The effects of maternal thyroid hormone levels on the course of pregnancy and birth weight have attracted interest. The aim of the present study was to consider FT3 and FT3/FT4 ratio in the evaluation of the effects of maternal thyroid functions in gestational transient thyrotoxicosis (GTT).This case-control study included 45 patients with GTT and 45 healthy pregnant women. Maternal history before pregnancy, thyroid function tests, thyroid autoantibodies, and thyroid ultrasonography results in 6th to 10th weeks of pregnancy were used in the differential diagnosis of GTT. In both groups, the effects of FT3, FT4 and FT3/FT4 ratios on gestational age and birth weight were evaluated.There was no significant difference in the gestational age between the GTT and control groups . Birth weights were similar in both groups . When maternal weight was adjusted, a positive correlation was observed between maternal FT3/FT4 ratio and birth weight . Additionally there was a positive correlation between the gestational age and the birth weight in the control group .GTT had no significant effect on the gestational age and the birth weight. On the other hand an increase in the maternal FT3/FT4 ratio had a positive effect on the birth weight in the patient with GTT. Maternal characteristics  and FT3/FT4 ratio should be taken into consideration in future impact assessment studies on this issue. Mild hyperthyroidism may occur in early stages of pregnancy due to an effect of increased human chorionic gonadotropin hormone. This condition is defined as gestational transient thyrotoxicosis and it is the most common cause of thyrotoxicosis in the first trimester of pregnancy. The incidence of GTT during pregnancy varies between 1-3%. While serum thyroid-stimulating hormone (TSH) levels are suppressed in GTT, FT4 and FT3 levels are normal or increase. The most important serological characteristic of patients with overt GTT is high FT3 level .th and 10th weeks of their pregnancies were analyzed. Absence of a known thyroid disease, serum TSH levels being <0.1 IU/mL, normal or high serum FT4 and/or FT3 levels, and negative thyroid auto-antibodies  were accepted as the basic criteria for the diagnosis of GTT  values and normal thyroid ultrasonography findings, had negative thyroid autoantibodies, and had no additional systematic diseases.Data of 45 patients who applied to the endocrinology outpatient clinic of Hatay Mustafa Kemal University Faculty of Medicine from September 2015 through December 2016 and who were diagnosed with thyrotoxicosis via thyroid function tests (TFTs) between the 6nd trimester. The control group had at least one normal TFT result in each trimester until the end of their pregnancy periods. Data relating to the pregnancy and perinatal outcomes were obtained from both the maternity service records and the pregnant follow-up system in our city. Besides, missing data in the anamnesis of the patients were obtained by phone calls to the patients.On the patients’ monitoring system, the patients with GTT had monthly follow-up records until their TFT values were normalized in 2In our clinic, blood samples were routinely collected in the morning after overnight fasting. For TFT and thyroid autoantibodies, chemiluminescent immunoassay technique  was used. Ultrasonographic measurements were performed by an experienced radiologist using the MyLab ClassC ultrasonography device  with a 14-MHz linear prob.Data were analyzed using the Statistical Package for the Social Sciences for Windows, Version 21.0 . In descriptive statistics, numerical variables were expressed as mean, standard deviation, median, minimum, and maximum and categorical variables were expressed as number and percentage. For the normality analysis of variables, the Shapiro-Wilk test was used. In the analyses, student-t test, Mann-Whitney U test, Chi-square test, Pearson correlation, Spearman's rank correlation, and Partial correlation were used. While drawing scatter graphics in partial correlation, unstandardized residual was calculated and drawn over linear regression. A p value <0.05 was accepted as a statistical significance limit within 95% confidence interval.There were no significant differences in maternal characteristics  between the GTT and control groups . The meThere was no relationship between the weight and birth weight  in the GTT group. When the effects of maternal thyroid hormones were evaluated, a positive correlation was found between the maternal weight and FT3/FT4 ratio  in this group. A positive correlation was observed between the birth weight and FT3/FT4 ratio in the GTT group  . HoweveAccording to the Spearman's rank correlation analysis results in the study groups, the increase in the gestational age in the GTT group had no significant effect on the birth weight . However, such correlation was found significant in the control group .In the current case-control study including the patients with GTT and the pregnant women having normal thyroid functions, the mean gestational age of the groups during birth were compared and no significant difference was obtained . Similarly Kinomoto-Kondo and cols.  evaluatAccording to the results of the correlation analysis between the birth weight and gestational age in the present study, the increase in the gestational age in the GTT group did not affect the birth weight (p=0.194 and p=0.140). However, a positive significant correlation was observed between the birth weight and gestational age in the control group (p=0.726 and p=0.001). This correlation observed in the control group may help to explain the difference in birth weights between our study and other studies. In our study, gestational age in patients with GTT was >37 weeks and this was compatible with the literature .In the present study, as expected, maternal FT4 and FT3 values were significantly higher and maternal TSH values were significantly lower in the GTT group as compared to those in the control group. However, these parameters had no significant effect on gestational age and birth weight. In the study by Kinomoto-Kondo and cols. , a negaIn the studies evaluating the effects of thyroid functions on pregnancy, it has been reported that an increase in maternal FT4 level in pregnant women achieving euthyroid state or having GTT negatively affects gestational age and birth weight –13. HThe major limitation of the present study is being a single center and small-scale study. On the other hand, in accordance with the literature, regular follow-up of the patients owing to our pregnancy tracking system is one of the advantageous of the present study.In conclusion, no significant difference was found between the birth weight and gestational age when comparing the patients with GTT with the healthy controls. On the other hand, maternal FT3/FT4 ratio had a positive correlation with the birth weight in the GTT group. Maternal characteristics  and FT3/FT4 ratio should also be taken into account when conducting an impact assessment study in patients with GTT. Future multi-center prospective studies are needed on this subject.


The optimal conditions for a steam explosion for pomegranate peels in terms of total phenol content were a pressure of 1.5 MPa, a maintenance time of 90 s, and a particle size of 40 mesh. Under these conditions, pomegranate peel extract presented a higher yield of total phenols, gallic acid, and ellagic acid. However, it also had a lower content of punicalin and punicalagin, compared to the unexploded peels. There was no improvement in the antioxidant activity of pomegranate peels after the steam explosion. Moreover, the content of total phenol, gallic acid, ellagic acid, punicalin, and punicalagin, as well as the antioxidant activity of pomegranate peels, all increased after gastric digestion. Nevertheless, there was a large variation in the pomegranate peel processed by different pressure, duration, and sieve fractions. Overall, this study demonstrated that steam explosion pre-treatment could be an efficient method for improving the release of phenolics, especially gallic acid, and ellagic acid, from pomegranate peels.Pomegranate peels, the main byproduct of pomegranate production, are rich in phenolic compounds that are known for their effective antioxidant properties and have vast application prospects. In this study, steam explosion, an environmentally friendly technique, was applied to pretreat pomegranate peels for phenol extraction. We investigated the effects of explosion pressure, duration, and particle size on the content of total and individual phenolics, and antioxidant activity of pomegranate peels before and after  Punica granatum L.), widely cultivated worldwide, is a food that is used in medicines and dietary supplements . α-Amylase (35 U/mg), pepsin from porcine gastric mucosa (250 U/mg protein), and pancreatin from porcine (24 U/mg of lipase) were purchased from Maclin Reagent Co. . Chromatographic grade acetonitrile and methanol were purchased from Merck Co. (Germany). Other reagents not otherwise specified were analytical grade and obtained from Sinopharm Chemical Reagent Co. .The pomegranate peels were pretreated in a steam explosion jar  according to the method described by Gong et al. . To optiThe dried pomegranate peel powders were fixed to the conductive adhesive tape and coated with gold-palladium alloy. Then, the morphologies of pomegranate peel samples were observed by a scanning electron microscope  at 1,000 × magnification.g for 15 min after cooled down. The supernatants were pooled and transferred to a 100-mL volumetric flask and made to volume with methanol