Background and Aim: Dapagliflozin and empagliflozin have demonstrated favorable clinical outcomes among patients with chronic kidney disease (CKD). However, their comparative monetary value for improving outcomes in CKD patients is unestablished. We examined the cost-per-outcome implications of utilizing dapagliflozin as compared to empagliflozin for prevention of renal and cardiovascular events in CKD patients.Methods: For calculation of preventable events we divided the allocated budget by the cost needed to treat (CNT) for preventing a single renal or cardiovascular event. CNT was derived by multiplying the annualized number needed to treat (aNNT) by the annual therapy cost. The aNNTs were determined based on data from the DAPA-CKD and EMPEROR-KIDNEY trials. The budget limit was defined based on the threshold recommended by the United States’ Institute for Clinical and Economic Review.Results: The aNNT was 42 both dapagliflozin  and empagliflozin (CI: 33-66). The CNT estimates for the prevention of one primary event for dapagliflozin and empagliflozin were comparable at $201,911  and $209,664 , respectively. However, diabetic patients had a higher CNT with dapagliflozin  than empagliflozin , whereas non-diabetic patients had lower CNT for dapagliflozin  than empagliflozin . The CNT for preventing CKD progression was higher for dapagliflozin  than empagliflozin . For preventing cardiovascular death (CVD), the CNT was lower for dapagliflozin  than empagliflozin .Conclusion: Among patients with CKD, empagliflozin provides a better monetary value for preventing the composite renal and cardiovascular events in diabetic patients while dapagliflozin has a better value for non-diabetic patients. Dapagliflozin provides a better monetary value for the prevention of CVD, whereas empagliflozin has a better value for the prevention of CKD progression. Chronic kidney disease (CKD) typically exhibits a progressive course leading to diminished quality of life and reduced life expectancy . The pro2, concluding that regardless of diabetic status, the risk of a composite of a sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo (2), empagliflozin therapy led to a lower risk of progression of CKD or death from cardiovascular causes than placebo regardless of diabetic status  inhibitors have shown favorable effects on kidney and cardiovascular outcomes in large-scale clinical trials involving patients with type 2 diabetes . The DAP placebo . More rec status .Based on the rapidly emerging new evidence of SGLT2 inhibitors’ efficacy and safety in CKD, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and The National Institute of Health and Care Excellence (NICE) clinical guidelines on CKD recommend SGLT2 inhibitors for patients with CKD and type 2 diabetes .Despite the results of these promising large-scale clinical trials, a recently published analysis suggests that SGLT2 inhibitors remain underutilized in patients with CKD, especially in patients without diabetes mellitus (DM) . An addiOutcome data for dapagliflozin and empagliflozin were extracted from the DAPA-CKD and EMPA-KIDNEY trials, respectively .Our main study outcome was the cost needed to treat (CNT) to prevent one event of the primary outcome, as defined in each trial in the total population and stratified by diabetic status . The secThe number of preventable primary renal or cardiovascular events achievable with dapagliflozin or empagliflozin was estimated by dividing the predefined maximum available budget by the CNT to prevent one event. The budget limit, $734 million, was set as the United States’ threshold suggested by the ICER . The CNTThe aNNT was derived by dividing one by the annualized absolute risk reduction (aARR). The aARR was determined as the absolute difference between the annualized absolute risk (aAR) observed in the control arm and the treatment arm. To calculate the aAR, the number of events in each study arm was divided by the patient-years of treatment . The eveWe conducted a one-way sensitivity analyses in order to mitigatedifferences in baseline risk among the different randomized controlled trials (RCT) populations. Accounting for parameters that may affect the NNT and CNT figures . Two par2 and urinary albumin-to-creatinine ratio of 200–5,000 compared to an eGFR of 20–45 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of at least 200 for the EMPA-KIDNEY trial  of 34–59 and 33-66, respectively . Since tIf the annual predefined budget of $734 million was allocated entirely for the prevention of renal and cardiovascular events, a similar number of events would be prevented using dapagliflozin  and empagliflozin  when utilizing the US high-cost estimate .Of note, among diabetic patients, the CNT was higher for dapagliflozin at $201,911  than empagliflozin at $134,784 . However, the CNT of dapagliflozin was lower than empagliflozin among patients without diabetes at $197,103  versus $394,368  .Interestingly, the drugs have varying effects on reducing secondary outcomes. Specifically, the CNT for reducing the progression of CKD was higher for dapagliflozin  than empagliflozin , while the CNT for CVD and all-cause mortality prevention was higher for empagliflozin  versus  and  versus , respectively .Our analysis suggests that dapagliflozin and empagliflozin provide similar NNTs for preventing one primary event in CKD. Overall, the monetary values of dapagliflozin and empagliflozin were similar. However, the CNT was lower for empagliflozin in diabetic patients but higher than dapagliflozin in patients without DM. Additionally, we found that CNT analysis has varying results on secondary outcomes, with empagliflozin ensuing a better monetary value for the reduction of CKD progression and dapagliflozin displayed a better monetary value for preventing CVD and all-cause mortality.EMPA-KIDNEY included 6,609 participants who were randomized to either empagliflozin or placebo . The priMcEwan et al. evaluated the potential long-term economic effect of dapagliflozin in CKD treatment . Their s2 , and CKD. It was recently indicated that empagliflozin improves frailty in elderly patients with DM and hypertension by mitigating oxidative stress in endothelial cells . An addiIn addition to the differences in the reported clinical outcomes of empagliflozin and dapagliflozin, it is worth noting that these medications also confer various pharmacological properties that may influence their therapeutic benefits. For example, empagliflozin is more selective for SGLT2 over SGLT1 than dapagliflozin . ExpressAlthough a growing body of evidence supports the role of SGLT2 inhibitors as disease-modifying agents for CKD, their use is still limited in clinical practice partially due to their cost . Our anaSeveral limitations should be acknowledged in our study. Firstly, it is important to recognize that our analysis does not supplant the necessity for a thorough cost-effectiveness assessment in relation to QALY. Furthermore, this analysis did not encompass the entirety of relevant data required for a formal cost-effective analysis, including factors such as expenses and benefits associated with healthcare services beyond the therapy itself. These considerations include adverse effects, hospitalization rates, and quality of life measures. However, given the absence of such comparative studies with empagliflozin and dapagliflozin in CKD patients, our CNT analysis could serve as a prompt tool for comparative monetary value. Moreover, CNT provides an actual, real-world comparison of the costs needed to prevent one primary event in patients with CKD. That way, CNT gives a practical insight into monetary value for those in the healthcare field in a position to make healthcare decisions for patients. Inherent limitations of the trials used in our analysis must also be considered, especially the differences in populations of the two trials. Our sensitivity analysis attempts to overcome these differences by simulating each drug’s effect in each RCT.In analysing data from the DAPA-CKD and EMPEROR-KIDNEY trials, the CNT to prevent one primary event was lower for empagliflozin than dapagliflozin in patients with DM, but lower for dapagliflozin than empagliflozin among patients without DM. Moreover, the CNT to prevent CKD progression was lower for empagliflozin, but lower for dapagliflozin to prevent CVD and all-cause mortality.


