyxia increases significantly in late–preterm, late–term pregnancies, low-birth weight, and macrosomia. Furthermore, maternal comorbidity, non-reassuring, and obstetric emergency conditions significantly increase the odd of birth asphyxia. In addition, an excellent quality of intrapartum care, a combined nursing model, low nurse work-hours, and obstetrician-conducted delivery significantly reduced birth asphyxia.Birth asphyxia problems may be resolved in the health service management offered by reducing the nurse work-hours. Excellent quality of care required the primary nursing care model combined with a team nursing care model. However, careful evaluation and monitoring are needed in cases of comorbidity, late–preterm, late–term pregnancies, low-birth weight, and macrosomia. Furthermore, increasing the obstetrician availability in obstetric emergencies and non-reassuring fetal status is important.The online version contains supplementary material available at 10.1186/s12884-023-05885-y. Birth asphyxia is the failure to initiate and sustain spontaneous breathing at birth, causing permanent brain cell damage and threatening the newborn's life. The recovery process requires lengthy hospital observation and intensive care, and may take a lifetime –4. BirthBirth asphyxia is a significant concern in Thailand due to its higher birth rate (16.0 per 1000 live births in 2021) compared to developed countries (1.5 per 1000 live births) , 9. The Previous studies reported that maternal–fetal factors affect birth asphyxia such as maternal age, BMI, gestational age, ANC visit, maternal health and obstetric complications , 11–14. Moreover, regarding the model of intrapartum care, literature reviews indicated that continuing care or the primary nursing care model was beneficial to perinatal outcomes and reduced neonatal death rates –33. AlthDespite a growing research interest in human resources and health outcomes, there is still a lack of evidence on the effects of healthcare service factors on birth asphyxia. Most research has focused on maternal and fetal factors, with less attention given to hospital factors and birth asphyxia. Therefore, this case–control study was aimed at determining intrapartum health services and maternal–fetal factors that contribute to birth asphyxia at three levels of hospital: university, advanced and secondary. In addition, it is hoped that the research findings will serve as an evidence base for developing national strategic proposals for improving maternal and fetal health outcomes and solving the disparity among intrapartum health services in Thailand.+0–41+6 weeks, admitted with signs of labour onset and delivered with a low Apgar score (≤ 7) at the first minute of life, were selected as the case group (852) and those with an Apgar score of > 7 as the control group (3408). Month and type of delivery were matched in the case and control groups. Pregnant women with twin or congenitally abnormal fetuses were excluded.The case–control study was designed to collect data from 4256 intrapartum care charts recorded in 23 hospitals in Thailand from 2016 to 2017. Pregnant women of gestational age 34The sample size was determined from the study by Berazategui et al. . The numThe number of estimated hospitals required for collecting data was based on a multilevel research design. The standardized proportion difference as an effect measure was applied to calculate the number of research settings needed to conduct the research .\documend = proportion difference as an effect sizep0 = proportion of birth asphyxia in secondary hospitals (0.011)p1 = proportion of birth asphyxia in primary hospitals (0.0068)pooled = pooled standard error of birth asphyxiaσn0 = number of cases of birth asphyxia in secondary hospitals (7231)n1 = number of cases of birth asphyxia in primary hospitals (6433)Zα/2 = percentile at (1 – α/2)100% of standard normal for two-sided t-test with α level of significance (i.e. Z0.025 = 1.96)Zβ = percentile at (1 – β) 100% of standard normal for power of test with 1 – β (i.e. Z0.2 = 0.84)ρ = intraclass correlation of birth asphyxia with hospitals ni = sample size average per hospital of birth asphyxia nj = hospital size estimatesnj) equals 23 hospitals. A Systematic random sampling technique was used to select the research setting . Frequencies and percentages were used to describe the maternal–fetal factors and health service structure. The intrapartum care quality data were calculated for frequency and rate. The intra-class correlation coefficient (ICC) tested for intrapartum health service level variance had a value of > 0.1 .p < 0.05) with the entering method. Furthermore, model testing for predictive factors was performed by considering the assumption for statistics using multilevel logistic regression analysis. The two required assumptions were that there was no multicollinearity for each independent variable and that the variance–covariance matrices were equal [Based on the results of the ICC tests for this study, the ICC value was < 0.1, which indicates that there were no variations of hospital level. Nevertheless, the variations of hospital levels were already explained as the independent variables of research. Therefore, multivariable logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for predictive factors associated with birth asphyxia. All independent variables were analysed using a univariable model to select the independent variables  during October 2017 to September 2018. The total rate of birth asphyxia was 38.19 per 1000 live births. The total rates of birth asphyxia in advanced hospitals  and university hospitals  were higher than in secondary hospitals . Furthermore, university hospitals had the highest rate of severe birth asphyxia , followed by advanced hospitals . The highest number of non-delivered high-risk pregnancies was found in university hospitals . Furthermore, the caesarean section rate in university hospitals was the highest , followed by advanced hospitals  and the lowest in the secondary hospitals . The nurse-to-client ratios in the university hospitals  and the advanced hospitals  were also higher than in the secondary hospitals . Of the 325 nurse-midwives, 44.62% had worked for ≥ 10 years. The mean nurse-midwife work-hours per week were 46.38 ± 6.78 h. Furthermore, the study found that nurse-midwives in advanced and secondary hospitals work for > 40 h per week . The study found that the team nursing care model was the most common (Table Table p < 0.001). Furthermore, deliveries conducted by residents or general physicians significantly increased the odds of birth asphyxia to 2.06 times for deliveries by obstetricians . As for gestational age, the odd of birth asphyxia increased significantly by 1.69- and 1.53-fold at late-preterm (34+0–36+6 weeks) and late-term (41+0–41+6 weeks), respectively, compared to full-term deliveries (37+0–40+6 weeks): 95% CI = 1.43–2.01 (p = 0.000) and 95% CI = 1.08–2.16 (p = 0.018), respectively. The odd of birth asphyxia was also significantly higher in the nulliparous group than the multiparous group . The odd of birth asphyxia increased significantly by 2.31- and 1.99-fold in low-birthweight newborns (≤ 2500 g) and newborns with macrosomia (≥ 4000 g), respectively, compared to the normal-weight newborns (2501–3999 g): 95% CI = 1.81–2.95 (p = 0.000) and 95% CI = 1.32–3.00 (p = 0.001), respectively. Furthermore, the odd of birth asphyxia was significantly increased in the maternal–fetal high-risk groups: maternal comorbidity, 1.73-fold ; fetal complications, 2.21 -fold ; and obstetric emergency, 1.87-fold . In particular, non-reassuring fetal status significantly increased the odd of birth asphyxia by 3.07-fold .Table p < 0.001). Furthermore, deliveries conducted by residents or general physicians significantly increased the odds of birth asphyxia to 2.06 times for deliveries by obstetricians . As for gestational age, the odd of birth asphyxia increased significantly by 1.69- and 1.53-fold at late-preterm (34+0–36+6 weeks) and late-term (41+0–41+6 weeks), respectively, compared to full-term deliveries (37+0–40+6 weeks): 95% CI = 1.43–2.01 (p = 0.000) and 95% CI = 1.08–2.16 (p = 0.018), respectively. Birth asphyxia was also significantly higher in the nulliparous group than the multiparous group . The odd of birth asphyxia increased significantly by 2.31- and 1.99-fold in low-birthweight newborns (≤ 2500 g) and newborns with macrosomia (≥ 4000 g), respectively, compared to normal-weight newborns (2501–3999 g): 95% CI = 1.81–2.95 (p = 0.000) and 95% CI = 1.32–3.00 (p = 0.001), respectively. Furthermore, odd of birth asphyxia was significantly increased in the maternal–fetal high-risk groups: maternal comorbidity, 1.73-fold ; fetal complications, 2.21 -fold ; and obstetric emergency, 1.87-fold . In particular, non-reassuring fetal status significantly increased the odd of birth asphyxia by 3.04-fold .Table p < 0.001. The Nagelkerke R2 value of 0.140 suggests that approximately 14% of the variation in the response variable is explained by the predictors included in the logistic regression model. The analysis indicated that the odd of birth asphyxia was significantly higher with good care quality compared to excellent care quality . Birth asphyxia was significantly reduced by 38% for nurse work-hours of < 40 h per week . Furthermore, the results show that birth asphyxia was significantly reduced by 26% when the combined nursing care model (primary and team) was applied in hospitals compared to the team nursing care model . In contrast, the primary care model had significantly higher the odd of birth asphyxia than the team nursing care model . The odd of birth asphyxia was significantly increased when the newborn was delivered by a resident or general physician rather than by an obstetrician . Moreover, delivery in the late-preterm and late-term groups significantly increased odd of birth asphyxia compared to the full-term pregnancy group . Pregnancies with comorbidity, obstetric emergency, non-reassuring fetal status, low birthweight or macrosomia significantly increased odd of birth asphyxia .However, the multivariable logistic regression results for the factors contributing to birth asphyxia. According to the chi-square statistic model, the overall model is significant at This case–control study aimed to determine the maternal–fetal and health service factors contributing to birth asphyxia. Among the 4256 samples, the average rate of birth asphyxia was 38.19 per 1000 live births. Although advanced hospitals had the highest rate of birth asphyxia (52.24 per 1000 live births), university hospitals had the highest rate of severe birth asphyxia (6.53 per 1000 live births), possibly due to the number of high-risk deliveries referred from other facilities.