solution. Finally, the pomegranate peel extracts were filtered through 0.45 μm microfiltration membrane and stored at −20°C for testing.The phenolic compounds of pomegranate peels were extracted by reference to Ge et al.  with sliin vitro digestion of pomegranate peel samples was carried out according to the standardized protocol and our previous study with slight modifications , simulated gastric fluid (SGF)  and simulated intestinal fluid (SIF)  were prepared as described by Minekus et al.  and 5.6 mL distilled water. The mixture was placed in darkness and incubated for 30 min. Then the absorbance was measured at 760 nm on a UV-5500PC spectrophotometer . The results were expressed as millimoles of gallic acid equivalents per gram of dry pomegranate peel powder (mg GAE/g).The TPC of pomegranate peel samples was determined by the classic Folin-Ciocalteu assay . BrieflyAccording to the previous method with some modifications , the HPLIn this study, the antioxidant activity was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2′-Azinobis-(3-ethylbenzthiazoline-6-sulfonate (ABTS)) radical scavenging and ferric reducing antioxidant powder (FRAP).The DPPH scavenging assay was conducted according to the method described previously with modifications . The sam2S2O8 solution (140 mmol/L) and ABTS stock solution (7 mmol/L) were mixed with a volume ratio of 88:5000 to make the ABTS working solution. Then, the diluted ABTS working solution (3.9 mL) was added to the sample extract (0.1 mL), blank methanol solution, or reference Trolox (0.1 mL) and vortexed. The absorbance was measured at 734 nm.The ABTS scavenging assay was determined based on the reported method with modifications . First, 3 solution (20 mmol/L) with a ratio of 10:1:1. The sample extract, or blank, or Trolox (1 mL) was mixed with distilled water (4 mL) and FRAR working solution (2 mL) and vortexed in water bath at 37°C for 10 min. The absorbance was measured at 593 nm on the UV spectrophotometer.For FRAP assay, a published method with some modifications was used . The FRAThe DPPH, ABTS and FRAP values expressed as the milligram of Trolox equivalent in per gram of dry peel powder (mg TE/g).P < 0.05.Each sample was tested at least in triplicate. The data was presented as mean ± standard deviation. Statistical analysis of variance followed with Duncan test was carried out using SPSS 22.0. Significant difference was considered as The microstructures of the pomegranate peels before and after the steam explosion , treatedThe changes in TPC in the pomegranate peel under various steam explosion conditions are listed in p > 0.05). Although the smallest pomegranate peels (100-mesh) had the highest TPC (219.93 mg GAE/g), during the steam explosion process, the occurrence of adhesion between samples led to the powders being heavily linked together. Accordingly, 40-mesh pomegranate peels are appropriate for use in actual operations.The TPC of pomegranate peels increased from 175.02 to 196.11 mg GAE/g as the explosion pressure increased from 0.5 to 1.5 MPa. However, when the pressure was increased to 2 MPa, the TPC decreased slightly (189.15 mg GAE/g). Therefore, 1.5 MPa was chosen as the subsequent steam-explosion pressure. As for duration, when the maintenance time was extended from 30 to 90 s, the TPC increased from 181.50 to 196.11 mg GAE/g. As the time increased to 120 and 150 s, the TPC of pomegranate peel showed a less pronounced increase (203.61 and 196.26 mg GAE/g). Considering the energy consumption, the appropriate duration was fixed at 90 s. When pomegranate peels were exploded at 1.5 MPa for 90 s, with the decrease of particle sizes from 20 to 100 mesh, the TPC increased, with no significant differences among the 40-, 60- and 80-mesh samples  and had a higher increment TPC after gastric digestion.Steam explosion pressure had little effect on the TPC of pomegranate peels after gastric digestion. After intestinal digestion, peels exploded at 1.5 MPa and had the highest TPC. When the pomegranate peels were pre-treated for different durations, the TPC of the samples after gastric and intestinal digestion increased and then decreased with time, which was the highest in the 90-s sample. Furthermore, the TPC of exploded pomegranate peels increased after in vitro digestion process. The overall trend was that the four phenolic compounds in pomegranate peels significantly increased after gastric digestion and then decreased after intestinal digestion. As a result, punicalagin contents became undetectable after intestinal digestion.After gastric digestion, the contents of gallic acid and ellagic acid released from pomegranate peels increased gradually with increasing pressure , whereasAs shown in According to in vitro digestion. The DPPH, ABTS, and FRAP values of pomegranate peels after gastric digestion were significantly enhanced, whereas they were significantly decreased after intestinal digestion. The DPPH, ABTS, and FRAP values of the unexploded pomegranate peels were similar to or even lower than those of the steam-exploded samples after gastric digestion. However, after intestinal digestion, the three values for the exploded pomegranate peels  decreased considerably in comparison with the unexploded samples .in vitro digestion did not change significantly with an increase in explosion pressure. For the duration, the three antioxidant assay values of pomegranate peels after gastric digestion increased initially and then decreased over time. Additionally, the highest values were observed in the 90 s exploded sample. After intestinal digestion, DPPH and FRAP showed the same trend as that after gastric digestion, whereas ABTS did not change significantly over time. As for particle size, the three values showed a relatively consistent upward trend due to the decrease in particle size, and the antioxidant activity in the 100-mesh peels after gastric and intestinal digestion was the strongest.In general, the antioxidant activity of DPPH and ABTS of pomegranate peels after The steam explosion has been shown to increase the release of phenolics in plants and enhance their antioxidant activity , 29. TheFurthermore, the explosion pressure (or temperature), duration, and particle size of the matrix are the main factors influencing the extraction of plant phenolics during the steam explosion process. Owing to the high energy density generated by steam explosion, the intercellular mass of the plant loosens, the complex structure is destroyed, and active ingredients are easily dissolved . SimultaBy analyzing the changes in the phenolic compounds of pomegranate peels after steam explosion pre-treatment, it was demonstrated that steam explosion could generate shear forces to break the chemical bonds of phenolics, including glycosidic bonds and hydrogen bonds . MeanwhiIt has been known that phenolic compounds play a vital role in the antioxidant activity of pomegranate peels . Phenolsin vitro digestion. Previous in vivo studies have reported that ellagitannins can be hydrolyzed to ellagic acid in the small intestine and cecum (Considering that pomegranate peel powder was used in the digestion experiment instead of the pomegranate peel extract, the dissolution and hydrolysis of phenolic substances occurred simultaneously during the process of digestion. Phenolic compounds are thought to be more reactive at an acidic pH in the gastric phase and less reactive in the intestinal phase . Therefond cecum . The incin vitro digestion were positively correlated with TPC, as well as punicalagin and ellagic acid content. These results imply that the bioaccessibility of specific phenolic compounds should be considered, except for the total phenols in the pomegranate peel processing, which could have influenced the health benefits of the fruit.Research suggests that higher TPC corresponds to greater antioxidant activity . AccordiIn summary, this study demonstrated that steam explosion is an efficient method for the extraction of phenolics from pomegranate peels. Through steam explosion pre-treatment, the TPC of pomegranate peels increased, whereas antioxidant activity was not significantly enhanced. The phenolic compounds in pomegranate peels could be influenced by steam explosion pre-treatment. This increased the contents of ellagic acid and gallic acid, and decreased the content of punicalin and punicalagin, thereby counteracting the antioxidant activity of phenolic compounds. The appropriate steam explosion conditions for pomegranate peels were pressure 1.5 MPa, duration 90 s and 40-mesh for the extraction of total phenols, and 1.5 Mpa and 120 s for the extraction of ellagic acid and gallic acid. Additionally, the levels of the four phenolic compounds and antioxidant activity increased after gastric digestion and significantly decreased after intestinal digestion. The steam explosion caused the phenolic compounds in the pomegranate peels to be released more rapidly during digestion. Nevertheless, little is known about how transformed molecules and other bioactive compounds contribute to the antioxidant activity of pomegranate peels. Further, the underlying mechanism of how steam explosion alters the interaction between phenols and other compounds present in pomegranate peels needs to be explored in the future.The original contributions presented in this study are included in the article/JG conceived the study. QW and XZ performed the experiments. TY wrote the original manuscript. GS, DW, and LL analyzed the data. TY, JG, and MH reviewed and edited the manuscript. All authors read, discussed, and agreed to the published version of the manuscript.