Gestational diabetes mellitus (GDM) may negatively affect offspring outcomes. A lifestyle intervention may therefore not only improve maternal, but also offspring outcomes. The effects of lifestyle interventions on birth, anthropometric, and psychobehavioral outcomes in offspring of women with GDM need further evidence.MySweetheart trial is a monocentric single-blind randomized controlled trial in 211 women with GDM. It tested the effect of a pre- and postpartum multidimensional interdisciplinary lifestyle and psychosocial intervention focusing on both the mothers and their infants and its effects on maternal (primary outcomes) and offspring (secondary outcomes) metabolic and psychobehavioral outcomes compared with guidelines-based usual-care. This paper focuses on offspring’s birth, anthropometric, and maternal report of psychobehavioral outcomes at singular timepoints.The Women with GDM aged ≥18 years, between 24-32 weeks of gestation, speaking French or English were included and randomly allocated to either the intervention or to an active guidelines-based usual-care group using a 1:1 allocation ratio. The intervention lasted from pregnancy until 1 year postpartum and focused on improving diet, physical activity, and mental health in the mother. For the offspring it focused on supporting breastfeeding, delaying the timing of introduction of solid foods, reducing the consumption of sweetened beverages, increasing physical activity of the family, and improving parental responsiveness to infant distress, hunger, satiety and sleeping cues, and difficult behavior.β:-0.64, CI:-1.27; -0.01, p: 0.05), i.e., offspring of mothers in the intervention group were born 0.64 cm shorter compared to those in the usual-care group.Adverse birth and neonatal outcomes rarely occurred overall. There were no differences between groups in offspring birth, neonatal, anthropometric, or psychobehavioral outcomes up to one year. After adjustments for maternal age and the offspring’s sex and age, there was a borderline significant between-group difference in birth length (This is the first pre- and postpartum multidimensional interdisciplinary lifestyle and psychosocial intervention in GDM focusing on both the mother and the offspring. It did not lead to a significant improvement in most birth, anthropometric, and psychobehavioral outcomes in offspring of women with GDM. ClinicalTrials.gov Identifier: NCT02890693 The preGDM is also associated with worsened maternal mental health, particularly with a higher risk of maternal depression –17. ThisMySweetheart trial, some lifestyle intervention studies mainly focusing on diet and physical activity in the mother had investigated the effect of these interventions on adverse birth and neonatal outcomes in offspring of mothers with GDM and mainly show there is low evidence for improvements in these outcomes for the intervention group  and offspring (secondary outcomes) metabolic and psychobehavioral outcomes.Previous studies in GDM investigating the impact of maternal lifestyle interventions on offspring health outcomes are scarce. Importantly, there are no published intervention trials intervening in the offspring of mothers with GDM . The MySThe aim of this paper was to focus on the secondary outcomes of the trial, i.e., on differences in the offspring’s birth, anthropometric or psychobehavioral outcomes up to one year of age between the intervention and an active guidelines-based usual-care group.22.1MySweetheart trial  was a monocentric single-blind randomized controlled trial (RCT) that tested the effect of a pre- and postpartum multidimensional interdisciplinary lifestyle and psychosocial intervention on metabolic and psychological outcomes in mothers with GDM and their offspring compared to an active guidelines-based control group. More details are provided in the study protocol , the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) and the Endocrine Society , 47, 48 2.4MySweetheart trial are characterized by several interacting components, several outcomes, a high degree of flexibility, and the possibility of tailoring the intervention. The Health Action Process Approach (HAPA) was chosen as the theoretical framework for this behavior change intervention , mothers received support for breastfeeding, recommendations regarding timing of solid food introduction, consumption of sweetened beverages, parental responsiveness to distress, hunger, satiety and sleeping cues and difficult behavior in the offspring, as well as his/her physical activity needs. Breastfeeding was additionally supported with the help of the midwife at birth and afterwards, as desired . MothersFollowing these visits, the lifestyle coach followed up with the goals by summarizing them through a text message sent to the mother. Questions and concerns were discussed during the bimonthly phone calls. Furthermore, co-parents were also invited to each session to reinforce a unified approach for both parents regarding the health goals of their offspring.2.5At the first visit, maternal anthropometric measures (height (cm), weight (kg)) were measured and pre-pregnancy weight was self-reported. Medical information, sociodemographic variables, and social support of the mother were also collected. HbA1c in pregnancy and the requirement for maternal medical treatment were recorded at the end of the pregnancy. In addition, the type of delivery was collected at the first postpartum visit. Breastfeeding presence (yes/no) was assessed by clinicians and self-reported at 6-8 weeks and 1 year. When clinician report of breastfeeding was missing, we retrieved the information from the participant’s report.At birth, the offspring’s baseline measures including birth and neonatal outcomes, gestational age, sex, weight, and height were assessed. At 6-8 weeks and at the one-year visits, the offspring’s weight, size, and skinfolds were measured and mothers completed additional self-report questionnaires at all visits. Data collection and outcomes were measured at the diabetes and pregnancy clinic at the Lausanne University Hospital at all time points. Data regarding birth and neonatal outcomes were extracted from medical charts and records. Secondary offspring outcomes also contained cardiometabolic laboratory outcomes in the cord blood of the offspring, but these are not presented here, as we have much fewer infants with this type of data  and thus the sample size would have been significantly reduced.2.62.6.1Adverse birth and neonatal outcomes including neonatal hospitalization to the neonatal intensive care unit, hyperbilirubinemia  ), hypogl2.6.2®). Macrosomia