+0–36+6 weeks and of low birthweight are associated with birth asphyxia. The immature pulmonary function may make it difficult for the fetus to maintain breathing after birth. Likewise, the placental deterioration in post-term neonates increases the likelihood of birth asphyxia more than in pregnancies delivered at term. Therefore, non-spontaneous late-term deliveries should be avoided in order to reduce birth asphyxia. Antenatal surveillance is recommended at 40+0–41+6 weeks, beginning twice weekly with the biophysical profile or non-stress testing plus amniotic fluid index measure, along with induction at 41+0 weeks’ gestation [Multivariable logistic regression analysis found significant increases the odds of birth asphyxia in late-preterm, late-term, low-birth weight, and macrosomia fetuses. This result was supported by previous studies finding that neonates born at 34estation .Furthermore, the study found that birth asphyxia increases significantly in pregnant women with comorbidities and obstetric emergency conditions. Maternal complications such as gestational hypertension and diabetes may cause utero-placental insufficiency, resulting in reduced blood flow and loss of placental integrity that predisposes the fetus to intrauterine hypoxia –46. An oThe research findings revealed that an excellent level of intrapartum care quality reduces birth asphyxia. Careful monitoring, such as partograph use for monitoring the descent of the fetal head to identify the cephalo-pelvic disproportion promptly, can effectively reduce birth asphyxia. Continuous fetal heart rate monitoring in non-reassuring fetal conditions can shorten the decision-to-delivery time and reduce the severity of hypoxic-ischaemic encephalopathy in newborns , 52. AppFurthermore, the research found that the combined primary and team nursing care model significantly lowered birth asphyxia compared to the team nursing care model. The result is different from the previous study, which found that the one-on-one care or primary/total patient care model can ensure that pregnant women received closer and more continuous care and had more desirable outcomes than other nursing models . HoweverLastly, the study found that newborns delivered by a resident or general physician had a higher risk of birth asphyxia. This may be because the general physicians or residents may not be trained to deal with complicated patients referred to the advanced and university-level hospitals. The high workload condition made it difficult to improve the quality of nursing care, therefore medical work experience requires the obstetrician to be closely supervised in order to improve client health outcomes .Pregnant women with comorbidity and late-preterm, late-term pregnancies, low-birth weigh, and macrosomia need close monitoring to prevent birth asphyxia. In addition, an appropriate number of nurse-midwives allocated in the advanced hospitals is needed to resolve the high workload, transferring non-intrapartum pregnant women with high-risk conditions to the appropriate unit to be managed by a specialized multidisciplinary team. Furthermore, the intrapartum nursing care model driven by applying the primary care model combined with the team model is feasible for providing good quality care.The retrospective case–control study was designed for data extraction from medical chart reviews, therefore unreported healthcare activity was not available to clarify the quality of intrapartum care.To ensure that birth asphyxia did not develop from immature fetal lungs or placental insufficiency, the research samples did not include very preterm and or post-term fetuses in the selection criteria and therefore such fetuses were not considered as factors affecting birth asphyxia in this study.Birth asphyxia in Thailand is a serious problem that requires more attention. An excellent level of intrapartum care quality is required to reduce the birth asphyxia rate, carefully evaluating and monitoring pregnant women with comorbidity, late-preterm and late-term pregnancies and newborns with low birthweight or macrosomia. The primary care model combined with the team nursing care model is the alternative strategy to improve the quality of care in the intrapartum unit. In addition, obstetric emergencies need early detection and appropriate intervention by a specialized care team to enhance staff allocation and reduce the nurse work-hours per week .Additional file 1. Intrapartum Care Record Form.Additional file 2. Asphyxia Risk Factors Record Form.Additional file 3. Intrapartum Health Care System Questionnaire.


P < 0.001), and one microgram/mL increase in adiponectin was associated with a 9% decrease in the odds of giving birth to an LGA infant . The associations did not withstand in the adjusted models. We found a significant interaction between adiponectin and infant sex on birth size. This interaction was driven by an inverse association between maternal adiponectin and birth size in female infants, whereas no such association was found in males.This study aimed to evaluate the association of maternal adiponectin with infant birth size in 1349 pregnant women at Uppsala University Hospital, Sweden. The mean age of the women was 31.0 years, and 40.9% were nulliparous. Maternal early mid-pregnancy adiponectin was measured in microgram/mL. Linear regression models were performed to evaluate the association between adiponectin and infant birth weight. Logistic regression models were used to evaluate adiponectin in relation to the odds of giving birth to an infant large-for-gestational-age . Adjustments were made for early pregnancy BMI and diabetes mellitus. Prior adjustments, adiponectin was inversely associated with infant birth weight  − 26.8 to − 7.4 g,  Excessive fetal growth is observed among women with obesity2 and diabetes mellitus3. Increased nutrient availability and elevated insulin levels promoting fetal growth are proposed as mechanisms behind these observations4.The intrauterine milieu has a considerable impact on fetal growth and later on the birth weight of the infant1 run an increased risk of complications at delivery, such as asphyxia, birth trauma, meconium aspiration, and stillbirth6. In the long term, infants born with a high birth weight are at increased risk of developing obesity and diabetes mellitus later in life7.A high birth weight is associated with infant morbidity and mortality, and prediction of a high birth weight is therefore of clinical importance. High birth weight infants (≥ 4000 g or ≥ 4500 g)8. Sex-specific differences in placental function has been suggested as one of the underlying mechanisms behind this fetal growth disparity1. For example, the fetal-placental unit of males is proposed to prioritize growth pathways, whereas that of females instead invests in placental reserve capacity9. In addition, sex-specific differences in early pregnancy placental biomarkers have been reported, indicating a possible impact of fetal sex on early placentation10.The average birth weight differs between female and male infants, the latter often being heavier13. The first two trimesters of pregnancy are anabolic. During this period, maternal fat stores expand due to increased calorie intake and enhanced lipogenesis11. Contrarily, late pregnancy is a catabolic state with decreased insulin sensitivity and hypertriglyceridemia13.Multiple endocrine and metabolic adaptions take place during pregnancy to secure sufficient energy and nutrient supply to the fetus14. The adipokine adiponectin has anti-inflammatory and insulin sensitizing properties15. There is an inverse relation between adiponectin levels and BMI; circulating adiponectin levels are lower in obese individuals compared with those with a normal weight16. Low adiponectin levels are also associated with diabetes mellitus type 217, and low adiponectin levels early in pregnancy are associated with development of gestational diabetes mellitus18. A meta-analysis suggests that adiponectin could be used in risk evaluation of gestational diabetes19. In fact, adiponectin and its receptors have been proposed as promising targets for intervention in obese pregnant women with low circulating adiponectin20.The fat tissue is as an important endocrine organ, regulating appetite, energy expenditure, and metabolism through adipokine secretion21. The decrease in adiponectin is seen in both normal weight and obese pregnant women, but is more profound among normal weight individuals22.First trimester adiponectin levels do not differ from those in non-pregnant individuals. However, adiponectin levels increase during pregnancy. The levels are highest around mid-pregnancy and decrease thereafter25. Ahlsson et al.23 reports an inverse relation between late-pregnancy adiponectin and maternal fat mass, insulin resistance, and estimated fetal weight in twenty non-diabetic pregnant women. The study did not include maternal BMI in the analyses. Retnakaran et al.24 demonstrates a negative association between late-pregnancy adiponectin and birth weight in 472 pregnant women after adjustments for maternal BMI. Likewise, Lowe et al.25 reports an inverse association of adiponectin measured in late pregnancy with birth weight in a cohort of 1477 women, with BMI included in the models. These findings suggest that low adiponectin levels might be of importance in the mechanisms linking obesity to excessive fetal growth.Previously, a correlation between maternal adiponectin levels and infant birth size has been demonstratedWe hypothesized that maternal adiponectin is associated with infant birth size and the risk of giving birth to a large-for-gestational-age (LGA) infant, and that there might be sex-specific differences. This study aimed to investigate the association between circulating levels of adiponectin measured in early mid-pregnancy and birth weight as well as the prevalence of LGA infants in a cohort of 1349 women and child-dyads.26.This study was based on data derived from the Uppsala Biobank for Pregnant Women. From 2007, blood samples were collected in this population-based biobank in conjunction with the second-trimester anomaly scan at 16‒20 weeks’ gestation at Uppsala University