Birth weight is an indicator of intra-uterine conditions but also a determinant for future health. The importance of preconception health for a healthy birth weight has been emphasized, but evidence is lacking on how modifiable factors in adolescence, such as body mass index (BMI) and smoking, affect future pregnancy outcome. We evaluated associations between BMI and smoking in adolescence and at the start of pregnancy and birth weight of the first-born child.This longitudinal study included 1256 mothers, born 1962–1992, and their first-born children, born between 1982–2016. Self-reported questionnaire information on weight, height and smoking at age 19 was cross-linked with national register data obtained at the start of pregnancy and with the birth weights of the children. Univariable and multivariable linear regressions were performed to determine the impact of maternal factors at 19 years of age and at the start of the pregnancy respectively, and the importance of BMI status at these points of time for the birth weight of the first child.p = 0.001) and smoking with a negative association of 180.5 g  p = 0.0002). Smoking and BMI at 19 years of age did not show this association. Maternal birth weight showed significant associations in models at both time-points. Becoming overweight between age 19 and the start of the pregnancy was associated with a significantly higher birth weight  p = 0.0002) compared to mothers with normal weight at both time points.BMI and smoking at the start of the pregnancy displayed strong associations with birth weight in a multivariable analysis, BMI with a positive association of 14.9 g per BMI unit (95% CI 6.0; 23.8 Our findings indicate that the time period between adolescence and first pregnancy could be a window of opportunity for targeted health promotion to prevent intergenerational transmission of obesity. The global disease burden of overweight and obesity is now one of the greatest threats to public health worldwide  and has Smoking during pregnancy is another well-known modifiable risk factor that has been linked to reduced birth weight in several large studies , 9. SmokLife course epidemiology is a useful technique capable of examining preconceptional factors and their effects on maternal and child health as it considers the timing and duration of exposures and their potential latent or cumulative effects. Adolescence could in this perspective be regarded as a sensitive period for future pregnancy outcome, since unhealthy life-style behaviors such as smoking and poor diet often originate during the teenage years . There iThe aim of this study was to evaluate the association between these modifiable maternal factors, BMI and smoking in the period between adolescence and young adulthood with the birth weight of the first-born child. We hypothesized that the adolescent period is a window of opportunity for improving future pregnancy outcome and the health of the next generation.This study originates from the prospective longitudinal study of 19-year-old women in Gothenburg, Sweden, initiated in 1981 . The parAuxiliary data to the information from the questionnaires regarding the women and their first-born children were retrieved by linkage to Swedish national registers, using the unique personal identification number allocated to every Swedish citizen . The Med2) and categorized into underweight (BMI < 18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) or obesity (BMI >  = 30) [The main exposure variables were maternal birth weight together with weight status at 19 years of age and at the start of the pregnancy and smoking status both at 19 years age and at the start of the pregnancy. Self-reported information at 19 years of age and register derived information from the first visit to the antenatal clinic (defined as start of pregnancy) on weight and height were used to calculate BMI (weight in kg/height in meter>  = 30) . Women wDescriptive data are presented with mean and standard deviation and categorical variables were presented with number and percentage. In order to test changes between 19 years of age and the start of the first pregnancy Wilcoxon sign rank test was used for continuous variables and Sign test for dichotomous and ordered categorical variables.p-value, and R2 are presented from the regression analyses. The standardized beta was calculated as beta*sx/sy, where sx and sy are the (estimated) standard deviations of x and y, respectively. Interaction testing for sex of the child and exposure variables were performed with a significance level set to 0.2. All analyses were performed using SAS 9.4 SAS Institute Inc., Cary NC, USA. All testing was made using a with alpha level 0.05 (interactions 0.20) with two-sided t-tests.In order to evaluate predictors of birth weight, univariable linear regressions were performed with the child’s birth weight as a dependent variable and maternal birth weight, mothers’ parents’ country of birth, maternal weight, height, BMI and smoking at 19 years as well as maternal age, weight, BMI, smoking, education and income at the start of the first pregnancy as predictors. BMI and smoking at 19 years of age and at the start of the first pregnancy were analyzed in a multivariable regression analysis, adjusted for maternal birth weight and maternal age and year of birth, and in the next step further adjusted for gestational age and sex of the child. Regression analysis was also performed based on groups of change in BMI status between 19 years of age and the start of pregnancy. This analysis was adjusted for maternal age at the first pregnancy, maternal birth year, maternal smoking at the start of pregnancy as well as gestational week and sex of the child. Beta (95% CI), standardized beta (95% CI) , p < 0.0001 for all comparisons). Regarding diagnoses that potentially influence birth weight, 6 women (0.5%) had hypertensive disorders and 9 women (0.7%) had diabetes in any form. No exclusions or adjustments were performed for these diagnoses. Table We included 1256 women-child pairs in the study  and hence results are presented for girls and boys together.Since birth weight differs by sex of the child, we tested whether there was an interaction between sex and the exposure factors in the association with birth weight. There was no significant interaction with sex of the child . Of the socioeconomic factors investigated, maternal income displayed a significant association with infant birth weight, with a reduction in birth weight of 54 g for income below the median . The highest R2 was seen for maternal birth weight, height at 19 years age and weight at the start of pregnancy, each explaining 6% of the variance in infant birth weight (R2 0.06 p < 0.0001).Univariable linear regressions, shown in Fig. p = 0.001) and smoking with a negative association of 180.5 g . R2 of this model was 0.08. Maternal birth weight was positively associated with birth weight in both models. Adjusting for gestational age and sex of the child increased the degree of explanation in the models but did not change the association with the examined exposures  was associated with significantly higher birth weight of the first-born child compared to that of women with normal weight at both time points (n = 626), Beta 144.6  p = 0.0002.In multivariable regression models grouped according to change in BMI status between19 years of age and the start of the first pregnancy , did not differ in birth weight from the children of mothers in the normal weight reference group. The groups with 54, 19, 26 and 10 individuals respectively were small, with wide confidence intervals, and thus no certain conclusions can be made for these BMI groups.Children born to women who were overweight or obese at both age 19 and at the start of the pregnancy (A healthy birth weight is important for the prevention of intergenerational transmission of obesity . StudiesInitiating smoking during the adolescent years has widespread negative long-term health effects , and smoMaternal obesity when entering pregnancy has been shown to influence not only birth weight but also the distribution and amount of fat mass in relationship to lean mass in the neonate . MaternaOur findings support the conclusions by Hanson et al., that lifestyle interventions in pregnant women do not limit gestational weight gain to the degree required to have a meaningful impact on pregnancy outcomes. Focus for interventions should be in the preconception period . Our finSocioeconomic factors, such as family income and education, are well known factors affecting the risk for development of childhood obesity. In a previous study from our group, we found parental income to be positively associated with birth weight . In the The main strengths of this study are the availability of longitudinal information for each woman on weight, height and smoking status at 19 years of age. This setting allows us to evaluate weight change and changes in smoking status during the time interval between late adolescence and at the start of pregnancy. The national Swedish registers are reliable and nearly complete .The limitations include a relatively low prevalence of overweight and obesity among mothers both at 19 years of age and at the start of pregnancy, which might be due to selection bias in the questionnaire study. The prevalence of birth weights outside normal range was also low, which prevented analyses of risk of LGA or SGA in the child.Obesity is the leading cause of poor health worldwide today , 30. TheIn this study, we had the rare opportunity to study BMI and smoking habits in women both at 19 years of age and at the start of their first pregnancy. We demonstrate that smoking at age 19 is not independently associated with birth weight of the first-born child, high-lighting late adolescence as highly important for promotion of smoking cessation when striving for a healthy birth weight in the next generation. Our results further indicate that weight gain during the period between late adolescence and the first pregnancy might be of importance for infant birth weight.


We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA).Preterm infants born between 28–32 weeks gestational age (GA) were studied at 32–36 weeks postmenstrual age (PMA), 36–40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events ) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months.R2 = 0.165, β = −0.416) and motor  composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex.%TST with respiratory events at term were significant predictors of language (In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months. Preterm birth remains a problem worldwide as 1 in 10 infants are delivered prematurely annually . InfantsAlthough prolonged apneas have been associated with adverse neurodevelopmental outcomes, the developmental impact of shorter apneas that are often undetected in the nursery have not been investigated despite studies showing that they are associated with falls in cerebral oxygenation. As temperament in preterm infants has been associated with neurodevelopment outcomes , we alsoInfants born between 28–32 weeks of GA were recruited between March 2018 and July 2021. We have specifically chosen this age group to minimize the complications of extreme prematurity. We did not recruit infants who continued to require ventilatory support or oxygen therapy, to avoid the confounding effect of parenchymal lung pathologies and chronic lung disease. Infants were not recruited if they had intrauterine growth restriction, a major congenital abnormality, major intracranial abnormality, or significant intraventricular hemorrhage (Grade III or IV), or if they had a hemodynamically significant patent ductus arteriosus because of the known independent effects on neurodevelopment. Ethical approval for this project was granted by Monash Health and Monash University Human Research Ethics Committees. Parents gave written informed consent before the first study. Results of the effects of periodic breathing on cerebral oxygenation in this cohort of infants have been published previously .2) measured using an oximeter set with a 2 s averaging time . Cerebral tissue oxygenation index  was measured using Near Infrared Spectroscopy   if the distribution was not normal and mean ± standard deviation (SD) if distribution was normal. Statistical significance was taken at p < 0.05.Statistical analysis was performed using SPSS software v27 . Data were first tested for normality and equal variance using the Shapiro-Wilk test. To assess the effects of sleep state on the %TST spent with respiratory events, nadir % changes in HR, SpOForty infants were recruited; and underwent the first study whilst in Monash Newborn. Thirteen infants were lost to follow-up after they were discharged home as parents decided against continuing participation and one was lost to follow-up due to COVID-19 restrictions. Six infants were unable to be studied at Study 3 and 6 studies at 6 months CA were delayed ( ~ 1 month) due to COVID-19 restrictions in Melbourne which prevented us entering the infant’s home. The 26 infants who completed the sleep study and neurodevelopmental assessments at 6 months CA were included in this study. The 26 infants included in this study  had a median [IQR] GA at birth of 30  weeks with a median birth weight of 1.4  kg, birth length of 41  cm and head circumference of 28  cm. Infant APGAR scores ranged from 1–9 (median 7) at 1 min, and 4–9 (median 9) at 5 min. All infants were administered caffeine after birth and 35% were still on caffeine treatment at the time of Study 1 (32–36 weeks PMA). Infants still on caffeine at the time of the first study had a median caffeine dose of 8.6  mg/kg calculated using the weight of infants at the first study and the dose given at the time of the study. None of the infants were discharged home on caffeine.All 26 infants were studied at 32–36 weeks PMA, 24 infants at 36–40 weeks, 19 at 3 months CA and 26 at 6 months CA. Demographic and sleep characteristics of the infants at each study are presented in Table All infants experienced isolated apneas up to 3 months CA and this fell to 92% at 6 months CA Fig. . In cont2 decreased with increasing age, with falls in SpO2 at 3- and 6-months CA being significantly less when compared to falls at 32–36 weeks PMA  were free of