was defined as birthweight ≥4000 g. Large-for-gestational-age (LGA) and small-for-gestational-age (SGA) were defined as sex-and GA–specific birth weight >90th and <10th centile, respectively, according to the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) guidelines (Birth weight (g) and length (cm) were recorded at birth using calibrated electronic offspring scales . Of the2.8post hoc power analysis was conducted to see whether or not there was sufficient power to detect differences between the usual-care and intervention groups for our most important outcome: offspring weight. The post hoc power analysis revealed a power of 1, 0.99 and 1 to detect differences between groups for weight at birth, 6-8 weeks, and one year respectively, when using model 2. All statistical significance tests were accepted at p<0.05.All statistical analyses were performed with R . Descrip3Baseline maternal characteristics were similar between both groups Table 1,3.1The rate of adverse perinatal outcomes was 5% for neonatal hospitalizations, 2% for hyperbilirubinemia and hypoglycemia and 8% for prematurity for all offspring together Table 2.3.2The prevalence of LGA and SGA in the entire population were both 11%. The weight- and BMI z-scores were close to 0 in both the intervention and usual-care group at birth, 6-8 weeks and 1 year Table 2.3.3In the overall offspring population, the mean Parenting Stress Index was 22.38, the mean night-time sleep duration was 639 minutes/night with a mean of 1.22 awakenings/night and 5% of mothers perceived their child’s sleep as “a very serious problem” Table 2.4MySweetheart trial is the first randomized multidimensional lifestyle and psychosocial intervention trial during and after pregnancy in women with GDM also intervening on the offspring up to one year. The intervention did not lead to a significant improvement in most birth and neonatal outcomes, offspring anthropometry, or their psychobehavioral outcomes up to one year compared to an active lifestyle and guidelines-based usual-care comparator. However, adverse birth and neonatal outcomes, increased anthropometric measures , and psychobehavioral problems were very low in both groups. No between group differences were found for birth and neonatal outcomes. No between-group differences were observed in weight, BMI, BMI z-scores, sum of four skinfold, fat mass (BIA) at birth, 6-8 weeks or one year, except for birth length, which was -0.64 cm lower in the intervention compared to the usual-care group and was close to reaching statistical significance. Furthermore, there were no differences in maternal perception of self-regulation difficulty, the offspring’s total nighttime sleep duration, number of night waking, or the maternal perception of their child’s sleep as being “a very serious problem”.To our knowledge, the Regarding birth and neonatal outcomes, we had very low rates of neonatal hospitalization, hypoglycemia, hyperbilirubinemia, and prematurity in both groups. Prior intervention studies investigating the effect of lifestyle interventions on offspring birth and neonatal outcomes are scarce. A recent retrospective analysis of a cohort using a special program for women, infants, and children  in women recently diagnosed with GDM showed a reduction in the risk of prematurity in the group of women with GDM who had benefitted from this program . This lath and < 10th percentile, respectively in an international control population , as this would have increased the participant burden. However, the mothers were regularly followed up by the coach who reviewed the adherence with the participants. Moreover, the WHO recommends exclusive breastfeeding for at least 6 months. However, in accordance with the local pediatricians and the usual practice in Switzerland, we based ourselves on European and Swiss guidelines to introduce solid foods after at least 4 months of age. This could be considered as a potential limitation. Unfortunately, we did not formally check if women were still breastfeeding at 6 months. In addition, the psychobehavioral outcomes were solely assessed 6Knowledge regarding the importance of the transgenerational impact of metabolic diseases has increased in recent years. This is the first interdisciplinary lifestyle and psychosocial pre- and postpartum intervention in women with GDM that also focused on their offspring. It did not lead to a significant improvement in most birth and neonatal outcomes, offspring anthropometry or psychobehavioral outcomes in the offspring up to one year compared to an active lifestyle guidelines-based usual-care group, but the rates of adverse outcomes were very low in both groups and anthropometric and psychobehavioral outcomes were similar to healthy control populations. Prematurity tended to be lower in the intervention group and length at birth was reduced in the intervention group, although, these between-group difference were only close to reaching statistical significance. Also, the clinical significance of the reduction in length at birth remains to be elucidated. There were few adverse outcomes in both groups and no differences between the intervention and the guidelines-and lifestyle-based usual-care group. Thus, we could conclude that following the current guidelines in mental health and lifestyle recommendations in women with GDM stringently, following up and motivating patients regularly might be sufficient, although this should continue far beyond one year postpartum. A future trial to improve offspring outcomes in mothers with GDM might benefit from an intervention starting early in pregnancy, a stronger focus on the offspring behavior and health, as well as on novel, culturally adapted technologies and should continue far beyond one year postpartum.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Human Research Ethics Committee of the Canton de Vaud (study number 2016-00745). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.JP and AH conceived the study, designed the trial, obtained grant funding, and oversaw management of the trial. LG, DQ, JG and SL helped in designing parts of the study and participated in the implementation of the study. LG performed the data analysis with the help of AL, BS and DQ. All authors  were involved in the interpretation of data. LG and DQ wrote the draft manuscript. Authors LG, DQ, SS, JG, AA, AH, AL, SL, BS and JP revised the manuscript for important intellectual content and gave final approval for the version to be published. JP and AH supervised all the work. All authors contributed to the article and approved the submitted version.