Hospital, Uppsala, Sweden. Pregnant women who were ≥ 18 years, Swedish-speaking, and without blood-borne disease  were invited to donate a blood sample to the Biobank. The Biobank is a convenience sample since invitations were performed when a research nurse was available. Approximately 30% of the respondents declined to participate. After acceptance to participate, a written informed consent was obtained. Overall, the Biobank is estimated to cover approximately half of Uppsala County´s pregnant population and a sub-population was selected for this study2 at the first antenatal visit and a singleton pregnancy (n = 755). Out of these, all women with BMI ≥ 35.0 kg/m2 (n = 256) and a random sample of women with BMI 30.0‒34.9 kg/m2 (n = 339) were included in the study (n = 595). We also included a random sample of women from the biobank with BMI 25.0‒29.9 kg/m2 (n = 437) and BMI 18.5‒24.9 kg/m2 (n = 469). Hence, the study population consisted of 1501 pregnant women. Subsequently, we excluded women who gave birth preterm (< 37 weeks + 0 days) (n = 40), post-term (> 41 weeks + 6 days) (n = 107), and cases with missing birth weight (n = 5). Hence, the final study population consisted of 1349 pregnant women who gave birth to singleton, term infants between January 2008 and August 2013.We identified all women who had donated a blood sample to the biobank who had body mass index (BMI) ≥ 30.0 kg/mThe study was approved by the Regional Ethical Review Board in Uppsala (Dnr: 2014/353). All research was performed in accordance with relevant national and international guidelines.27.A questionnaire was filled out by the women in conjunction with the blood sampling including age, height, weight, smoking habits, medication and chronic disorders. Body mass index was calculated as the weight in kilograms divided by the square of the height in meters. Information on infant birth weight, sex, and gestational age at birth was obtained from the standardized antenatal and delivery medical records. We calculated birth weight standard deviation scores (BWSDS) by the use of Swedish reference standards for birth weight with respect to sex and gestational age28.The exposure of this study was the maternal adiponectin level at pregnancy week 16‒20. Blood samples were collected with venesection by a research nurse, centrifuged within 2 h, and stored at -70 °C. All laboratory analyses were performed at the Clinical Chemistry Laboratory, Uppsala University Hospital. Adiponectin was analyzed by commercial sandwich ELISA kits from R&D Systems  with a limit of detection of 2 ng/mL. Multiple linear regression models were used to evaluate the association of adiponectin levels with infant birth weight in grams and BWSDS. The observed standardized residuals of the linear regression models were normally distributed. The VIF (variance inflation factor) values were ≤ 1.4, indicating that multicollinearity was not an issue in the model. Logistic regression models were performed to evaluate adiponectin levels in relation to the odds of giving birth to an LGA infant (BWSDS > 90th percentile). Covariates included in the models evaluating birth size were early pregnancy BMI and pregestational or gestational diabetes mellitus (yes or no). These covariates were identified by drawing and analyzing a directed acyclic graph (DAG) . This interaction analysis was followed by linear and logistic regression analyses evaluating the relation between adiponectin and birth size on female and male infants separately.The statistical analyses were performed by the use of IBM SPSS Statistics version 28. A nominal two-sided P-value < 0.05 was considered to indicate statistical significance. Non-parametric tests were chosen because the adiponectin levels were not normally distributed according to Shapiro-Wilks test. Differences in adiponectin levels (microgram/mL) between the World Health Organization BMI classes were determined by Kruskal–Wallis test followed by post-hoc paired tests with Bonferroni correction for multiple testing. Spearman’s correlation coefficients were calculated to evaluate the relations between early pregnancy BMI, maternal age, adiponectin, and infant birth sizeThe study population consisted of 1349 mother and child-dyads. The women were between 18 and 48 years of age, 552 (40.9%) were pregnant with their first child, and 915 (67.8%) had either overweight (BMI ≥ 25) or obesity (BMI ≥ 30). The study population characteristics are presented in Table The overall range of adiponectin was 0.52‒18.20 µg/mL. The adiponectin measures according to BMI classes are presented in Supplementary Table P < 0.001) (Table P = 0.953)  − 26.8 to − 7.4 g, P = 0.006), but the association did not withstand in the adjusted model    in female infants (Supplementary Table  P = 0.013) among female infants  is probably not the main mechanism linking low circulating adiponectin to excessive fetal growth and subsequently increased birth weight.30. Hence, it seems that sex-specific adaptions to in-utero environmental changes occur, but the precise mechanisms behind are unknown. Nonetheless, altered placental function and feto-placental hormonal changes may contribute to the sex-specific divergences in adaption to intra-uterine milieu variations9.We found an inverse association between adiponectin and birth size in female infants, but not in males. To the best of our knowledge, this is the first study to evaluate the relation between maternal adiponectin levels and infant birth size in females and males separately. We have previously reported on sex-specific differences regarding maternal blood-based proteins measured in early mid-pregnancy in relation to infant birth size32. Migda et al.31 reports lower first trimester adiponectin levels among women delivering macrosomic (> 4000 g) and LGA-infants compared with controls. The study did not adjust for maternal BMI. Wang et al.32 measured maternal adiponectin right before delivery in 100 mother-and-child dyads. The results demonstrate decreased adiponectin levels in women giving birth to macrosomic infants compared with controls. Of note, BMI was not included in the analyses. Moreover, the authors investigated placental adiponectin expression and report reduced adiponectin expression in placentas from women delivering macrosomic infants compared with control mothers. In line with these findings, early pregnancy adiponectin has been suggested as a feasible biomarker in prediction of macrosomic infants33. Interestingly, a study investigating adiponectin measures multiple times during pregnancy reports that women giving birth to LGA infants had the largest decrease in adiponectin throughout their pregnancy34.An inverse association of maternal adiponectin with infant birth size has been described by other investigators35 and the adiponectin receptors ADIPOR1 and ADIPOR2 are expressed by placental cells36. Actually, expression of ADIPOR2 in the placenta differs between obese and non-obese women, with a down-regulation among obese pregnant individuals37. By these receptors, adiponectin could influence placental nutrient transport to the fetus and thereby regulate fetal growth. It is shown that adiponectin inhibits the expression of glucose and amino acid transporters in placental cells, which could limit nutrient availability for the fetus. In addition, adiponectin can induce placental apoptosis. Hence, placental function, and subsequently fetal growth, could be affected by maternal adiponectin through inhibition of nutrient transport expression as well as apoptosis activation38.The mechanisms underpinning the association between low circulating maternal adiponectin and increased birth weight are not fully understood. However, several explanations have been proposed on this matter. Fetal growth, and subsequently infant birth weight, is dependent on adequate nutrient transport from the placenta. Maternal adiponectin does not cross the placenta to the fetal circulation, but both adiponectin39. Another study comparing adiponectin infusion with sham injection in obese mice demonstrates reduced fetal size in mice administered adiponectin compared with controls, strengthening the hypothesis that adiponectin could be a link between maternal fat tissue and fetal growth40.The relation between adiponectin and birth size has been investigated in animal studies. Pregnant mice were given adiponectin infusions and fetal growth was evaluated. The results show an 18% decrease in fetal weights among mice given adiponectin compared with controls42. In addition, we found that maternal BMI had a stronger correlation with birth size than did adiponectin.Our results showed an inverse relation between adiponectin and maternal BMI, which is in line with previous findingsThis study has limitations and strengths. The cross-sectional design of this study is a limitation since we were not able to investigate a possible longitudinal association between adiponectin and birth weight. Previous studies investigating the relation between maternal adiponectin levels and infant birth size are performed on smaller study samples compared with this present study, especially those evaluating early pregnancy adiponectin. This study contributes to the field by confirming the association between maternal adiponectin measured in early pregnancy and birth size in a large population-based cohort of pregnant women. It should be noted that there was no independent association between adiponectin and birth weight, the association disappeared when maternal BMI was added to the models. To the best of our knowledge, this is the largest study evaluating maternal early pregnancy adiponectin levels in relation to infant birth size and the likelihood of giving birth to an LGA infant, including sex-stratified analyses. Yet another strength is the population based setting, increasing the generalizability of the results.This study confirmed previous work showing an inverse relation between maternal early mid-pregnancy adiponectin and infant birth weight and the likelihood of giving birth to an LGA infant. However, the association between adiponectin and birth size was not independent of maternal BMI. There were also sex-specific differences, the association between adiponectin and birth size was observed only in female infants, not in males. Hence, adiponectin could possibly be a factor linking maternal fat accumulation mechanistically to fetal growth and subsequently birth size in female infants.Supplementary Information.