artifact and were included in this part of the analysis: 1397 events (94%) at 32–36 weeks PMA, 1113 (97%) at 36–40 weeks PMA, 302 (95%) at 3 months and 267 (96%) at 6 months CA. Physiological consequences of respiratory events separated by event type  and respiratory events combined at 32–36 weeks PMA, 36–40 weeks PMA, 3- and 6-months CA are presented in Tables Infants completed the BSID-III assessments at a median [IQR] of 6.7  months CA. Infants had a median [IQR] cognitive composite score of 100 , language composite score of 100 , motor composite score of 99 , social emotional composite score of 100 , and adaptive behavior score of 103 . All infants scored >85 in the cognition and adaptive behavior domains. One infant (4%) scored <85 in the language domain, 4 infants (15%) scored <85 in the motor domain, and 3 infants (12%) scored <85 in the social emotional domain.R2 = 0.165, p = 0.039; TSTPB, Unstandardized β = −0.431, R2 = 0.162, p = 0.041) and motor outcomes , at 6 months CA. %TSTevents and %TSTPB at 32–36 weeks PMA, 3 and 6 months were not associated with any of the BSID-III domains. %TST in isolated apnea or SA were not associated with any of the BSID-III domains. There was no association between nadir % change in SpO2 or TOI during respiratory events (isolated or combined) and the BSID-III outcomes.Stepwise linear regression identified that GA, sex and birth weight were not predictive of BDSI-III scores. %TST with all respiratory events combined and %TSTPB at term CA (36–40 weeks PMA) were significant predictors of language  and approach . Increased %TSTevents at 36–40 weeks PMA predicted a lower perceptual sensitivity score  and increased %TSTevents at 6 months CA predicted a higher falling reactivity score  and duration of orienting .IBQ-R questionnaires were available for 25/26 infants and were completed at a median [IQR] age of 6.4  months CA. Infants scored (mean ± SD) 4 ± 1.1 for activity level, 3.9 ± 0.9 for distress to limitations, 3.2 ± 1.3 for fear, 3.8 ± 1.1 for duration of orienting, 4.6 ± 1.1 for smiling and laughter, 6.0 ± 0.8 for high pleasure, 5.2 ± 0.9 for low pleasure, 5.4 ± 0.8 for soothability, 5.0 ± 1.1 for falling reactivity, 5.5 ± 0.8 for cuddliness, 4.1 ± 1.6 for perceptual sensitivity, 3.6 ± 0.8 for sadness, 5.3 ± 1.0 for approach and 5.0 ± 1.0 for vocal reactivity. Increased %TSTevents at 32–36 weeks PMA predicted a lower score for perceptual sensitivity  with a mean duration of 2.26 ± 0.11 minutes was associated with permanent neurofunctional deficit and white matter hypomyelination [Preterm born infants are at a higher risk for adverse neurodevelopmental outcomes at 2 years of age , school lination . Furtherlination . Additiolination . Taken tIn our cohort of clinically stable preterm infants, an increased time spent with respiratory events at 36–40 weeks PMA was a determinant of reduced language and motor scores at 6 months CA. Our results suggest that a delayed maturation of respiratory control resulting in respiratory events, particularly periodic breathing, continuing after discharge from the neonatal unit at around term CA may have deleterious effects on neurodevelopment. This suggestion is supported by a study in very low birth weight infants , where t2 ≤ 80% for ≥4 s) [2 < 90% for ~2 min), similar to those experienced by preterm infants, was associated with systemic and brain inflammation, altered brain structure and metabolism [2) in extremely preterm infants from the Canadian Oxygen Trial (COT) found a significant association between exposure to prolonged hypoxemic episodes (SpO2 < 80% for at least 1 min) during the first 2–3 months after birth and the risk of late death or disability at 18 months corrected age CA [Among the respiratory events we observed, periodic breathing occupied the highest proportion of the infants’ sleep time, hence, our finding that time spent in periodic breathing, and not time spent in isolated or sequential apneas, was associated with reduced language and motor scores. This finding suggests that intermittent breathing pauses accompanied by mild hypoxia may contribute to poorer neurodevelopmental outcomes in these infants. This finding complements another study in infants born at 27–34 weeks GA and studied at 33–37 weeks PMA, similar to the infants in our cohort, that also found that periodic breathing was the most common cause of prolonged desaturation . In addition, the median nadir % change in TOI for each type of respiratory event was <10%, a change in cerebral oxygenation that would not be deemed clinically significant . HoweverIn addition to developmental outcomes, we also identified that %TSTevents  was a significant predictor of several areas of temperament using the IBQ-R. As the IBQ-R is not designed for use in diagnosis of psychological disorders or adverse outcomes, there are no reference scores or thresholds for adverse outcomes. However, infant temperament has been associated with neurodevelopment in preterm infants at 2 years of age  and in y. In addition, our study was affected by COVID-19 restrictions, resulting in missing values at 36–40 weeks PMA (8%) and at 3 months CA (27%). Our statistical approach accounted for these missing values when assessing on the effects of respiratory events on BSID-III and IBQ-R outcomes. We assessed the children at 6 months of age to coincide with the final sleep study, which was timed to coincide with the resolution or near resolution of periodic breathing [Our study has several limitations that need to be considered when interpreting our findings. Firstly, our sample size was limited to 26 infants. However, our longitudinal design allowed us to follow individual infants across the first 6 months of life, providing longitudinal data on the frequency and physiological consequences of respiratory instability. Furthermore, our findings of significant differences in developmental outcomes are similar to previous nutritional and environmental intervention studies which have shown that a difference of 4–5 points on the BSID-III has clinically meaningful outcomes , and thireathing , 23. Thereathing . Resultsreathing  as well reathing . We planreathing  and in preathing  and longreathing . A strenIn conclusion, our study identified that the majority of time spent with respiratory events was spent in periodic breathing, and both %TSTPB and %TSTevents at 36–40 weeks were associated with poorer language and motor outcomes at 6 months CA in clinically stable preterm infants who had been discharged home with no concerns of respiratory instability. These short apneas are generally not of sufficient duration to cause bradycardia or desaturation that would trigger monitor alarms, and therefore unlikely to be recognized and treated in the neonatal unit. Our findings add to a growing literature suggesting periodic breathing is not benign and the accompanying brief desaturation and re-saturation may contribute to adverse outcomes in preterm infants. Our results highlight the need for a randomized controlled trial of treatment of respiratory instability identified prior to term equivalent age and potentially continuing until the resolution of periodic breathing.


Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks’ gestation).Preterm birth cohort study of 693 mother-infant dyads. Severe HDPwas defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, based on the NICHD Consensusstatement.225 (32%) mothers developed severe HDP and 234 (34%) infants hadmoderate-severe BPD. There was an interaction between severe HDP and gestational age (p=0.03). Infants born at earlier gestational ages to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born at later gestational ages to mothers with severe HDP had decreased odds for the outcome.Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age. Premature very low birth weight infants comprise approximately 1.5% of all U.S. births, yet contribute to more than 50% of the neonatal mortality rate.  More recPreeclampsia, HELLP  syndrome, and eclampsia are hypertensive diseases of pregnancy (HDP) associated with abnormal vascular growth within the uteroplacental interface resulting in dysfunctional placentation. , 10 TherWe conducted a retrospective cohort study using records from a Retinopathy of Prematurity (ROP) registry developed by the Department of Ophthalmology at the University of Colorado School of Medicine. Infants included in the registry delivered at the University of Colorado Hospital between January 1, 2012, through December 31, 2020. The study received approval from the Colorado Multiple Institutional Review Board. The study was performed in accordance with the Declaration of Helsinki. All infants fulfilled the American Academy of Pediatrics 2013 screening criteria for ROP defined as “infants with a birth weight of ≤ 1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist) and selected infants with a birth weight between 1500 and 2000 g or gestational age of > 30 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who were believed by their attending pediatrician or neonatologist to be at high risk for ROP.”The ROP Registry is described in detail elsewhere. , 23 In bThe primary exposure was severe HDP  consensus panel and adjusted for altitude in Denver, CO to define BPD.–28 InfanInformation on maternal demographics, maternal self-designation of race/ethnicity, pregnancy and delivery history were included in the analysis. Adverse outcomes related to preterm birth were also assessed, including severe (grade 3 or 4) intraventricular hemorrhage (IVH), surgicaWe excluded from the original cohort (n = 926) infants with: 1) ROP screening criteria by unstable clinical course alone, rather than by gestational age or birth weight criteria, 2) congenital or chromosomal anomalies, 3) a transfer to an outside institution prior to ROP examination, 4) an uncertain BPD classification, and 5) babies from women with gestational hypertension (as the focus of the study was severe forms of HDP). Following exclusions, 693 mother-infant dyads remained in the analytic dataset, with all infants surviving to 36 weeks PCA for their BPD determination. A consort diagram describing exclusion of infants from the analytic dataset is shown in supplementary Fig. 1.Descriptive statistics were calculated using means and standard deviations for continuous variables and percentages for categorical variables. Risk factors were compared across HDP and BPD groups using chi-squared tests and two-sample t-tests for categorical and continuous variables, respectively. The association between severe HDP, gestational age and moderate-severe BPD was evaluated graphically using a loess scatterplot smoother. The multivariable logistic regression model included both an interaction between HDP and gestational age as well as birth weight. Statistical analysis was performed using SAS 9.4 .In our cohort, 225 (32%) mothers had severe HDP, 234 (34%) had moderate-severe BPD. We show in Women with severe HDP were more likely to be older, have a cesarean delivery, deliver an infant with a birth weight < 10%, and be at a higher gestational age at delivery. We found a significantly lower incidence of treatment with antibiotics in women with severe HDP compared with women who had a preterm birth and remained normotensive. There was no difference in the frequency of the secondary infant outcomes examined between infants born to normotensive women compared to hypertensive women.We demonstrate in The association between HDP and the moderate-severe BPD outcome was first inspected graphically . In thisWe show in The odds of BPD associated with HDP across gestational age is displayed in In this cohort, we investigated the relationship between severe HDP and moderate-severe BPD. We found no association between HDP and moderate-severe BPD in a univariate analysis or after adjusting for GA and birthweight. However, we found an important and critical interaction between gestational age and severe HDP and severity of the BPD outcome. Infants born < 25 weeks gestation to mothers with HDP had twice the odds of developing moderate-severe BPD compared to infants of normotensive mothers. This risk decreased with progressive gestational age.Several studies have investigated the association of HDP with BPD, defined as oxygen need at 28 days and at 36 weeks post conceptual age, with inconsistent findings. Hansen et al examined a cohort of babies born between 23 and 32 weeks gestation and found that BPD was increased in infants exposed to preeclampsia. Gemmell The pathophysiology of BPD is characterized by an arrest of both alveolarization and of pulmonary vascular development, secondary to multiple antenatal and perinatal insults when infants are born at the late canalicular stage of lung growth.–7 PreeclOur study was limited by sample size. It is understood that the risk of BPD increases with lower gestational age, and severity of HDP resulting in premature delivery is also inversely related to gestational age. As such, there is no inherent control group when examining premature deliveries, which is an unresolvable challenge for any such study. Placental vascular abnormalities were not available thus not included in this analysis. However, strengths of our study include strict definitions of HDP and severity of BPD classification, not included in other investigations. We utilized the NICHD classification for BPD severity, to limit the variability in the clinical spectrum of BPD seen in previous studies. Our cohort’s outcome definition included a rigorously defined oxygen reduction test to determine BPD severity. Another major strength of our analysis is the inclusion of the important interaction between gestational age and HDP, addressing this recognized inter-relationship.We found that severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age among preterm infants at risk for ROP. The presence of this effect may explain why certain studies have found an association while others have not. These findings suggest that biologic factors specific to severe HDP occurring earlier in pregnancy contribute to the development of moderate-severe BPD. Further investigation in larger carefully characterized cohorts is warranted to study these biologic mechanisms between maternal pathophysiology and subsequent neonatal pulmonary vascular development among preterm infants.