Objective Changes in bleeding patterns could influence the decisions of healthcare professionals to change the levonorgestrel-releasing intrauterine system (LNG-IUS) before 7 years of use, the recommended period of extended use. We evaluated changes in the bleeding patterns of users of the 52 mg LNG-IUS at the end of use of the first (IUS-1) and during the second device (IUS-2) use.Methods We performed an audit of the medical records of all women who used two consecutive LNG-IUSs at the Family Planning clinic. We evaluated the sociodemographic/gynecological variables, the length of use, and the bleeding patterns reported in the reference periods of 90 days before removal of the IUS-1 and at the last return in use of IUS-2. We used the McNemar test to compare bleeding patterns. Statistical significance was established at p < 0.05.Results We evaluated 301 women aged (mean ± SD) 32 (±6.1) years, with lengths of use of 68.9 (±16.8) and 20.3 (±16.7) months for the IUS-1 and IUS-2, respectively. No pregnancies were reported. Bleeding patterns varied significantly among women who used the IUS-2 for ≥ 7 months to 6 years when compared the bleeding patterns reported in IUS-1 use. Eighty-nine out of 221 (40%) women maintained amenorrhea and infrequent bleeding; 66 (30%) evolved to bleeding patterns with light flow, and 66 (30%) maintained or evolved to heavy flow patterns (p = 0.012). No differences were observed among the 80 women with ≤ 6 months of use.Conclusion Changes in bleeding patterns occur during the use of LNG-IUS and should not be decisive for the early replacement of the device. The 52 mg levonorgestrel-releasing intrauterine system (LNG-IUS) is a long-acting, reversible contraceptive method, also used as treatment for heavy menstrual bleeding.th year of use.The high effectiveness of LNG-IUS is attributable to two mechanisms of local action: the antiproliferative effect upon the endometrium, which induces amenorrhea, and the effect on cervical mucus, which impairs sperm penetration.st and 5th year of use, respectively, and only slightly less (0.4/100 WY) for the LNG-IUS loaded with 13.5 mg , which releases 12 µg/day and 5 µg/day at the end of the 1st and 3rd year of use, respectively.Despite the lower release of LNG with over time use, the described contraceptive failure is 0.2/100 women-years (WY) and is similar to the rates reported for new LNG-IUSs loaded with 19.5 mg , which release 16 µg/day and 7.4 µg/day of LNG at the 1nd or 3rd consecutive LNG-IUSs is scarce.Despite the large body of evidence concerning efficacy and bleeding patterns among 52 mg LNG-IUS users, information about the use of 2The objective of our study was to assess and compare self-reported bleeding patterns of LNG-IUS users with reference periods of 90 days before the removal of first IUS (IUS-1), after the approved lifespan and same-day replacement with a second IUS (IUS-2), and at the last annual return visit of IUS-2.This was a retrospective cohort study conducted at the Family Planning clinic, Department of Obstetrics and Gynecology, The ethical committee of the institution approved the study protocol and authorized the data collection and analysis; the information was unidentifiable following collection. The medical records of all women who received a 52 mg LNG-IUS  for contraception at our service and consecutively received an IUS-2 were included in the study. The data were collected from information contained in the medical records of the service. Women who did not have information about bleeding patterns in the medical records were not included. We obtained sociodemographic and obstetrics information, total length of use, bleeding patterns and rates and reasons for discontinuation of the IUS-2. The professionals of our service followed an interview script about the women's menstrual history at the time of insertion of the IUS, and the women are questioned about the menstrual bleeding presented in the last 90 days on subsequent return visits. They were categorized into 5 patterns: amenorrhea (no bleeding), infrequent bleeding (1–2 episodes of bleeding and/or spotting), frequent bleeding (> 5 episodes of bleeding and/or spotting), regular bleeding (3–5 episodes of bleeding and/or spotting), and prolonged bleeding (> 14 consecutive days of bleeding and spotting).2, Fisher exact, Mann-Whitney, and Kruskal-Wallis tests followed by a post-hoc Dunn test to identify the variables with association. For comparisons between bleeding patterns, we used the McNemar test. Statistical significance level was established at p < 0.05. The Statistical Analysis System (SAS) software program, version 9.4  was used for the analysis.We used the χnd consecutive LNG-IUS on the same day as the removal of the 1st one at the end of the approved lifespan. From those women, 15 were excluded due to lack of reliable information; consequently, we report information regarding 301 women with information about bleeding patterns. The mean (±standard error of the mean [SEM]) age at IUS-1 and IUS-2 insertion was 32.0 (±0.35) and 37.7 (±0.37), respectively. The length of use of IUS-1 and IUS-2 was 68.9 (±0.97) and 20.3 (±0.96) months, respectively. Most of the women attended ≤ 8 years of schooling and were living with a partner  and infrequent bleeding (28.5%), and a low proportion of women with regular (15.6%) or frequent/prolonged bleeding (4.9%) .p = 0.012). Among the 104 women with amenorrhea at the end of IUS-1 use, only 70 continued to experience amenorrhea (enorrhea .p = 0.1163). At the end of the data collection (September/2017), 277 (92%) women were still using the device and 9 were using a 3rd LNG-IUS after the end of the approved lifespan. Also, 24 women had the device removed: 3 wished to become pregnant, 9 reached menopause, and 12 had expulsions.Of the 80 women who used the IUS-2 for only 6 months, there were no differences when comparing the bleeding patterns with those observed at the end of use of the IUS-1 , and even regular and frequent/prolonged bleeding (8.6%), during the use of the IUS-2.Our findings are important to HCPs to determine how to counsel women on when to change the LNG-IUS and to consider the possibility of extended use for 7 years and beyond.th year of use of the 52 mg LNG-IUS maintain the high contraceptive efficacy independently of the observed bleeding patterns, which were observed previously.Because no correlation was reported between serum LNG concentrations and bleeding patterns, we can speculate that low doses of LNG after the 5We found at end use of IUS-1 that amenorrhea was observed in 43.8% of users; this result is in agreement with a recent prospective study that described 41.8% of amenorrhea at 5 years of use of the LNG-IUS.nd consecutive IUS placement after 7 years of use with the 1st one, and the authors reported that 26% and 60% of participants experienced amenorrhea in the 1st period for the 1st IUS and for the last 5 years of use for the 2nd device, respectively, while showing 70% and 28% with regular/scanty bleeding patterns while using the 1st and 2nd IUSs, respectively.Our results showed that women with amenorrhea displayed infrequent and regular bleeding patterns in the 2 study periods within the range described in previous prospective studies with slight variations, possibly due to the retrospective characteristic of our study.st LNG-IUS (between 4.3 and 4.9 years) and showed a mean of 7 and 8 days of bleeding/spotting at 90 days before and after changing the device, respectively, decreasing to 4 days after 1 year of use with the 2nd IUS.nd IUS showed reductions of bleeding in 70% of the women, while > 49% of women experienced amenorrhea, which was associated with high rates of satisfaction and continuation.In addition, a multicenter study of 204 women with a 15-month follow-up evaluated bleeding patterns during the 1The main limitation of the present study was the retrospective design, which could introduce bias. On the other hand, the main strength is that we evaluated the same cohort of women at two different moments, which may have contributed, at least in part, to the quality of the evaluation of the variations between bleeding patterns. Additionally, another strength is that we assessed the bleeding patterns 90 days before the last annual consultation of the IUS-2, which occurred between 7 months and 6 years after placement.nd device placement, it is expected that the bleeding patterns will vary from the pattern observed when removing the 1st IUS. This information may help users and HCPs to more readily accept the extended use of the method and prevent both from interpreting changes in bleeding patterns as decreasing the efficacy of the method.Our study has two major implications for HCPs who provide care in family planning. First, the bleeding patterns observed in LNG-IUS users did not change in the first 6 months after changing the device for a new one. Second, in the period from 7 months up to 6 years after the 2Although users of a second LNG-IUS reported high rates of amenorrhea and infrequent bleeding and lower rates of regular, frequent/prolonged bleeding after changing the LNG-IUS, some women also experienced bleeding pattern changes from light flow to frequent/prolonged flow, which has not been found to be linked to contraceptive efficacy.As we evaluated the time of IUS-2 use for up to 6 years of use, a period in which its efficacy is still high, these changes in bleeding pattern did not appear to indicate a decrease in the contraceptive efficacy of the method. In addition, we did not have any pregnancy in the period of IUS-2 use.Changes in bleeding patterns occur during the use of LNG-IUS and should not be decisive for the early replacement of the device.