To describe the perinatal mortality rate (PMR) of birth defects and to define the relationship between birth defects (including a broad range of specific defects) and a broad range of factors.χ2trend) were used to determine trends in PR and PMR by year, maternal age, income, education level, parity, and gestational age of termination. Crude odds ratios (ORs) were calculated to examine the association of each maternal characteristic with perinatal deaths attributable to birth defects.Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2010–2020. The prevalence rate (PR) of birth defects is the number of birth defects per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond). PMR is the number of perinatal deaths per 100 fetuses. PR and PMR with 95% confidence intervals (CI) were calculated using the log-binomial method. Chi-square trend tests . Congenital heart defects caused the most perinatal deaths (2264 cases); the PMR was 23.15%. PMR is highest for encephalocele (86.79%). Birth defects accounted for 45.01% (7454 cases) of stillbirths, and 96.16% (7168 cases) were selective termination of pregnancy. Perinatal deaths attributable to birth defects were more common in rural than urban areas  and in females than males . PMR of birth defects showed downward trends with rising maternal age , income , maternal education level , parity  and gestational age of termination .Our study included 1,619,376 fetuses, a total of 30,596 birth defects, and 18,212 perinatal deaths  were identified. The PR of birth defects was 18.89‰ (95%CI: 18.68–19.11), and the total PMR was 1.12%(95%CI: 1.11–1.14). Birth defects accounted for 42.0% (7657 cases) of perinatal deaths, and the PMR of birth defects was 25.03%. From 2010 to 2020, the PMR of birth defects decreased from 37.03% to 2010 to 21.00% in 2020, showing a downward trend (In summary, birth defects are an important cause of perinatal deaths. Rural areas, female fetuses, mothers with low maternal age, low income, low education level, low parity, and low gestational age of termination were risk factors for perinatal deaths attributable to birth defects. Future studies should examine the mechanisms. Our study is helpful for intervention programs to reduce the PMR of birth defects. Perinatal deaths were the combination of fetal and neonatal deaths, including infant deaths that occur at less than 7 days of age and fetal deaths with a stated or presumed period of gestation of 28 weeks or more . Birth dAnalysis of the epidemiology of perinatal deaths attributable to birth defects has significant implications for clinical care and consultation , 12 and Therefore, we conducted an epidemiological study on perinatal deaths attributable to birth defects based on data from the Birth Defects Surveillance System in Hunan Province, south-central China (from 2010 to 2020), to describe the PMR of birth defects, and to define the relationship between birth defects (including a broad range of specific defects) and a broad range of factors.This study is a record analysis of hospital-based surveillance. This study used data from the Birth Defects Surveillance System in Hunan Province, China, 2010–2020, which is run by the Hunan Provincial Health Commission and involves 52 representative registered hospitals in Hunan Province. Surveillance data of fetuses (births and deaths at 28 weeks of gestation and beyond) and all birth defects included demographic characteristics such as residence, gender, maternal age, and other key information.According to the WHO International Classification of Diseases , birth defects were classified into 23 subtypes: anencephaly (Q00), spina bifida (Q05), encephalocele (Q01), hydrocephalus (Q03), cleft palate (Q35), cleft lip (Q36), cleft palate with cleft lip (Q37), microtia/anotia , other external ear defects (Q17), esophageal atresia (Q39), atresia of rectum and anus (Q42), hypospadias (Q54), extrophy bladder (Q64.1), talipes equinovarus (Q66.0), polydactyly (Q69), syndactyly (Q70), limb reduction , diaphragmatic hernia (Q79.0), omphalocele (Q79.2), gastroschisis (Q79.3), conjoined twins (Q89.4), Down syndrome (Q90), congenital heart defects (Q20-26) or ‘other’ .Perinatal deaths include stillbirths  and early neonatal deaths (infant deaths less than 7 days of age). PR of birth defects is the number of birth defects per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond). PMR is the number of perinatal deaths per 100 fetuses.The study was approved by the Hunan Provincial Maternal and Child Health Care Hospital. (NO: 2022-S051). It is a retrospective study of medical records; all data were fully anonymized before we accessed them. Moreover, we deidentified the patient records before analysis. We confirmed that all experiments were performed following relevant guidelines and regulations. We confirmed that informed consent was obtained from all subjects and/or their legal guardian(s). Doctors obtain consent from pregnant women before collecting surveillance data, witnessed by their families and the heads of the obstetrics or neonatal departments. Doctors obtain consent from their parents or guardians for live births witnessed by their families and the heads of the obstetrics or neonatal departments. Since the Health Commission of Hunan Province collects those data, and the government has emphasized the privacy policy in the “Maternal and Child Health Monitoring Manual in Hunan Province”, there is no additional written informed consent.To carry out surveillance, the Hunan Provincial Health Commission formulated the “Maternal and Child Health Monitoring Manual in Hunan Province”. Data were collected and reported by experienced doctors. To reduce the integrity and information error rates of surveillance data, the Hunan Provincial Health Commission asked the technical guidance departments to conduct comprehensive quality control each year.χ2trend) were used to determine trends in PR and PMR by year, maternal age, income, education level, parity, and gestational age of termination. Crude odds ratios (ORs) were calculated to examine the association of each maternal characteristic with perinatal deaths attributable to birth defects. Statistical analyses were performed using SPSS 18.0 .We calculated the PR, PMR, and its 95% confidence intervals (CI) by the log-binomial method. Chi-square trend tests , while the PMR attributable to birth defects was stable  were identified. The PR of birth defects was 18.89‰(95%CI: 18.68–19.11), and the total PMR was 1.12%(95%CI: 1.11–1.14). Birth defects accounted for 42.0% (7657 cases) of perinatal deaths, and the PMR of birth defects was 25.03%. From 2010 to 2020, the PMR of birth defects decreased from 37.03% to 2010 to 21.00% in 2020, showing a downward trend  of stillbirths, and 96.16% (7168 cases) were selective TOP. In other words, most perinatal deaths caused by birth defects were TOP. Similar to the total perinatal deaths, from 2010 to 2020, the stillbirth rate attributable to birth defects was stable , income , maternal education level , parity  and gestational age of termination   and in females than males . PMR of birth defects showed downward trends with rising maternal age  . From 20In our study, birth defects accounted for 42.0% of perinatal deaths, and the PMR attributable to birth defects was stable in 2010–2020. It seems higher than in some high-income countries (about 20-30%) , 22 and Second, there were significant differences in the PMR of specific defects. Usually, specific defects with high PMR were easy to diagnose and significantly impacted the patients . In this study, the most common specific defects that impact the physiological functions with high PMR include hydrocephalus, Down syndrome, spina bifida, diaphragmatic hernia, gastroschisis, anencephaly, encephalocele, and conjoined twins, and the most common specific defects that impact the with high PMR include cleft palate with cleft lip. It is similar to previous studies . HoweverThird, some factors increase the risk of perinatal deaths attributable to birth defects, including rural areas, female fetuses, mothers with low maternal age, low income, low education level, low parity, and low gestational age of termination. There were several interesting findings. (1) Previous studies have shown birth defects were more common in males than females –35, inclSome things could be improved in our study. First, our study only includes birth defects at 28 weeks of gestation and above due to data limitations. A considerable proportion of birth defects are diagnosed and terminated before 28 weeks of gestation (such as Down syndrome), significantly impacting the death rate of birth defects. Second, as mentioned before, many factors are correlated, and a multifactorial analysis of risk factors of perinatal deaths attributable to birth defects would be appropriate. However, we could not conduct a multifactorial analysis due to data limitations, as the Birth Defects Surveillance System in Hunan Province was electronically rebuilt in 2012 and 2015, respectively, and some key information could not be effectively combined. Third, multiple birth defects may increase the risk of perinatal death. In our study, many birth defects were multiple birth defects. However, we did not analyze it. Fourth, there are large differences in the severity of some subtypes of specific defects with high PR, such as congenital heart defects. Further analyses of perinatal deaths in the different subtypes of those specific defects would be appropriate.In summary, birth defects are an important cause of perinatal deaths. Rural areas, female fetuses, mothers with low maternal age, low income, low education level, low parity, and low gestational age of termination were risk factors for perinatal deaths attributable to birth defects. Future studies should examine the mechanisms. Our study is helpful for intervention programs to reduce the PMR of birth defects.