More and more very low birth weight (VLBW) infants around the world survive nowadays, with consequently larger numbers of children developing prematurity-related morbidities, especially bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and its rising incidence in recent years means that general pediatricians are much more likely to encounter a child born extremely preterm, possibly with BPD, in their clinical practice. Short- and long-term sequelae in VLBW patients may affect not only pulmonary function , but also other aspect including the neurological , the sensorial , the cardiological , nutritional , and auxological (extrauterine growth restriction). For the most premature infants at least, a multidisciplinary follow-up is warranted after discharge from the neonatal intensive care unit in order to optimize their respiratory and neurocognitive potential, and prevent respiratory infections, nutritional deficiencies or cardiovascular impairments.Conclusion: The aim of this review is to summarize the main characteristics of preterm and BPD infants, providing the general pediatrician with practical information regarding these patients’ multidisciplinary complex follow-up. We explore the current evidence on respiratory outcomes and their management that actually does not have a definitive available option. We also discuss the available investigations, treatments, and strategies for prevention and prophylaxis to improve the non-respiratory outcomes and the quality of life for these children and their families, a critical aspect not always considered. This comprehensive approach, added to the increased needs of a VLBW subjects, is obviously related to very high health-related costs that should be beared in mind.   Preterm birth is a frequent event, happening in about 10% of pregnancies. Although very preterm and extremely preterm births occur less frequently nowadays, every year 1.1% of newborn infants are born at less than 28 weeks of post-menstrual age (PMA), and with a birth weight of less than 1500 g, defined as very low birth weight (VLBW) [Recent advances in neonatal care have enabled more infants to survive extremely preterm birth, giving rise to more children with prematurity-related morbidities like bronchopulmonary dysplasia (BPD). However, efforts to minimize lung injury have not reduced the incidence of BPD , so geneBPD is diagnosed most commonly as oxygen need for 28 days after birth and graded with respiratory support at 36 weeks PMA . DependiEven VLBW infants not diagnosed with BPD can experience some degree of lung abnormality during childhood and adulthood, suggesting the presence of a chronic lung disease of prematurity. Their poor lung function poses a risk of a chronic obstructive pulmonary disease (COPD)-like phenotype later in life. Hence the growing attention to monitoring lung function and managing respiratory symptoms in VLBW subjects beyond the neonatal period.BPD is a multifactorial disease  thought Several interventions have shown potential for acting on the above-mentioned factors and limiting the burden of BPD and respiratory sequelae of prematurity. They include  antenataThere are few options for the pharmacological treatment of evolving BPD and BPD during the newborn’s hospital stay. Systemic corticosteroids are among the most studied: they have shown promise in reducing the incidence of BPD, especially when used within the first 8–14 days of life . The risOther frequently prescribed drugs are diuretics, like furosemide, chlorothiazide, and spironolactone, which may be started in hospital, then discontinued at home, depending on the infant’s need for oxygen therapy and post-discharge growth .Preclinical and early clinical studies have generated positive results with stem cells , 19 and Meanwhile, general pediatricians will see increasing numbers of preterm-born children with chronic lung disease persisting into adult life .To better support this population, general pediatricians and neonatologists need to work together even before patients are discharged from the neonatal intensive care unit (NICU). Pediatricians should meet the infants and their parents already in hospital and plan the patients’ short-term clinical follow-up with the neonatologist. This is especially crucial for the most fragile infants, like those needing oxygen supplementation at home.Children born extremely preterm are at higher risk of both short- and long-term respiratory sequelae . Among tDuring the first 2 years of life, infants born extremely preterm, with or without BPD, are hospitalized more often than children born at term , 27, sugMonitoring lung function in preschoolers born preterm is not an easy task. It entails using non-routine methods like the forced oscillation or interrupter resistance techniques. Such methods have demonstrated reduced expiratory flows in preterm infants regardless of any BPD diagnosis , but resSeveral children with airway flow limitations (reduced FEV1) in school age do not improve as they grow older , 34. In Children born very preterm, and those with BPD especially, may have an impaired exercise tolerance that persists in adolescence and adulthood . This coA main concern for general pediatricians is the current lack of treatments for symptoms of chronic lung disease and its re-exacerbations. Drugs for asthma are frequently prescribed to former BPD and preterm subjects, especially inhaled corticosteroids and bronchodilators , but thiThe chronic inflammation in BPD subjects , 44, andSpirometry has documented a certain response to bronchodilators in BPD subjects , but theThe ERS task force  suggestsSumming up, the evidence on chronic and acute therapies for BPD and its re-exacerbations is scarce. Treatments should be adequately tailored to individual patients. In cases of moderate-severe BPD, or frequent re-exacerbations, we recommend follow-up visits with pediatric pulmonologists, who can help general pediatricians assess patients’ respiratory symptoms and monitor the benefits of any therapies, preferably measuring lung function .On the matter of preventive measures, the picture changes completely.Palivizumab is a monoclonal IgG antibody against the RSV’s protein F. Adopting a monthly administration protocol, it has been demonstrated to reduce 55%) the hospitalizations for severe RSV infections involving preterm-born infants, especially those with BPD. There is still no standardized European guideline on the use of palivizumab, and national guidelines follow cost-effectiveness considerations . In gene% the hosGiven the immature and less competent immune system of infants born preterm, their immunization schedules should not be delayed. Vaccinations should be administered at the same chronological age and according to the same schedule as for term-born infants. Exceptions include: the hepatitis B birth dose, which should be deferred until discharge from hospital or one month of age for infants born at < 2000 g from mothers who test negative for the hepatitis B surface antigen; and the rotavirus vaccine, which is contraindicated in preterm-born infants who have had necrotizing enterocolitis . AdverseUsing lung imaging to monitor the respiratory health of BPD subjects is not currently routine, but high-definition CT or MRI may be useful in cases of particularly severe respiratory symptoms and/or recurrent hospital admissions . DespiteThere is no standard respiratory follow-up schedule for BPD, but a recent US experts’ survey recommended an early pulmonary consultation (1–2 months after discharge from the NICU) for infants with moderate or severe BPD, and at least a one-off specialist assessment for cases of mild disease . Lung fuGeneral pediatricians have a crucial role in managing BPD infants discharged home with oxygen supplementation. The ERS consensus guidelines  recommenParents of children born preterm will likely ask for their general pediatricians’ advice about attending daycare centers or kindergarten. Despite the limited scientific evidence available, this advice should take into account local experience, the child’s age, the time of year, the parents’ wishes and possibilities. The first winter of very young infants with severe BPD is clearly of greatest concern, but many factors could influence parents’ decisions, and the potential benefit of kindergarten to their child’s social development should not be overlooked .Caring for children born preterm also includes: avoiding second- and third-hand smoking and the related preventable inflammation and oxidative stress of their already-damaged lungs, and to protect their respiratory health ; avoidinPrematurity affects multiple systems with potentially lifelong consequences , Crump eBPD is independently associated with adverse neurological outcomes at 12 and 24 months of corrected age. On Bayley III assessments, impairments in one or more neural functions relating to adaptability, gross motor, fine motor, language, or social skills are significantly more common in preterm-born children with BPD. Pulmonary hypertension can also have a negative influence on such neurodevelopmental outcomes .Recent brain MRI studies comparing term-born infants with those born preterm and developing BPD showed a delayed brain maturation in the latter . BPD alsIUGR is a worsening factor also in the neurological development, being associated with both alterations in brain growth on MRI evaluation at term and poorer toddlerhood outcomes. Infants with a previous diagnosis of IUGR present lower cognitive and motor scores at 22 months and a positive Modified-Checklist for Autism (OR 2.12) compared with adequately grown controls .Infants born preterm are also at higher risk of neuropsychiatric disorders during childhood. The “preterm behavioral phenotype” features a higher risk of symptoms and disorders associated with inattention, anxiety and social difficulties, and a markedly greater prevalence of autism spectrum disorders , but alsFinally, preterm-born infants with severe brain lesions such as stage 3 or 4 intraventricular hemorrhage, periventricular leukomalacia or a history of altered findings on electroencephalography (EEG) should be monitored with serial EEG because they are at higher risk of developing