Low birth weight is associated with an increased risk of developing chronic diseases in adulthood, with a particularly high incidence in Japan among developed countries. Maternal undernutrition is a risk factor for low birth weight, but the association between the timing of food intake and infant birth weight has not been investigated. This study aimed to examine the association between breakfast intake frequency among Japanese pregnant women and infant birth weight.Of all pregnant women who participated in the Tohoku Medical Megabank Project Three Generation Cohort Study, 16,820 who answered the required questions were included in the analysis. The frequency of breakfast intake from pre- to early pregnancy and from early to mid-pregnancy was classified into four groups: every day and 5–6, 3–4, and 0–2 times/week. Multivariate linear regression models were constructed to examine the association between breakfast intake frequency among pregnant women and infant birth weight.The percentage of pregnant women who consumed breakfast daily was 74% in the pre- to early pregnancy period and 79% in the early to mid-pregnancy period. The average infant birth weight was 3,071 g. Compared to women who had breakfast daily from pre- to early pregnancy, those who had breakfast 0–2 times/week had lower infant birth weight . Similarly, compared to women who had breakfast daily from early to mid-pregnancy, those who had breakfast 0–2 times/week had lower infant birth weight .Less frequent breakfast intake before and mid-pregnancy was associated with lower infant birth weight.The online version contains supplementary material available at 10.1186/s12884-023-05603-8. Low birth weight is associated with an increased risk of neonatal death , stuntinFactors influencing the decline in infant birth weight include low maternal weight , low gesIn addition, since night shifts during pregnancy may be associated with birth weight , pregnanThis study aimed to investigate the association between the frequency of breakfast consumption among pregnant women in Japan and infant birth weight.st percentile , 49 had type 1 or 2 diabetes, 606 had multiple pregnancies, 24 had no medical record of birth weight, 1,042 had a preterm delivery, and 20 were excluded because of chromosomal abnormalities. Of the remaining 18,890 pregnant women, 2,070 were excluded because of missing covariates. Finally, the remaining 16,820 pregnant women were included in the analysis , the details of which are described elsewhere , 26. PreFrequencies of breakfast and other food intake were assessed using the 130-item self-administered semi quantitative FFQ. The FFQ used in this study had the response option “constitutionally unable to eat or drink” , which wInfant birth weight (g) was the outcome variable (continuous variable). Infant birth weight was obtained from birth records.2. The smoking status was categorized into four groups: never-smoked, quit before pregnancy, quit after pregnancy, and currently smoking. Alcohol consumption was categorized into three groups: never, former, and current. Morning sickness was categorized into four groups: never, nausea only, able to eat with vomiting, and unable to eat with vomiting. The employment status was categorized as employed or unemployed. Insomnia was defined as a score ≥ 6 on the Japanese version of the Athens Insomnia Scale [Based on previous studies, the following covariates were selected –11, 23: ia Scale . Intake The variance inflation factor was <1.2, which was considered to be noncollinear .p-value for trend. Three models were constructed to examine these associations. Model 1 was a crude model. Model 2 was adjusted for age at birth, BMI before pregnancy, smoking status, alcohol consumption, morning sickness, parity, employment status, insomnia, child sex, and gestational week. Model 3 was adjusted for model 2 and folic acid supplements, intake of energy, grains, meat, fish, beans, vegetables, and fruits. To assess the goodness of fit of the model, coefficients of determination were calculated. Additional analyses were conducted, including risk factors for low birth weight . Futhermore, because low energy intake is a risk factor for low birth weight [p-value < 0.05.Statistical analyses were performed using the analysis of variance for continuous variables and the chi-square test for categorical variables to examine differences in characteristics of pregnant women according to their breakfast intake frequency. The association between maternal breakfast intake frequency and infant birth weight was evaluated with the multivariate linear regression analysis to calculate the regression coefficient β, 95% confidence interval (CI), and h weight , we perf12, sugar, meat, confectionery, and alcoholic beverage . Supplementary Table 3. Multivariate linear regression analysis of the association between breakfast intake frequency and infant birth weight.