Psoriasis is a chronic autoimmune disease involving both environmental and genetic risk factors. Maternal psoriasis often results in poor pregnancies that influence both mothers and newborns. However, the influence of paternal psoriasis on the newborn remains unknown. The aim of this study was to investigate whether paternal psoriasis is associated with increased risk of adverse neonatal outcomes, within a nationwide population-based data setting.Singleton pregnancies were identified in the Taiwan National Health Insurance database and National Birth Registry between 2004-2011 and classified into four study groups according to whether mothers and spouses had psoriasis /maternal(−), paternal(+)/maternal(−), paternal(−)/maternal(+), and paternal(+)/maternal(+)). Data were analyzed retrospectively. Adjusted odds ratios (aOR) or hazard ratios (aHR) were calculated to evaluate the risk of neonatal outcomes between groups.A total of 1,498,892 singleton pregnancies were recruited. Newborns of fathers with psoriasis but not of mothers with psoriasis were associated with an aHR (95% CI) of 3.69 (1.65–8.26) for psoriasis, 1.13 (1.06–1.21) for atopic dermatitis and 1.05 (1.01–1.10) for allergic rhinitis. Newborns of mothers with psoriasis but not of fathers with psoriasis were associated with an aOR (95% CI) of 1.26 (1.12-1.43) for low birth weight (<2500 g) and 1.64 (1.10–2.43) for low Apgar scores, and an aHR of 5.70 (2.71–11.99) for psoriasis.Newborns of fathers with psoriasis are associated with significantly higher risk of developing atopic dermatitis, allergic rhinitis and psoriasis. Caution is advised for adverse neonatal outcomes when either or both parents have psoriasis. It inPositive associations between maternal psoriasis and poor pregnancies have been well demonstrated. Previously we conducted a nationwide population-based study evaluating 2,350,339 singleton pregnancies to investigate the effects of maternal psoriasis on pregnancy and fetal outcomes . We founPrevious studies have indicated that the inherited type psoriasis displays an autosomal recessive pattern , 15. Fur22.1This observational cohort study used data from the Taiwan National Health Insurance (NHI) database linked to the National Birth Registry. The NHI database is currently the largest and most accurate population-based nationwide database, and contains the health-related data of 99% of the Taiwan population; it includes comprehensive records of maternity care as well as antenatal examinations . All inf2.2The study protocol was approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No: 201601155B0). Informed consent of patients was waived because of the retrospective nature of this study and anonymity of data.2.3Women with singleton births in Taiwan between 2004 and 2011 whose data were recorded within the NHI database and the National Birth Registry were identified. Among the initially recruited pregnancies, those with stillbirths, absence of neonate’s ID, or mothers aged < 15 years old or > 44 years old, were excluded. The remaining pregnancies were further divided into four study groups based on whether mothers or fathers had psoriasis, as follows: normal ; fathers had psoriasis while mothers did not have psoriasis ; fathers did not have psoriasis while mothers had psoriasis ; both parents had psoriasis . Clinical determination of psoriasis was according to the International Classification of Disease, ninth revision (ICD-9-CM), clinical modification code 696.1. This study only recruited adult patients who had undergone at least two consensus diagnoses of psoriasis within one year by qualified dermatologists or rheumatologists.2.4Pregnancy and neonatal outcomes were identified from the National Birth Registry. The maximum observational term for newborns was 12 years, till December 2015. Adverse neonatal outcomes included infant death, low birth weight (<2500 g), preterm (< 37 weeks), low Apgar scores (at 5 min < 7), atopic dermatitis (ICD-9-CM: 691.88), allergic rhinitis , asthma (ICD-9-CM: 493.xx), rheumatoid arthritis (ICD-9-CM: 714.0), autism (ICD-9-CM: 299.0), psoriasis (ICD-9-CM: 696.1), systemic lupus erythematosus (ICD-9-CM: 710.0), and cleft palate (ICD-9-CM: 749.xx).2.5Maternal and paternal covariates included age groups  and Charlson comorbidity index (CCI) values. Additional maternal covariates included smoking and alcohol consumption, as well as maternal country of origin. Comorbidity identified for CCI included myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatologic disease, ulcer disease, mild liver diseases, diabetes with or without chronic complications, hemiplegia or paraplegia, renal disease, any malignancy (including leukemia and lymphoma), moderate or severe liver disease, metastatic solid tumor, and HIV infection. Neonate covariates included sex, birthweight, and gestational age. The validated versions of ICD-9 codes were used, as previously described by Deyo et al.  model was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CI) for each outcome between the four study groups. Correlation analysis was based on an autoregressive model. Odds ratios (ORs) and hazard ratios (HRs) were adjusted for confounders, including maternal and paternal age, sex of neonates, maternal and paternal CCI, and maternal nationality. A two-tailed test with 5% level of significance was used for all statistical hypotheses. All statistical analysis was performed using SAS version 9.3 statistics software .33.1Initially, 1,557,680 women who had singleton births in Taiwan between 2004 and 2011 were identified in the NHI database and the National Birth Registry. The flow chart of the data retrieval process is illustrated in The mean ages of the mothers at the time of delivery and the fathers were significantly different between the four study groups (both P<0.0001). Maternal comorbidities with significant differences between the groups included congestive heart failure (P=0.0041), peripheral vascular disease (P=0.001), chronic pulmonary disease (P=0.0019), rheumatologic disease (P<0.0001), gastric ulcer disease (P<0.0001), mild liver disease (P=0.0112), diabetes without chronic complications (P<0.0001), diabetes with chronic complications (P=0.0068), and malignancies (P=0.0006). Paternal comorbidities with significant between-group differences included myocardial infarction (P=0.017) and malignancies (P=0.0001). Both maternal and paternal CCI values were significantly different between the four study groups.3.23.3Complications in the neonates are illustrated in 4The present study was the first to elucidate the clinical effects of paternal psoriasis on neonatal outcomes within a nationwide, population-based database. Results of the present study revealed that paternal psoriasis significantly increased the risks of neonatal psoriasis, atopic dermatitis and allergic rhinitis compared with those in normal parents, while no significant differences were found in stillbirth, low birth weight, preterm birth, and low Apgar scores. Maternal psoriasis was also observed to significantly increase the risks of low birth weight, low Apgar scores and newborn psoriasis, which agreed with our previous findings and other observations , 21, 22.Maternal psoriasis is well established as often leading to poorer pregnancies , 21–23. Psoriasis and atopic dermatitis have been viewed as distinct diseases. The first onset of atopic dermatitis usually occurs in infancy or early childhood, while psoriasis occurs sporadically in young children but has its peak onset in late adolescent or early adulthood . PsoriasThe group of paternal (+)/maternal (+) of patients had a 5.29-fold higher risk for stillbirth, a 1.23-fold higher risk for low birth weight, a 4.71-fold higher risk for low Apgar score, a 1.29-fold higher risk for atopic dermatitis and a 2.54-fold higher risk for autism, but no significant differences were found between these associations. Notably, no psoriasis occurred in the offspring of this group of patients. However, the lack of statistical significance for these adverse neonatal outcomes and zero events for neonatal psoriasis may be due to the small sample size of this group. In addition, we cannot rule out the possibility that some patients in this group had relatively mild psoriasis, therefore it was not significantly associated with adverse outcomes of the newborns. According to Yang et al., severe maternal psoriasis is associated with higher risk of low birth weight as compared with mild maternal psoriasis [4], consequently, rare or no symptoms may occur in the offspring when psoriasis is mild in the parents. However, we cannot exclude the possibility that complications may occur later in life, and studies with longer follow-up are required to investigate this issue.It has been reported that maternal psoriasis and low maternal socioeconomic position may increase the rate of offspring psoriasis . FurtherAlthough psoriasis can be a hereditary disease and has an estimated heritability of 66% , the parThe present study has several limitations. First, despite comprehensive validation of the records in the NHI database and National Birth Registry, the possibility of misclassification of psoriasis could not be excluded. Second, the definition of the population is based on the eligibility of the databases, which did not include data on pregnancies with less than 21 gestational weeks or an abortus whose weight was less than 500 g. Third, the number of neonates in the paternal (+)/maternal (+) group was few which led to difficulty in interpreting their effect on the offspring outcomes. Lastly, data about the fathers’ environmental factors and clinical severity of psoriasis, such as air pollutant, psoriasis with or without psoriatic arthritis, was not available in the NHI database, therefore we were unable to assess the associations of disease severity with the risk of adverse neonatal outcomes.5The results found that most of offspring were not significantly associated with parental psoriasis, except for atopic dermatitis and allergic rhinitis in the paternal (+)/maternal (-) group, and psoriasis in neonates with parental psoriasis. These findings suggest that parental psoriasis may increase the risk of long-term offspring outcome, and further research is needed to understand the underlying mechanisms and potential interventions to reduce this risk.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Chang Gung Memorial Hospital. The ethics committee waived the requirement of written informed consent for participation.Y-HH, S-FY and C-FK had made substantial contributions to the conception and study design. Y-HH and C-FK collected the data. M-JC analyzed the data. Y-HH prepared the manuscript, Y-HH, M-JC, S-FY and C-FK critical revision of the manuscript. Y-HH Funding acquisition. All authors contributed to the article and approved the submitted version.