epilepsy .Premature and BPD infants may experience feeding problems, and swallowing dysfunctions that can affect their growth and respiratory function. BPD infants may have tachypnea or low oxygen saturation episodes during breastfeeding due to a poor coordination of sucking and swallowing, and gastroesophageal reflux is common . Little Feeding problems, diuretics, postnatal steroids, and an inadequate intake of minerals may impair optimal growth in the first years of life, with consequent deficiencies (such as low iron levels or metabolic bone disease) in preterm infants . So, supVitamin D contributes to bone mineralization and neuromuscular function, and can also have an anti-inflammatory function . The EurMost VLBW infants are discharged home without an optimal growth during their hospital stay, when the targeted caloric intake is not always achievable . The resCardiovascular problems associated with prematurity, such as pulmonary hypertension, need monitoring with echocardiography and specialist cardiologist consultations. Young adults born preterm are also at higher risk of non-communicable diseases  like iscThe numerous aspects of metabolic syndrome  should be clinically monitored too, especially in VLBW infants with a history of IUGR, which are at higher risk , and it Assessing children’s physical activity levels should be part of the general pediatrician’s routine, especially for children born preterm. Physical activity is recommended in this population, given its known benefits , which cIt is strongly advisable to test preterm-born infants’ sensory functions because their early exposure to numerous drugs  can cause hearing impairment. To identify and treat this issue early on, screening is usually done before discharge, but a follow-up visit should be scheduled a few months later to check infants’ hearing function and ensure any necessary action is taken before they are 6 months old .Visual function should be monitored too, as preterm infants are more likely to have a reduced visual acuity, strabismus, abnormal stereopsis and refractive errors, but routine screening may not detect other problems, such as reduced visual fields, impaired contrast sensitivity, or deficits in cortical visual processing, that may occur in this population . All theA final aspect that should be beared in mind concerns the preterm infants’ families. The birth of an extremely premature child dramatically upsets the balance of any couple and family. Then the infant’s discharge from hospital brings new disruptions, imposes new daily routines, adds to parents’ stress and anxiety, leaves them less time for their other children, and so on . IdentifA comprehensive approach to the VLBW subject is consequently strongly recommended and will imply a large multi-specialistic team, coordinated by the general pediatrician and the neonatologist, but including pneumologists, cardiologists, neurologists, neuropsychiatrists, nutritionists, gastroenterologists, nephrologists, endocrinologists, radiologists, ophthalmologists, audiologists and speech, deglutition, and physical therapists. This should also include non-medical figures like support teachers, psychologists and social workers. The access to this panoply of services is not always easy and families could benefit from the support of patients’ associations that can help subjects and their families address the high demand for care and health needs associated with very preterm birth. Patients’ associations have also the important role of patients’ advocacy, speaking out their best interests and highlighting to every involved figure the importance of their role. One of these associations, the European Foundation for the Care of Newborn Infants (EFCNI), has fully accepted this responsibility, and recently published a comprehensive guideline  for the care of all the facets of the newborn infant, especially if preterm born .As can be deduced, a preterm born infant requiring a prolonged hospitalization with intensive care needs, implies quite high health-related costs. However, the first hospitalization is only the beginning of an expensive journey, requiring a significantly higher expenditure compared with the neonatal admission of a term born infant, as shown by many different papers on this topic showing similar results even if in different realities –103, witTo sum up, Table VLBW infants with and without BPD warrant a long-term medical care that still has many aspects that remain unclear. After these infants’ discharge from the NICU, collaboration between the neonatologist and the general pediatrician is fundamental to the child’s proper follow-up and the discontinuation of previously-used therapies. Our increasing understanding of the main problems of children born very preterm suggests the need for a multispecialist follow-up into adulthood, especially for those with severe BPD  Fig. 1)1). From


Seafood is a good source of essential fatty acids which has a presumably beneficial effect on developing embryos and fetuses, although it is also a source of contaminants. In this context, pregnant women are faced with conflicting reports on the risk and benefits of seafood consumption. This study aims to assess whether the consumption of seafood during pregnancy was associated with fetal growth in an inland city in China.This study included 10,179 women who delivered a singleton live birth in Lanzhou, China. Seafood consumption was assessed using a Food Frequency Questionnaire. Maternal data including birth outcomes and maternal complications information is extracted from the medical records. Associations between seafood consumption and fetal growth indicators were analyzed using multiple linear regression and multiple logistic regression.β = 0.027, 95%CI:0.030–0.111) but no association concerning birth length or head circumference. Seafood consumption was associated with decreased risk of low birth weight . The frequency of seafood consumption during pregnancy showed a trend toward a positive association with low birth weight. Significantly reduced rates of low birth weight were found in women who consumed more than 75 g of seafood/week during pregnancy as compared to women with no or very low intakes (P for trend 0.021). A significant interaction was observed between pre-pregnancy BMI and seafood consumption on birth weight among underweight women, but not among overweight women. Gestational weight gain partially mediated the association between seafood consumption and birth weight.There was a positive association between total seafood consumption and birth weight (Maternal seafood consumption was associated with decreased risk of low birth weight and increased birth weight. This association was mainly driven by freshwater fish and shellfish. These results further corroborate the present dietary recommendation to the Chinese Nutrition Society for pregnant women, especially those with underweight pre-pregnancy BMI and inadequate GWG. In addition, our findings provide implications for future interventions to improve seafood consumption among pregnant women to prevent low birth weight babies in the inland city in China. Seafood, defined as marine and freshwater fish and shellfish, has been well-demonstrated to contain nutrients that maintain and promote health . The pasAbundant evidence has consistently shown that seafood consumption during pregnancy is associated with favorable fetal growth and birth outcomes. A recent literature review and meta-analysis concluded that increased seafood consumption was associated with a reduced risk of low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB) . SeafoodHowever, substantial studies have also indicated that seafood may be a potential source of chemical pollutants such as polychlorinated biphenyls (PCB), dioxins, and methyl mercury (Hg), which may lead to adverse birth outcomes , 9. In pThe inconsistent findings on the association between maternal seafood consumption and fetal growth may arise from the differences in the types of seafood assessed, which may contain different types and levels of nutrients and pollutants . It is tThe objective of the present study was to examine the association between seafood consumption and fetal growth  and to determine the importance of the type of fish in this association. In addition, we also examined how seafood consumption during pregnancy affects the risk of low birth weight. In a secondary analysis, we examined whether the association between maternal seafood consumption and fetal growth varied by pre-pregnancy BMI, and whether gestational weight gain (GWG) mediated the association between seafood consumption and birth weight.The birth cohort study was conducted from 2010 to 2012 in the Gansu Provincial Maternity and Child Care Hospital (GSMCH), the largest maternity and childcare hospital in Lanzhou, China . InclusiAll study procedures were approved by the human investigation committees at the Gansu Provincial Maternity and Child Care Hospital (No. 2010GSFYIRB09). Each eligible woman who came to the hospital for delivery was explained the study’s purpose and procedure in detail. Those who agreed to participate in the study were invited to participate in face-to-face interviews within 1–3 days after delivery after providing written informed consent. A standardized and structured questionnaire was used to collect information on demographic, reproductive and medical history, smoking behavior, alcohol, occupational and residential history, physical activity level, and seafood consumption during pregnancy. On the other hand, information on birth outcomes and maternal complications was extracted from medical records.Seafood consumption was assessed using a Food Frequency Questionnaire (FFQ) that inquired about the dietary habits of a wide range of various food during pregnancy. The FFQ contains 33 items assessing 33 types of various food, among which 3 items were about seafood, including freshwater fish , saltwater fish , and shellfish . For each seafood item, participants were asked about both the frequency and the amount (g) of consumption. For each item, participants need to circle whether they eat on a daily, weekly, or monthly basis, followed by how many times (direct