Electroosmotic flow (EOF) is of utmost significance due to its numerous practical uses in controlling flow at micro/nanoscales. In the present study, the time–periodic EOF of a viscoelastic fluid is statistically analyzed using a short 10:1 constriction microfluidic channel joining two reservoirs on either side. The flow is modeled using the Oldroyd-B (OB) model and the Poisson–Boltzmann model. The EOF of a highly concentrated polyacrylamide (PAA) aqueous solution is investigated under the combined effects of an alternating current (AC) electric field and a direct current (DC) electric field. Power-law degradation is visible in the energy spectra of the velocity fluctuations over a wide frequency range, pointing to the presence of elastic instabilities in the EOF. The energy-spectra curves of the velocity fluctuations under a DC electric field exhibit peaks primarily beneath 20 Hz, with the greatest peak being observed close to 6 Hz. When under both DC and AC electric fields, the energy spectra of the velocity fluctuations exhibit a peak at the same frequency as the AC electric field, and the highest peak is obtained when the frequency of the AC electric field is near 6 Hz. Additionally, the frequency of the AC electric field affects how quickly the viscoelastic EOF flows. Higher flow rates are obtained at relatively low frequencies compared to under the DC electric field, and the greatest flow rate is found close to 6 Hz. But as the frequency rises further, the flow rate falls. The flow rate falls to a level below the DC electric field when the frequency is sufficiently high. The invention of microfluidic devices and their applications in microelectromechanical systems has made it possible to organize and combine the processes of sample handling, detection, and analysis in integrated microfluidic platforms. In these applications, such as drug-delivery systems, biochemical analysis, rapid-mixing tools, and microelectromechanical systems ,2,3, wheIn actuality, a direct current (DC) electric field is employed in the EOF to drive the fluid in microchannels. The EOF of Newtonian fluids under a DC electric field is time-independent and in a steady state. The EOF of complex viscoelastic fluids, however, is only stable when the Weissenberg number, Wi,  is very low, because of the existence of extra elastic stress in viscoelastic fluids. The term “electro-elastic instability” (EEI) refers to the fluctuations in the EOF caused by the strong elastic effect when the Wi is relatively high . Bryce and Freeman  conducteDue to the bubble-formation issue in the electrolytes near the electrodes that the DC electric field experiences, periodic EOF is gaining more and more attention as a substitute for microfluidic control and transport in the microchannels. It has been discovered that some natural chemical processes, such as the electroosmosis of the human epidermal membrane , are assNewtonian fluids were the primary focus of all the pulsating EOF research work mentioned above. With only a small body of literature, the impact of periodic EOFs on non-Newtonian fluids is not well understood. The analytical solutions for the time–periodic EOF of general Maxwell fluids between micro parallel plates were initially examined by Liu et al.  utilizinThe mechanism of the time–periodic EOF of viscoelastic fluids is still unknown due to the relatively few investigations that have been undertaken. Therefore, the time–periodic EOF of viscoelastic fluids is investigated in the current study using 10:1:10 contraction microchannels. The viscoelastic properties of the PAA water solution are simulated using the OB model, and the electrokinetic phenomenon is described using the Poisson–Boltzmann (PB) model. The microchannel is subjected to both a continuous DC electric field and AC electric fields with different frequencies. The effects of the AC electric field frequency on the viscoelastic time–periodic EOF are investigated.cp is mixed with the electrolyte solution that has a bulk concentration of c0 and contains ions such as K+ and Cl−. The computational domain’s dimensions are depicted in Hr and length Lr on either side of a short microchannel with height HC, length LC, and width W. Researchers have generally acknowledged that the zeta potential in the EOF of non-Newtonian fluids is constant [ξ0. Two electrodes are placed at both ends of the reservoirs, and an external potential bias U = U0 + UAsin(2fEπt) is applied between the inlet (Anode) and outlet (Cathode). The apparent electric field between the inlet and outlet is defined as Eapp = U/(2Lr + LC). We assume that the channel width is significantly larger than the channel height and length, and the flow can be simplified to a 2D problem, as schematically shown in x-axis running along the length direction and the y-axis running along the height direction.We assume that the incompressible PAA polymer solution of concentration constant . As a reu is the velocity field; p is the pressure; t is the time; ρ is the fluid density; ηs is the solvent dynamic viscosity; τ is the extra polymeric stress tensor; ρE represents the volume charge density in the electrolyte; ϕExt represents the externally applied electric potential. For different types of viscoelastic fluids, the polymeric stress τ, which accounts for the deformation memory of the fluid, can be described by various constitutive models. The most widely used viscoelastic models include the OB model [τ is described as [ηp is the polymer dynamic viscosity; λ is the relaxation time of the polymer describing the time for polymer chains to return to equilibrium after deformation; c is the polymeric conformation tensor; I is the identity matrix. For the OB model, the conformation tensor c is governed by [The governing equations of the induced viscoelastic EOF are given as follows:OB model  for diluOB model  for concOB model  describiOB model  capturinOB model . Thereforibed as ,(3)τ=ηperned by ,(4)∂c∂tΘ) is defined as the natural logarithm of the conformation tensor,Λ is a diagonal matrix, whose diagonal elements are the eigenvalues of c, and R is an orthogonal matrix with its columns being the eigenvalues of c. Equation (4) for the conformation tensor written in terms of Θ, then becomes [Typically, the numerical simulation of viscoelastic flow is difficult to converge for the high-Weissenberg-number problem (HWNP) ,56. To s becomes ,(6)∂Θ∂tΩ and B are, respectively, the antisymmetric matrix and the symmetric traceless matrix of the decomposition of the velocity gradient tensor ∇u [In the above, ensor ∇u .c is recovered from Θ,Then, the conformation tensor Ψ, is decomposed into two variables, Ψ = ϕExt + ψ [ϕExt represents the potential originating from the externally applied electric potential and ψ is the potential arising from the charge distribution inside the EDL. The EDL thickness is dependent on the bulk ion concentration. A larger bulk ion concentration leads to a smaller EDL and more refined mesh near the walls to resolve the local wall-normal gradients accurately. To save computational cost, a relatively small bulk ion concentration is adopted in the current study. However, the EDL thickness is still on the order of nanometers, which is much smaller than the microchannel height. Therefore, the Poisson–Boltzmann equation [ψ:The total electric potential, ϕExt + ψ , where ϕequation  is used F is the Faraday’s constant ; e is the elementary charge ; k is Boltzmann’s constant ; T is the absolute temperature of the fluid ; ε represents the permittivity of the solution ; c0 is the bulk ion concentration . The EDL thickness can then be calculated by 