The cases consisted of two subgroups: one included women whose children’s growth in late pregnancy was in the lowest quartile, and another included women from the remaining growth quartiles. Corresponding maternal serum samples were collected from a biobank and analyzed for concentrations of four types of PFAS: perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) using liquid chromatography–tandem mass spectrometry (LC/MS/MS). The results were combined with information from birth registers and analyzed using Mann–Whitney U-tests and logistic regression—unadjusted as well as adjusted for potential confounders. In conclusion, elevated maternal concentrations of PFAS were not associated with an increased risk of SGA birth. However, significant ORs were observed in a subgroup analysis restricted to women of Nordic origin (unadjusted OR 3.2 and adjusted OR 2.4) for PFHxS.Small for gestational age (SGA) is considered an adverse birth outcome. Per- and polyfluoralkyl substances (PFAS) have become increasingly investigated as contributing environmental factors, thus far with inconclusive results. The current study aimed to investigate the hypothesized association between increased maternal PFAS levels in early pregnancy and an increased risk for SGA birth. This population-based study used data from a sample of children born in Scania, Southern Sweden, between 1995 and 2009. Two groups were compared: cases born with SGA ( In recent years, per- and polyfluorinated alkyl substances (PFAS), a class of widely used, highly persistent, industrially produced compounds, have become a cause for environmental concern and are associated with adverse health outcomes .PFAS are a vast and complex group of manmade substances classified as organic pollutants with half-lives of several years ,3. TheirPFAS are released and distributed to the environment through direct emissions during the production, use, and disposal of products in which PFAS are present . The envBirth weight is an established indicator of fetal development and healthy birth outcomes . Small fThe most recent opinion by the European Food Safety Authority (EFSA) concluded that “there may be a casual association between PFOS and PFOA and birth weight” . In addiThe present study aimed to investigate the hypothesized association between maternal levels of specific PFAS in early pregnancy and the risk of SGA birth by combining medical birth register data with serum samples from a biobank in Scania, the southernmost county in Sweden.This study was approved by the Ethical Committee (Reg. No. 2014/696) at Lund University, Sweden, and was conducted as a register- and biobank-based case-control study where the following sources were used:This study was based in Scania, where the Southern Sweden Maternal Biobank (SSMB) has collected >250,000 maternal blood samples from infection screening in early pregnancy (weeks 10–14) since 1989. The coverage in the biobank has been shown to be >90% .Various maternal and obstetric registers and databases were utilized: the Swedish Medical Birth Register (MBR) and the Perinatal Revision South (PRS), a local Scanian birth register. As part of the Scanian regional ultrasound routines, examinations in early  and late  pregnancy were performed and registered in a separate database ,18.a priori statistical power analysis was performed to determine the study population size. Based on the aim of including 300 SGA cases and 600 controls, detecting an odds ratio of 1.6 or higher with statistical significance (p < 0.05) was deemed possible while not exceeding the project budget.An The SGA diagnosis was defined as birth weight below two standard deviations from the expected, according to the national intrauterine growth curve, which takes gestational week and gender into account . Fetal gAmong the 225 SGA with a poor growth spurt, the 225 SGA other, and the 900 controls, 95%, 96%, and 95% serum samples were available in the biobank, respectively. The biobank was instructed to select samples with the aim of later reaching 150, 150, and 600 analyzed samples, respectively. After randomly sorting the individuals within the respective groups, the first 158 SGA with a poor growth spurt, 151 SGA other, and 603 controls were therefore selected for PFAS analysis—accounting for potential loss. The remaining samples were excluded from this study due to budgetary reasons. Although available in the biobank, not all samples met the criteria regarding sample volume to be analyzed for concentrations of PFAS. Six SGA with a poor growth spurt, five SGA other, and twenty-three controls could not be analyzed, and the final numbers of participants were 152 SGA with a poor growth spurt, 146 SGA other, and 580 controls.The maternal serum samples were analyzed using liquid chromatography–tandem mass spectrometry  using a method by Norén et al. at the laboratory of Occupational and Environmental Medicine at Lund University . In summn = 32) was 8% for PFHxS at 2 ng/mL and 10% at 3 ng/mL, for PFOA, 12% at 3 ng/mL and 9% at 4 ng/mL; for PFNA 10% at 2 ng/mL and 9% at 4 ng/mL; and for PFOS 7% at 12 ng/mL and 8% at 13 ng/mL. The laboratory participated successfully in the HBM4EU QA/QC program and participates in G-EQUAS for PFOS and PFOA analysis coordinated by the University of Erlangen-Nuremberg, Germany  of the QC samples , smoking habits , sex of the child, diabetes (yes/no), gestational diabetes (yes/no), involuntary childlessness for at least a year (yes/no), gestational week at partus, and maternal country of origin (eight categories).Additional information was obtained from the MBR, which includes data on practically all deliveries in Sweden with information acquired from medical records on prenatal, delivery, and neonatal care . The fola priori defined models adjusted for maternal age , BMI , smoking (2 categories: yes and no), and parity (primipara and multipara). Based on prior research, women of Nordic origin have among the highest concentrations of PFAS; therefore, we conducted separate analyses including only women of Nordic origin [p-values below 0.05. All statistical analyses were conducted in SPSS (Version 27.0) .Background characteristics and PFAS concentrations for the cases and controls are presented as mean/median with minimum and maximum values for continuous variables or numbers and percentages for categorical variables. As a first step, comparisons of PFAS concentrations as continuous variables between cases and controls were analyzed with the Mann–Whitney U-test. In addition to managing the cases as a single group, the cases were divided into two subgroups (SGA with poor growth spurt and SGA other) and analyzed separately. As a second step, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. In these analyses, the concentrations of the PFAS variables were categorized into quartiles based on their distribution among the controls. The lowest exposure quartiles were used as reference categories. The PFAS variables were analyzed individually. Crude analyses were completed with c origin . In addic origin ,24. Due Background characteristics and demographics of the study participants are presented in The highest maternal serum concentrations were observed for PFOS in all study groups, followed by PFOA . There wWhen the different PFAS were analyzed as categorical variables and when the highest vs. lowest exposure categories were compared, the only statistically significant associations observed were ORs below one in the adjusted analysis for PFOS when all cases were included , PFOS (OR 1.77 95% CI 1.02–3.10), as well as for PFHxS (OR 3.19 95% CI 1.60–6.34) . In the The present study showed no statistically significant increased risk of SGA birth with higher maternal serum concentrations of PFAS in the general population in Scania, Southern Sweden. Results indicating a reduced risk of SGA birth with higher levels of PFOA and PFOS were observed in some instances—however sporadic and inconsistent across exposure quartiles. In contrast, we found significant associations between exposure to PFHxS and an increased risk of SGA birth in the analysis restricted to women of Nordic origin.Our main results are in agreement with recent EFSA opinions lacking strong support for the hypothesized association between increased PFAS exposure and SGA birth . The mosThe inconsistent and occasionally conflicting evidence from epidemiological studies on PFAS exposure and reduced birth weight is an ever-recurring predicament, perhaps further complicated by the physiological changes related to pregnancy. A recently updated meta- and bias-analysis on serum PFOA and birth weight found little or no association when exclusively including studies where blood was sampled from mothers in early pregnancy . HoweverThe analyses restricted to male infants and women of Nordic origin were specifically selected based on results from previous studies. Numerous research articles on the subject have presented sex-specific effects of PFAS, with male fetuses being more affected regarding birth weight ,24. In oThe strengths of our study include the use of the Southern Sweden Maternal Biobank, extensive birth registers, and a population-based design, which increases generalizability. The high-quality registers enabled us to adjust for important potential confounders, such as smoking habits and parity. By selecting subjects from a regional screening program, the risk of selection bias was minimized, and ultrasound data allowed us to take infant growth in the last trimester into account. Also, all samples were taken at the same gestational age and analyzed using state-of-the-art laboratory equipment. As previously mentioned, PFAS are stable molecules with half-lives of several years, meaning the concentration in a single sample can characterize exposure in epidemiological studies with relative accuracy.Several limitations should be acknowledged. We could not account for the mother’s educational level or socioeconomic status, which have been identified as key confounders. Furthermore, mothers born SGA are more likely to give birth to SGA children themselves, and maternal birth weight was not accounted for in our study. Pathophysiological mechanisms of intrauterine growth restriction (IUGR), namely infections, various maternal diseases, chromosomal aberration, immunization, and placenta-associated complications such as preeclampsia, were not accounted for. In addition, growth estimates based on ultrasound data are susceptible to operator-dependent differences as well as inherent random errors. This could potentially lead to a nondifferential misclassification and bias estimates towards the null. As pointed out in the introduction, thousands of specific molecules constitute the group of PFAS, and the current study chose to investigate only four of them. Although we selected the most widespread and frequently studied substances, this may limit the external validity and applicability of the results.In conclusion, the present study found no association between higher maternal serum levels of PFAS in early pregnancy and an increased risk of SGA birth. However, an increased risk was observed for PFHxS when restricting the analysis to women of Nordic origin. This was a population- and biobank-based study using early-pregnancy sampling while also taking the fetal growth spurt in late pregnancy into account, which is, to our knowledge, a new approach. Future investigations of the potential fetotoxic effects of PFAS are needed to further our understanding of their biological impact on humans.


Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18–23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- . The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions. Preterm birth is a major public health issue concerning perinatal mortality, long-term morbidity, and economic burden, with a worldwide prevalence of 5–18%, 90% of which occurs in developing countries . SpontanIn vivo, cytokines are part of the molecular network mediates innate immune and inflammatory responses . All cytThere is a pathophysiological association between preterm premature rupture of membranes (PPROM) and PB, both triggered when the intrauterine or maternal environment is hostile. Moreover, PPROM is among the leading causes of preterm birth , probablAmong the screening techniques to detect women at a high risk for PB, the most used measurement in clinical practice is cervical length (CL), obtained by vaginal ultrasound in the second trimester of gestation, with a detection rate of 50 to 70%. Also, some clinical calculators incorporate CL, gestational age, and obstetric history to provide a patient-specific risk for developing PB. The calculator that is considered the gold standard in clinical practice is the Fetal Medicine Foundation (FMF) calculator, having a detection rate for preterm spontaneous birth of <28 weeks = 75%, 28–30 weeks = 57%, 31–33 weeks = 46%, and 34–36 weeks = 24%, considering a false positive rate of 10% .In recent years, artificial intelligence has been used in different healthcare fields to predict, prevent, diagnose, and monitor different pathologies, even in obstetrics . Models Although the role of cytokines as critical mediators in the inflammatory process that triggering labor has been demonstrated , very feA total of 60 pregnant women were recruited, including 40 participants who were considered at low risk and 20 at high risk for PB. The low-risk group had a prevalence of spontaneous preterm birth before 37 gestation weeks of 7.5% versus 45% in the high-risk group. The maternal characteristics of both groups are shown in p = 0.001). As regards of cytokines with anti-inflammatory function, an increase in the concentration of IL-4 and IL-10 was found in the high risk group for PB (p = 0.001). In contrast, the IL-1ra concentration was significantly lower (p < 0.01) compared to women in the low-risk group for PB group. The mean concentration of the pro-inflammatory cytokines, IL-2, IL-6, and IFN-γ, was significantly higher in the high-risk group , obtaining the following results: a detection rate of 79% with FPR = 6.60% and FNR = 11.66%  showed a detection rate of 87%, with FPR = 3.33%, FNR = 6.66%, and an AUC of 0.875; to compare our model with the performance of the calculator used by the FMF, we entered our data in the FMF’s online calculator  by incorporating quantification of cytokines because these are the crucial mediators of the inflammatory process observed in preterm labor. The main areas that may benefit from ML techniques in the medical field are diagnosis and outcome prediction; ML can transform how medicine works ,44. The In most studies involving cytokines in high- and low-risk groups for PB, the classification only considers the obstetric history . Thus onAnother contribution of our work is comparing the FMF calculator and the predictive model obtained by the Random Forest analysis. With this analysis, we demonstrate that if we add the measurement of IL-2 to the prediction model, we can increase, by 8 percentage points, the detection rate reported by the gold standard in clinical practice, which would help to identify more accurately those cases at high risk for PB, allowing us to implement preventive medical strategies  that can offer efficiency up to 90% ,50.The main limitation of our study is the number of patients included; however, it was possible to identify significant statistical differences between groups. As regards the construction of the model, this fact is compensated by the nature of the analysis performed since the Random Forest analysis builds the ideal model and then replicates it thousands of times to test its efficiency . HoweverAs we aimed to design an effective screening model for PB with the inclusion of clinically applicable markers based on cost, availability, efficacy, and timeliness of the test, the next step is undoubtedly to perform a cost/benefit analysis to assess whether adding the IL-2 measurement to the screening model is endorsed by the resources saved with the risk detection and prevention of PB.Our results contribute to a better understanding of the cervical-vaginal inflammatory network elicited in patients classified as high and low risk for preterm delivery in accordance with to the current screening gold standard. The prediction model that incorporates cytokines in cervical-vaginal mucus showed a DR 8 percentage points higher than the gold standard used in clinical practice, with a lower FNR. The increase in DR with the reduction in FNR may allow us to identify women at risk for PB more accurately and implement strategies to prevent this outcome. Our work could represent a significant advance screening to reducethe prevalence of PB, a goal that has not yet been achieved in the last 30 years.The study was conducted at the Instituto Nacional de Perinatologia in Mexico City between January 2017 and December 2021. The protocol was approved by the Ethics, Research, and Biosafety Internal Review Boards (2017-2-69). Women who met the inclusion criteria were invited to participate, and they read and signed the informed consent form.Recruitment at convenience was performed by considering women who attended the Maternal-Fetal Medicine Department at the Instituto Nacional de Perinatologia, in Mexico City, to screen for PB with a singleton 18–23.6 weeks of gestation pregnancy. Clinical data that included age, weight, pregestational weight, socioeconomic status, smoking, history of preterm delivery, gestational age by date of last period as well corroborated by first trimester US, presence of urinary or vaginal infections, and use of antibiotics, and follow-up of pregnancy until its termination, were collected. Fetuses with structural alterations or women with a confirmed diagnosis of isthmic cervical incompetence were not included. The primary outcome was considered to be spontaneous preterm birth, defined as the delivery of the fetus before 37 weeks of gestation, calculated by the last menstrual period or reliable first-trimester ultrasound, without any medical intervention that produced this outcome [Participants were classified as having high or low risk for developing PB according to the cervical length measurement, using a cut-off point of <20 mm in patients with a history of preterm delivery and <25 mm for patients without a history of PB . Our insA cervical-vaginal mucus sample from the posterior vaginal fornix was obtained using a dacron polyester-tipped swab which was rinsed in collection buffer containing 1X PBS, 0.05% Tween-20, 1% BSA, and a protease Inhibitor Cocktail (Roche). Samples in the collection buffer were centrifuged at 3200 rpm, for 15 min at 4 °C, and the supernatants were stored at −80 °C until further cytokine analysis. Before preservation, an aliquot was tested to rule out subclinical vaginal or uterine infection by fresh examination and negative microbiological cultures.Cytokine concentration in cervical-vaginal mucus was measured using the Luminex X-Map platform with the Bio-Plex Pro Human Cytokine 10-plex that includes IL-2, IL-4, IL-6, IL-8, IL-10, INF-γ, TNF-α, IL-1β, IL-12p70, and IL-1ra (Cat 12020756). The protocol was performed in accordance with he manufacturer’s instructions, and the value for each cytokine was expressed as pg/mL. The inter- and intra-assay variation was <10%.Data were analyzed with the SPSS software, version 24. Descriptive statistics were performed to characterize groups: for qualitative variables, frequency measures expressed in percentages were used, while for quantitative variables, measures of central tendency , and measures of dispersion standard deviation (SD) were used. Data distribution was verified before the statistical analysis with a Kolmogorov–Smirnov test. Cytokine concentration was evaluated, and differences between groups were assessed using the Mann–Whitney U test. The Chi-square test was used to calculate the difference in proportions. No sample size calculation was performed beforehand, but the statistical power was calculated for all variables with significant differences to verify that it was greater than 80%.A Random Forest classifier first model was created to predict the incidence of preterm infants using 12 clinical variables , precedent urinary or vaginal infections, use of antibiotics, and gestational age at the time of pregnancy resolution) and 10 cervical-vaginal cytokine determinations . Secondly to obtain an adjusted the model, we performed hyperparameter selection by out-of-bag error and simple cross-validation, resulting in 50 trees, 1 mtry (number of predictors considered in each split), and 1 as maximum depth.. The models were analyzed in a mathematical matrix to determine false positive rates (FPR) and false negative rates (FNR), their overall efficiency, as well as to compare the area under the ROC curves (AUC).