estimated numbers) and how much quantity (assessed by portion size images) they eat under each circled category based on their choice. Seafood consumption frequency was further classified into four categories: “never “, “≤1 time a week “, “2 -3 times a week”, and “≥4 times a week”. Seafood consumption quantity was further classified into five categories by quartiles: “never”, “< 14 g/week”, “14–75 g/week”, “76–176 g/week” and “> 176 g/week”.Infant birth weight (g), birth length(cm), and head circumference(cm) measures were extracted from medical records. Gestational age was established based on the date of the last menstrual (LMP) self-reported by the mothers. However, in the case of a discrepancy between LMP and an early ultrasound measurement of ≥7d, the latter was used to determine gestational age. Low birth weight was defined as any newborn with a birth weight < 2500 g . Macroso2) before pregnancy, which was categorized as underweight (BMI < 18.5 kg/m2), normal weight (18.5 kg/m2 ≤ BMI < 24 kg/ m2), and overweight and obese (BMI ≥ 24 kg/m2) using the standard of Working Group on Obesity in China [Maternal height and pre-pregnancy weight were used to compute maternal body mass index .Statistical significance was assessed with the chi-square statistic for all categorical variables. Associations between seafood consumption and continuous variables such as birth weight, birth length, and head circumference were analyzed using multiple linear regression. Associations between seafood consumption and categorical variables such as low birth weight, macrosomia, SGA, and LGA were analyzed using multiple logistic regression. We used linear regression to calculate P for trend when examining seafood intake across the ordered categories and Student’s t-test for dichotomous variables. In addition, all regression models were adjusted for potential confounders of maternal characteristics. The variance inflation factor test for multicollinearity was well within limits, indicating that all confounders in the model could reliably assess their independent contribution. All n = 8441) of women, while 17.1%(n = 1738) of women reported no seafood consumption in our study. In the total sample, the median energy intake calculated by the FFQ was 1613·94 kcal, with the 25th and 75th percentile being 1347 kcal and 1906 kcal, respectively. Table Consumption of any seafood was reported by 82.9%n = 844 of womenP < 0.001) but not with birth length or head circumference. When examining such associations by seafood type, both freshwater fish  and shellfish  consumption were significantly positively associated with birth weight, while saltwater fish consumption was not associated with any fetal growth indicators.Table P < 0.001) and SGA , but not with macrosomia or LGA. Compared to those who never consumed seafood, those who consumed seafood had decreased risk of low birth weight by 42.5% and SGA by 41%.Table P < 0.001). Compared to women consuming no seafood, the risk of low birth weight decreased by 35.9% among women consuming ≤1 time a week , by 48.4% among women consuming 2–3 times a week , and by 49.3% among women consuming ≥4 times a week . In addition, an increased quantity of weekly seafood consumption was associated with a decreased risk of low birth weight, with a significant trending effect (P < 0.001). Compared to women consuming < 14 g/week, the risk of low birth weight decreased by 44.2% among women consuming 76–176 g/week  by 47.8% among women consuming > 176 g/week . No significant association was observed between the 14–75 g/week consumption group with the risk of low birth weight.Figure P = 0.008), but not in the overweight group (P = 0.802). Additionally, further mediation analysis showed a partial mediation effect of GWG on the association between seafood consumption and infant birth weight. Increased seafood consumption was associated with increased GWG, which in turn, was associated with increased birth weight. The indirect effect of GWG on the association between seafood consumption and infant birth weight accounted for 11.8% of the total effect (p < 0.05).Considering the important effect of pre-pregnancy BMI and GWG on birth weight, we further tested the interaction between pre-pregnancy BMI and seafood consumption on birth weight, as well as the mediation effect of GWG on the association between seafood consumption on birth weight in our secondary analysis. The results of the interaction analysis were shown in Table In this cohort study, we found higher consumption of seafood had a beneficial effect on low birth weight, which was mainly driven by freshwater fish and shellfish consumption. No association between seafood consumption and birth length or head circumference was observed in our population. Significantly reduced rates of low birthweight were found in women who consumed more than 75 g of seafood/week during pregnancy as compared to women with no or very low intakes. Also, significant interactions between pre-pregnancy BMI and seafood consumption on birth weight were found among the underweight group, but not in the overweight group. GWG partially mediated the association between seafood consumption and birth weight.Our study demonstrated a positive association between maternal seafood consumption and increased birth weight, which is consistent with previous epidemiological studies showing that increased seafood intake was associated with increased fetal growth measures –25. Thesn = 55). For instance, some previous studies have demonstrated that prediction models built using logistic regression in small data sets, might lead to poor predictions that are too extreme and uncertain [We also examined seafood consumption with the risk of low birth weight, and the results showed that seafood intake had a protective effect on low birth weight, which is consistent with some earlier findings , 24, 34.ncertain –37. Othencertain , 31. AnoSeveral investigators have reported an increased risk of low birth weight associated with a maternal diet low in marine fish, or even with no association . DiffereIn our secondary analysis on the interaction between pre-pregnancy BMI and seafood consumption on birth weight, we found a significant interaction effect among underweight women, but not among overweight women. Abundant evidence has shown that pre-pregnancy BMI was an important factor associated with fetal growth. Specifically, pre-pregnancy underweight was associated with an increased risk of low birth weight, while pre-pregnancy overweight was associated with an increased risk of high birth weight , 44. TheIn addition, the significant mediation effect of GWG on the association between seafood consumption and birth weight in our secondary analysis was also consistent with a recent study showing similar medication effects of GWG . InadequOne thing noteworthy is that the rate of gestational diabetes among pregnant women of Lanzhou City in our study was 1.01%, which was slightly lower than the reported 3% in another study conducted in Lanzhou . HoweverThe main strength of this study is the relatively large sample of Chinese pregnant women in this study and their high rates of participation and follow-up, which allowed us to extensively collect information on many potential confounding variables. A second highlight is the prospective study design allowing us to collect a range of data from pregnancy to birth outcomes. A third strength is we collected detailed information on a wide variety of maternal characteristics including demographic and nutritional predictors of fetal growth as well as various types of seafood consumption.Nonetheless, there were some limitations to our study. First, the pregnant women all came from one hospital and about 85% of them completed all routine prenatal visits in the hospital. Our sample may not represent pregnant women in other hospitals or the 15% lost-to-follow-up women with missing information on maternal complications. Second, the assessment of most variables including seafood consumption was based on pregnant women’s self-reports, which may be subject to recall bias and thus limit the methodological strength. However, we also used some metrics such as nutritional intake, infant birth weight, birth length, and head circumference measures to complement this limitation. Third, although careful adjustment for potential lifestyle confounding variables did not appreciably alter the results, we did not control the confounding for other dietary variables. For instance, pregnant women may also get long-chain n-3 fatty acids from other supplements apart from seafood. However, a previous study had shown that adjusting for meat, milk or other dietary factors did not attenuate the associations between seafood consumption and birth weight . Fourth,In summary, our study showed that maternal seafood consumption was associated with decreased risk of low birth weight and increased birth weight. This association was mainly driven by freshwater fish and shellfish. Seafood is still an important dietary source of N-3 LCPUFA and proteins for pregnant women and fetuses. These results further corroborate the present dietary recommendation to the Chinese Nutrition Society for pregnant women. However, in our population, 10.7% of pregnant women followed this recommendation. Therefore, our findings suggest that seafood consumption may be strengthened among pregnant women who never consumed or consumed not enough seafood, especially those with underweight pre-pregnancy BMI and with inadequate GWG. Our findings have implications for the future development of intervention programs to improve birth outcomes and fetal growth through the improvement of seafood consumption. This may be realized by the joint efforts of multiple stakeholders involved in seafood and pregnancy care. For instance, healthcare providers can provide more information and education to pregnant women about the beneficial effect of seafood consumption on fetal growth to promote their knowledge, awareness, and behavior in seafood consumption. The local government could collaborate with the seafood market to provide some incentives such as free seafood stamps to encourage seafood purchase and consumption among pregnant women.