1 = 1, and z2 = −1. The dimensionless Debye number is defined as c0 was selected to have λD affordable for numerical simulations. The study of Afonso et al. [c0 = 0.000091 mM was used, and the numerical results showed agreement with experimental results. Therefore, we consider that ϕExt is governed by the following Laplace equation [In the above, o et al.  showed ta et al. , a similequation ,(9)∇2ϕE(1)n∙u = 0; p = 0; τ = 0; ϕExt = U0 + UAsin(2fEπt); n∙ψ = 0; Θ = 0; where n denotes the normal unit vector on the surface;At the Anode (edge AL in (2)n∙u = 0; p = 0; n∙τ = 0; ϕExt = 0; n∙ψ = 0; n∙Θ = 0;At the Cathode (edge FG in (3)u = 0; n∙ϕExt = 0 ψ = ξ0; and n∙Θ = 0.On the reservoir walls . For Newtonian fluid, the third term, τ, in the right-hand side of Equation (2) is dropped, and the model includes Equations (1), (2), (8) and (9).Note that the electric potentials and the flow are only one-way coupling. The electric potentials https://github.com/fppimenta/rheoTool). The equations are discretized in OpenFOAM using the finite-volume method. The details of the viscoelastic solver can be found in the work of Pimenta and Alves [t = λ/105, is used to ensure accuracy. The well-known SIMPLEC (Semi-Implicit Method for Pressure-Linked Equations–Consistent) algorithm [−8 and 800, respectively. The velocity field is computed by the PBiCG (Preconditioned Biconjugate Gradient) solver, of which the tolerance and the maximum iteration are set to be 1 × 10−10 and 1000, respectively.The governing equations are numerically solved using an open-source framework, OpenFOAM , integrand Alves ,58. A sund Alves . Centralnd Alves , which ind Alves . All thelgorithm  is used c0= 0.0001 mM, and the EDL thickness is about 954 nm in this study. The edge size of the layer of cells adjacent to the walls is 25 nm, and there are 15 cells in the EDL. Contraction microchannels with three different lengths  are investigated in this study. As shown in The structural mesh used to discretize the 2D computational domain is shown in ηp = 0.0111 kg/(m∙s) and λ = 0.0476 s were adopted for the 500 ppm PAA–water solution, which were experimentally measured [ξ0 is −110 mV. The solvent dynamic viscosity ηs is 0.001 kg/(m∙s). The external potential bias is U = U0 + UAsin(2fEπt), and the apparent electric field is defined as Eapp = U/(2Lr + LC) = E0 + EAsin(2fEπt). In the current study, Lr = Hr = 400 µm; HC= 40 µm; LC = 10 µm, 15 µm, and 20 µm; U0 = 40 V; UA = 16 V; the range of fE is investigated from 0 Hz to 20 Hz. In order to quantify the viscoelastic effect of the EOF, the Weissenberg number (Wi) is calculated in this study, which is defined as Wi = λu/HC. Here, is the height of the microchannel, and u is the cross-sectional averaged velocity at the center of the microchannel (x = 0). In this study, the Wi is between 1 and 3 depending on the velocity.In this work, measured , and theA thorough code validation of the solver was carried out in our earlier study , includiIn this section, the flow features of the viscoelastic EOF through short constriction microchannels are obtained when imposed to constant and pulsating electric fields. Three different lengths  of the microchannel are studied. Newtonian fluid is investigated for the 10 µm microchannel to provide reference flow characteristics. The frequency of the pulsating electric field is investigated from 1 Hz to 20 Hz. The instabilities of the viscoelastic EOF are described. The energy spectra of the viscoelastic EOF under a constant electric field shows a main frequency. Finally, the influence of the frequency of the pulsating electric field on the viscoelastic EOF is analyzed.x-axis and y-axis. fE = 4 Hz and 10 Hz). Under the DC electric field, the velocity is time-independent, and no fluctuation is observed. Under the AC electric field, the velocity fluctuates at the same frequency as the electrical driving force. No minor fluctuation is observed in the velocity other than the fluctuation in the main frequency. Under different frequencies, the amplitude of the velocity fluctuation and the cross-sectional time-averaged velocity show no significant difference. However, for the PAA solution, the velocity at the center of the microchannel fluctuates dramatically even under the DC electric field, as shown in The results of Newtonian fluid with the same total viscosity as the 500 ppm PAA solution are first presented as a reference for the viscoelastic fluid. Under the DC electric field, the EOF reaches a steady state for Newtonian fluids. As shown in fC) in the viscoelastic flow. In order to have a deeper understanding of the instabilities observed in the viscoelastic EOF under the DC electric field, the power spectra of the velocity fluctuation are obtained by conducting Fast Fourier Transformation. In order to investigate the effects of the characteristic frequency on the viscoelastic EOF, a pulsating electric field is applied to the microchannel. The energy spectra of the velocity fluctuation under the DC electric field show that the majority of the energy of the fluctuation is distributed under 20 Hz in the frequency domain, and the characteristic frequency of the viscoelastic EOF is between 5 Hz and 7 Hz. Therefore, the frequency of the externally applied electric field is studied from 1 Hz to 20 Hz. The velocity at the center of the microchannel ) is used for the frequency analysis. As shown in t = 1 s, a pair of large vortices are observed in the left inlet reservoir before the entrance of the constriction microchannel, resulting in a stagnation area along the centerline of the microchannel. Then, the pair of vortices vanish because of the shifting electric field; at t = 1.08 s, the vortices form again. However, at t = 1.10 s, the pair of vortices move away from the centerline of the microchannel to the corner of the left inlet reservoir, forming a stagnation in the flow near the upstream lips of the constriction microchannel, and the fluid at the centerline of the inlet reservoir flows through the constriction microchannel. Moreover, in the right outlet reservoir, two small vortices form near the downstream lips of the constriction microchannel. The upstream lip vortices are unstable and move to the centerline of the microchannel with the change in the pulsating electric field, as shown in the streamlines at t = 1.12 s and t = 1.14 s, resulting in the fluid near the charged walls of the inlet reservoir flowing through the constriction microchannel. At t = 1.16 s, the streamlines are even more chaotic, in which two small unsymmetric vortices form before the entrance of the constriction microchannel and lead to the fluid flowing through only the lower half of the microchannel. And in the outlet reservoir, the fluid flows near the charged walls, forming a large circulation near the centerline of the reservoir. The upstream lip vortices and the downstream vortices observed under the pulsating electric field are unique and not observed under the DC electric field. xxτ − yyτ) of the 500 ppm PAA solution in the 10 µm microchannel under the 5 Hz pulsating electric field at different times. A significant positive increase of N1 is induced, which indicates that the polymer molecules are strongly stretched in the x-axis direction, whereas in the y-axis direction, the polymer molecules are relatively compressed. The increase of N1 is due to the high velocity gradient at the entrance of the microchannel. Due to the relaxation time of the polymer molecules, the stretched polymer molecules take time to relax. Therefore, the positive N1 is observed downstream of the constriction microchannel.fE = 5 Hz, while for the 