Blood cell populations, including red blood cells (RBC) unique to the extremely preterm (EPT) infant, are potentially lost due to frequent clinical blood sampling during neonatal intensive care. Currently, neonatal RBC population heterogeneity is not described by measurement of total haemoglobin or haematocrit. We therefore aimed to describe a subpopulation of large RBCs with hyper high haemoglobin content, >49 pg (Hyper-He) following EPT birth.Prospective observational cohort study.Two Swedish study centres.+0 to 26+6.Infants (n=62) born between gestational weeks 22Prospective data (n=280) were collected from March 2020 to September 2022 as part of an ongoing randomised controlled trial. Blood was sampled from the umbilical cord, at postnatal day 1–14, 1 month, 40 weeks’ postmenstrual age and at 3 months’ corrected age.At birth, there was a considerable inter-individual variation; Hyper-He ranging from 1.5% to 24.9% (median 7.0%). An inverse association with birth weight and gestational age was observed; Spearman’s rho (CI) −0.38 (−0.63 to −0.07) and −0.39 (−0.65 to −0.05), respectively. Overall, Hyper-He rapidly decreased, only 0.6%–5.0% (median 2.2%) remaining 2 weeks postnatally. Adult levels (<1%) were reached at corresponding term age.Our results point to gestational age and birth weight-dependent properties of the RBC population. Future work needs to verify results by different measurement techniques and elucidate the potential role of differing properties between endogenous and transfused RBCs in relation to neonatal morbidities during this important time frame of child development.NCT04239690. Erythropoietic contributions from different physiological and cellular origins may contribute to a heterogeneity in the peripheral red blood cell (RBC) population during 22 to 26 weeks’ gestation.The proportion of neonatal RBCs with hyper high haemoglobin content (Hyper-He) decreases rapidly during first weeks in neonatal intensive care.Proportions of Hyper-He measured early after birth could be indicative of erythropoietic transitions and/or stress erythropoiesis and are associated with gestational age as well as birth weight.The role that the decrease of characteristic endogenous neonatal RBCs plays for oxygenation, perfusion and the development of neonatal morbidities in EPT infants is not well understood. Future studies addressing these knowledge gaps are warranted.Globally, preterm birth affects 15 million newborns each year.In contrast to the RBCs from the adult definitive erythroid lineage, originating from bone marrow and haematopoietic stem cells (HSC), the liver is the main erythropoietic organ during the gestational period ascribed to extremely preterm (EPT) birth.A gradual process where the HSC definitive erythroid lineage transitions to the more protected environment in the bone marrow is initiated at 16th to 18th week of gestation.With potentially different physiological, microenvironmental and cellular origins, the resulting peripheral RBC population may not be homogeneous, potentially having different properties between subpopulations. The mean cell haemoglobin concentration index (MCHC) after EPT birth is similar to adult values,Our objective of this study was to describe proportions of Hyper-He following EPT birth as a potential biomarker of an erythropoietic transitional process. We also aimed to investigate the influence of gestational age, birth weight and fetal growth on early proportions of Hyper-He.+0 to 26+6 weeks. Clinical data were obtained from clinical records. Fetal growth restriction (FGR) was diagnosed in cases with abnormal fetal Doppler velocimetry combined with estimated fetal weight deviationAt birth, the infants had a gestational age of 22Blood samples were collected at birth  and thereafter through an umbilical catheter, peripheral arterial catheter or peripheral venous puncture. During postnatal day 1–14, only blood from clinical sampling was used to analyse the RBC data presented in this study thereby not causing any additional blood loss, essential for the main study design. Blood (250 µL) was collected in microtainer EDTA tubes . In addition to the clinical samples, study samples were obtained at postnatal age 1 month , at postmenstrual age week 40 and at 3 months corrected age. All blood samples were promptly sent to the hospital laboratory for analysis to avoid RBC swelling. Samples were analysed for Hyper-He (proportion of cells with haemoglobin >49 pg/cell), haemoglobin concentration (Hb), mean cell haemoglobin content (MCH), mean cell volume (MCV) and reticulocyte counts (RET).Blood was analysed on Sysmex XN  at the clinical laboratories at Lund University Hospital and at Karolinska University Hospital. The instrument uses laser to measure forward and side scatter light on a cell-by-cell basis. Measurements of RBC count are based on impedance. Total haemoglobin concentration is measured by an absorption photometric method. The index MCH is derived by the ratio haemoglobin/RBC count and MCV by the ratio haematocrit/RBC count. The instruments were under regular quality control for commonly used haematological parameters and laboratories were accredited according to ISO15189.Data are presented as mean (±SD), median (IQR), range (min – max) or number (%) where appropriate. Correlations were estimated using Spearman’s rho where p values <0.05 were considered statistically significant. SPSS V.27.0  was used for data analysis.+4. Gestational ages and clinical characteristics are presented in Blood measurements (n=280) were available from 62 of 73 infants enrolled in the randomised controlled trial at the two neonatal intensive care units during the present time period. The mean (SD) birth weight of the 62 infants was 727 g (171 g) and median gestational age at birth 24Umbilical cord samples (n=15) were analysed. One sample with an outlier Hb result (57 g/L) was excluded due to suspected measurement interference. In the remaining samples (n=14), there was a large inter-individual variability in Hyper-He ranging from 1.5% to 24.9% (median 7.0%). Association between Hyper-He and RET in the umbilical cord blood was not statistically significant but pointed towards a possible weak inverse association, Spearman’s rho −0.47 (CI −0.81 to 0.10), p<0.09. Overall, the median proportion of Hyper-He rapidly decreased with increasing postnatal age, at postnatal day 14 reaching 2.2% (0.6%–5.0%) and by term age adult levels <1%. The corresponding total haemoglobin concentration in cord samples was median 133 g/L (115–146 g/L), slightly decreasing to 127 g/L (95–146 g/L) at postnatal day 14. The lowest median Hb concentration was observed at term age, 104 g/L (91–136 g/L). Strong associations were found between the proportion of Hyper-He  and the mean haemoglobin content of the red cells, MCH  as well as MCV (derived from haematocrit and RBC count). As for MCH, Spearman’s rho was 0.87 (CI 0.77 to 0.93), p<0.001 . The assAs by ratio, a large MCH indicates higher total haemoglobin distributed over a lower number of RBC counts, this could mean that infants having a high proportion of Hyper-He at birth also overall have haemoglobin accumulated in fewer, larger cells. The 2.5th percentile and 97.5th percentile for MCH were 32 and 47 pg, respectively. Corresponding percentiles for MCV were 99 and 139 fL.For 40 infants, Hyper-He was measured within 48 hours. There was a statistically significant inverse association between birth weight and Hyper-He, Spearman’s rho −0.38 (CI −0.63 to −0.07), p=0.02. Also, if the infants with FGR  were excluded (n=34), we found an association of similar magnitude with regard to gestational age, Spearman’s rho −0.39 (CI −0.65 to −0.05), p=0.02, We report the measurement of a subpopulation of RBCs with a particularly high content of haemoglobin (>49 pg) in EPT infants. Early after birth, the proportion of these cells is inversely associated with birth weight as well as gestational age and varies substantially between individuals. Also, a rapid decrease postnatally is observed.Development of anaemia after EPT birth has so far mainly been attributed to the decreasing erythropoietin levels following birth. This study adds further aspects to this model.First, as individual variation during the first postnatal days was considerable (2%–25%), we hypothesise that infants with a high proportion of Hyper-He at birth are more at risk for severe nadirs in Hb, as this cell population mainly seems to be lost reflected by the considerable decrease during the first 14 postnatal days. Avoiding loss of large endogenous RBCs by minimising clinical blood sampling volumes might therefore be of particular importance for these infants.Second, although the origin of these cells is currently unknown, their presence as well as prolonged raised values might suggest a general transitional delay in the establishment of definitive HSC erythropoietic lineage erythropoiesis. The Hyper-He RBCs could be a result from stress erythropoiesis,Our current knowledge of the neonatal red cell population in clinical care has so far mostly been limited to describing the RBC population as homogeneous, using parameters such as total Hb, Hct and mainly derived indices such as MCHC (ratio of Hb and haematocrit) and MCH . The 2.5th to 97.5th interval of MCH estimated in our study was 32 to 47 pg during the first postnatal days. The 97.5th percentile was thereby higher than previously reported for infants of the same gestational age (33 to 41 pg).et alWith regard to fetal growth, we observed that infants born after FGR seemed to have a high proportion of Hyper-He early after birth, suggesting a positive relationship between chronic fetal hypoxia and proportion of Hyper-He cells. Reibel Strengths of our current study include utilisation of the blood from clinical sampling for measurement of the RBC population, thereby requiring no extra phlebotomies day 1–14. Samples were promptly transported to the laboratory and thus RBC swelling was avoided. This is also a prospectively studied, longitudinally followed cohort.We also identify several weaknesses, and our results do need verification by other methodologies. Mainly, these instruments and algorithms are developed for adults and for children at older ages than our cohort. The extent to which they are verified for the blood from the most preterm infants is currently unknown, thereby introducing analytical uncertainty. The risk for interferences or misclassification of cells cannot be ruled out. Yet, we observed excellent repeatability as well as a strong association with MCH, an index being derived from different measurement techniques in the instrument. An additional drawback to this study is a bias towards more critically ill infants during postnatal day 1–14 due to the blood sampling scheme. Neither does the current study differentiate between a possible dilution effect resulting from pRBC transfusions to an actual loss of these cells due to intrinsic or extrinsic factors. This also needs to be addressed in future studies.Further, with regard to antenatal steroids, these may have influenced the results stimulating erythropoiesis.Endogenous neonatal RBCs could hypothetically play an important role during this critical time frame for future development. Haematopoietic observations that differ from adults, that historically have been described as ‘immature’ are now beginning to be more widely understood as intricate pathways unique to fetuses and neonates allowing to populate the bone marrow and concurrently meet the needs for increasing blood volumes following rapid growth.In conclusion, our hypothesis generating study implies a possible heterogeneity in the endogenous RBC population after EPT birth where high proportions of peripheral large hyper haemoglobin-loaded RBCs might be indicative of an erythropoietic transitional process. Future work needs to verify results by different measurement techniques. Further investigations regarding endogenous RBCs in relation to sampling-related blood loss, development of anaemia, transfusions as well as neonatal morbidities are warranted.