Herein, we present a case of pseudoaneurysm following PCNL and describe an alternative technique for its removal using a grasper under C-arm vision. Percutaneous re-surgical approach to post-PCNL hemorrhage due to pseudoaneurysm by using a nephro-grasper to pick up the renal artery pseudoaneurysm would be safe, effective and can provide a direct view of pyelocaliceal system for surgeons; And can be a proper alternative for angioembolization.Post percutaneous nephrolithotomy (PCNL) vascular complications included arteriovenous fistula and pseudoaneurysm can cause early or late bleeding and result in unstable condition. Selective  She underwent PCNL surgery with lower pole access under spinal anesthesia. The procedure lasted approximately 40 minutes without any complications. After two days, both the Foley catheter and the ureteral catheter were removed, and she was discharged from the hospital. Four days later, the nephrostomy tube was removed in the office. After three weeks, she presented to the emergency ward with gross hematuria and unstable vital signs. After patient's resuscitation, a pseudoaneurysm was detected in the middle pole of the kidney at the surgery site by CT angiography  is an unusual complication that may occur very rarely. Beside percutaneous nephrolithotomy, RAPs can also be seen in patients after renal biopsy, partial nephrectomy, or trauma and hematuria is the most common symptom associated with RAP. A high level of clinical suspicion is needed for diagnosis. Noninvasive diagnostic modalities, Eco-color Doppler, CT angiography or digital subtraction angiography are useful diagnostic modalities while Conventional angiography continues to be the standard method for the diagnosis of pseudoaneurysm; It provides endovascular treatment options including embolization.In our patient we used a nephro-grasper to pick up the RAP under fluoroscopy guide and took it out of the kidney. This technique has the potential to reduce the need for angioembolization, which is costly for both the patient and the hospital. Furthermore, performing the procedure under direct surgeon visualization with C-arm control increases the likelihood of success.4Percutaneous re-surgical approach to post-PCNL hemorrhage due to pseudoaneurysm by using a nephro-grasper to pick up the renal artery pseudoaneurysm would be safe, effective, not expensive and can provide a direct view of pyelocaliceal system for the surgeon; And can be a proper alternative for angioembolization.Informed consent from the patients was obtained in this report.The consent was obtained from the patient to publish this report.No fund was used in this project.AN: project administration, conception, critical review; NR: data curation; NR: drafting, HM: drafting; BN: critical review; MD: drafting, critical review.All authors declare that they have no conflict of interests.


To examine the effect of twin birth on long-term neurodevelopmental outcomes in a cohort of Italian preterm infants with very low birth weight.We performed a retrospective cohort study on children born in a tertiary care centre. We included children born between 1 January 2007 and 31 December 2013 with a gestational age (GA) of ≤32 weeks and birth weight of <1,500 g. The infants born from twin pregnancies complicated by twin-to-twin transfusion syndrome and from higher-order multiple pregnancies were excluded. The children were evaluated both at 2 years corrected age and 5 years chronological age with Griffiths mental development scales revised (GMDS-R). The linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R scores, adjusting for GA, being born small for gestational age, sex, length of NICU stay, socio-economic status, and comorbidity score (CS) calculated as the sum of the weights associated with each of the major morbidities of the infants.A total of 301 children were included in the study, of which 189 (62.8%) were singletons and 112 (37.2%) were twins; 23 out of 112 twins were monochorionic (MC). No statistically significant differences were observed between twins and singletons in terms of mean general quotient and subscales at both 2 and 5 years. No effect of chorionicity was found when comparing scores of MC and dichorionic twins vs. singletons; however, after adjusting for the CS, the MC twins showed lower scores in the hearing and language and performance subscales at 5 years.Overall, in our cohort of children born very preterm, twin infants were not at higher risk of neurodevelopmental impairment compared with singletons at pre-school age. The rate of twin births has increased in the recent four decades across many high-income countries; this is mainly due to the augmented maternal age at childbearing and the increase of medically assisted reproduction , 2. AccoPreterm birth is associated with long-term neurodevelopmental impairments, with the youngest infants bearing the highest risk, even in the absence of overt brain damage in conventional neuroimaging studies , 8. DespWithin this framework, twin gestation has been traditionally associated with an increased risk of perinatal mortality and morbidity , 16. MorChorionicity may play an important role in the neurodevelopmental outcome of twins. Monochorionic (MC) twins share a single placenta with vascular anastomosis connecting the two foetal umbilical circulations and creating haemodynamic instability . MC gestThe aim of the present study was to compare the neurodevelopmental outcomes at 2 and 5 years of age of singletons vs. uncomplicated twins from a cohort of premature infants with GA ≤32 weeks and birth weight (BW) <1,500 g. Furthermore, we explored the associations between different chorionicity features and neurodevelopmental outcomes.We performed a retrospective cohort study. The children were considered eligible if they were born between 1 January 2007 and 31 December 2013 at the Tertiary Neonatal Intensive Care Unit of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy, with GA ≤32 weeks and BW <1,500 g and were admitted to the NICU within 6 h of life. The exclusion criteria were major congenital anomalies, metabolic and genetic syndromes, death before NICU discharge, transfer to another NICU within the first 24 h of life, infants born as singletons after intrauterine death of one or more foetuses, twin pregnancy complicated by TTTS, and higher-order multiple pregnancies. Only the children who underwent neurodevelopmental assessment at both 24 ± 6 months of corrected age and 5 ± 1 years of chronological age were included in the analysis. This study is a part of a larger cohort study evaluating the effects of very premature birth and related complications on long-term neurodevelopmental outcomes; the results regarding the effects of red blood cell transfusion have already been published . The cohThe neurodevelopment of the infants was assessed at the Paediatric Physical Medicine and Rehabilitation Unit of the same Foundation according to the local follow-up programme for preterm infants. Approval from the Ethical Committee of Foundation IRCCS Ca’ Granda Area 2 was obtained. Due to the retrospective nature of the study and the anonymisation of all the data collected, which are presented as aggregate data, the requirement for informed consent was waived.The twins were classified as MC or DC twins according to chorionicity assessed by the first-trimester ultrasound scan , 30. TheThe follow-up data were retrieved from the clinical files of the infants. Neurodevelopmental assessments at 24 ± 6 months of corrected age and 5 ± 1 years of chronological age were assessed using the Griffiths mental development scales revised (GMDS-R)  and extet-test or Mann–Whitney U test. The categorical variables are presented as the absolute frequency (percentage) and were compared with χ2 test or Fisher's exact test (when some of the cells had counts fewer than 5). To control for between-family variability, the linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R at 2 and 5 years of age, and the family was considered a random effect. The models were adjusted for GA, SGA, sex, length of NICU stay (LoS), SES, and comorbidity score (CS).The statistical analyses were performed using R Software  . The desThe CS  was calcp-value <0.05 was considered significant.All tests were two-tailed, and a During the study period, a total of 772 infants were born with GA ≤32 weeks and birth weight <1,500 g. A total of 312 infants were excluded due to predefined criteria . A totalp = 0.421) and 5 ± 1 years . No significant differences were observed between singletons and twins in the GMDS-R subquotients  and 5 ± 1 years . No significant differences were observed between MC twins and singletons in the GMDS-R subquotients when not corrected for the main clinical characteristics (The mean GMDS-R GQ was similar in singletons and MC twins at both 24 ± 6 months of corrected age (singletons = 89.8, SD = 15 and MC twins = 88.9, SD = 16.4; eristics . Howevereristics , with MCeristics .The impact of twin birth on the long-term neurodevelopment of prematurely born infants is still a matter of debate. Our findings show that preterm twins have similar neurodevelopment at 2 and 5 years of age compared with singleton preterm-born children, supporting the hypothesis that being born twin is not an additional risk factor for neurodevelopmental impairment and that the neurodevelopmental outcomes are mainly related to prematurity itself and consequential morbidities.The available evidence on this topic is controversial, and previous studies have reported contrasting results. Consistent with our findings, Gnanendran et al.  observedIn their review, Lorenz  highlighper se, resulting in sicker preterm infants at birth. These observations may at least partially explain the differences compared with the other studies; unfortunately, due to the retrospective nature of our study, the data regarding maternal or obstetric complications were not available to support this hypothesis.Interestingly, our data concerning perinatal characteristics of singletons and twins are somewhat in contrast with the literature. Kalikkot Thekkeveedu et al.  found thFinally, in the review of Babatunde et al.  on neuroa priori decided to exclude MC pregnancies complicated by TTTS, which represents a well-known neurological risk factor, with both donor and recipient survivors at risk for antenatally acquired brain damage. A higher risk of neurological morbidities (We decided to further investigate the impact of twin birth by considering the role of chorionicity as a risk factor for adverse neurodevelopmental outcomes. We bidities  in MC prbidities . Howeverbidities , 49. NonSeveral studies previously compared MC twins with DC twins but not with singletons. Hack et al.  did not The major limitations of our work are the small sample of the MC cohort and the retrospective design of the study. The latter limited the possibility of retrieving obstetric variables that could affect the neurodevelopmental outcomes in twin pregnancies, such as information about assisted reproductive technology pregnancy, evidence and severity of placental blood flow alteration, and weight discordance fluctuation between the foetuses. In particular, we were not able to investigate the effect of selective IUGR, which is a known condition potentially affecting the neurodevelopment outcome. In addition, although we adjusted for severe comorbidities and socio-economic status, it was not possible to deepen the analysis of the family condition, as we could not gather information on the presence of other siblings and, more generally, on the home environment, which is known to play a key role in child neurodevelopment . Lastly,One of the main strengths of the study was the relatively large cohort of VPT and VLBW infants assessed longitudinally up to 5 years of age. Indeed, the previous studies mainly focused on short-term developmental outcomes , 54 thatIn conclusion, in our cohort of children born very preterm, twin birth was not associated with an increased risk of neurodevelopmental impairment compared with singletons, both at 24 months and 5 years of age. This confirms that twin birth itself is not an added risk factor for an unfavourable developmental outcome, although uncomplicated MC twins seem to have a somewhat less favourable neurodevelopmental outcome at 5 years of age supporting the need of a close neurodevelopmental follow-up. Although the present study may be useful when counselling the parents of twin foetuses at risk for preterm delivery, it is important to note that the number of infants in our MC group was too small to draw a definite conclusion on this population.