15 µm and 20 µm microchannels, the highest energy magnitude appears at fE = 6 Hz. Such results show consistency with the energy-spectra curves in t = t2 − t1 is calculated. The time-averaged velocity is calculated as:t = 2 s is adopted in the current study. Intriguing characteristics of the statistical outcome of the average velocities can be seen in the following aspects: (1) The length of the microchannel shows significant influence on the pulsating viscoelastic EOF. The average velocity is generally higher in shorter microchannels. In the constriction microchannel, the polymer molecules are stretched in the x-axis direction and compressed in the y-axis direction. A shorter microchannel allows the molecules to pass through the channel faster, and thus relax faster. Therefore, a smaller resistance is experienced when the molecules flow through the microchannel, leading to a higher flow rate; (2) The average velocity in the microchannel is highly dependent on the frequency of the pulsating electric field, and the average velocity increases dramatically under the pulsating electric field with increasing fE until fE reaches a value close to the characteristic frequency of the viscoelastic fluid. However, with the further increasing of fE = 9 Hz; when fE is relatively high (>9 Hz), the average velocity decreases to a level smaller than the average velocity under the DC electric field; (3) The highest average velocity is obtained when fE = 4 Hz for the 10 µm and 15 µm microchannels, and the highest average velocity in the 20 µm microchannel is observed at fE = 5 Hz, which are slightly smaller than the frequencies observed for the highest energy amplitude in (1)Under the DC electric field, the Newtonian EOF is time-independent. Under the pulsating electric field with the same amplitude, the amplitude of the velocity and the average velocity in the Newtonian EOF is independent of the frequency of the pulsating electric field. However, the viscoelastic EOF shows significant fluctuations under the DC electric field and strong dependence on the frequency of the pulsating electric field;(2)For the viscoelastic EOF under the DC electric field, the dynamic energy spectra of the velocity fluctuation at the center of the microchannel viscoelastic EOF shows a dominant frequency, which indicates the existence of the characteristic frequency of the viscoelastic fluid;(3)Under pulsating electric fields with various frequencies, strong instabilities are triggered in the viscoelastic EOF, with random upstream and downstream vortices observed. The energy-spectra curves of the velocity fluctuations share similar general features with a peak at the dominant frequency and a power-law decay over a wide range of frequencies, which is a typical characteristic of elastic turbulence;(4)The highest magnitude of the energy spectra is observed at the frequency of the pulsating electric field. However, the highest magnitude varies with the exciting frequency, and resonance occurs in the EOF when the frequency of the pulsating electric field is near the characteristic frequency of the viscoelastic fluid observed under the DC electric field;(5)The average velocity in the microchannel is highly dependent on the frequency of the pulsating electric field. When the frequency is relatively low, the average velocity increases with the increasing frequency, and the highest average velocity is observed near the characteristic frequency of the viscoelastic fluid. However, at relatively high frequencies, the average velocity decreases to a level even smaller than under the DC electric field.The electroosmotic flow (EOF) of viscoelastic fluid through short 10:1:10 constriction microchannels was numerically investigated as a function of the frequency of the pulsating electric field. Three lengths of the constriction microchannel were studied. The frequency of the pulsating electric field was varied from 1 Hz to 20 Hz. The EOF of Newtonian fluid under the pulsating electric field was studied for reference. Compared with the Newtonian EOF and viscoelastic EOF under the DC electric field, the pulsating viscoelastic EOF shows the following distinct results:


Preterm birth (before 37 completed weeks of gestation) is a global health problem, remaining the main reason for neonatal mortality and morbidity. Improvements in perinatal and neonatal care in recent decades have been associated with a higher survival rate of extremely preterm infants, leading to a higher risk of long-term sequelae in this population throughout life. Numerous surveillance programs for formerly premature infants continue to focus on neurodevelopmental disorders, while long-term assessment of the impact of preterm birth and low birth weight on child growth and the associated risk of cardiovascular disease in young adults is equally necessary. This review will discuss the influence of prematurity and low birth weight on childhood growth and cardiovascular risk in children, adolescents and young adults. The risk of cardiovascular and metabolic disorders is increased in adult preterm survivors. In early childhood, preterm infants may show elevated blood pressure, weakened vascular growth, augmented peripheral vascular resistance and cardiomyocyte remodeling. Increased weight gain during the early postnatal period may influence later body composition, promote obesity and impair cardiovascular results. These adverse metabolic alterations contribute to an increased risk of cardiovascular incidents, adult hypertension and diabetes. Preterm-born children and those with fetal growth restriction (FGR) who demonstrate rapid changes in their weight percentile should remain under surveillance with blood pressure monitoring. A better understanding of lifelong health outcomes of preterm-born individuals is crucial for developing strategies to prevent cardiovascular sequelae and may be the basis for future research to provide effective interventions. Preterm birth (before 37 completed weeks of gestation) is a global health problem, remaining the main reason for neonatal mortality and morbidity ,2.Former preterm individuals experience subsequent long-term adverse effects of preterm birth on nutritional status, growth pattern, neurological development and heart function ,4.Preterm infants are a heterogeneous group. Therefore, a precise definition of this prematurity is necessary to evaluate the outcomes of this condition. The classification based on gestational age (GA) at birth includes late preterm infants (GA 34 0/7 to 36 6/7), moderately preterm birth (GA 32 0/7 to 33 6/7), very preterm birth (GA 28 0/7 to 31 6/7) and extremely preterm birth (GA < 27 6/7) .The incidence of preterm birth in developed countries has remained in the range of 11–15% over the past decades, despite advances in perinatal care ,7. In adSurvival rates for premature infants significantly increased in the late 20th century due to the implementation of a three-level perinatal care system and the introduction of new therapies such as surfactant, antenatal corticosteroids and noninvasive ventilation into daily practice. However, prematurity still remains the cause of a number of complications underlying the increased morbidity and mortality of preterm infants, as compared with children born at term. The risk of death and the risk of complications increases with decreasing GA. Subjects born at GA less than 27 weeks had the lowest survival rate, as compared with those born at term and those born late preterm ,4. EarlyDue to advances in perinatal and neonatal care and markedly improved survival rates of extremely preterm infants in the 1990s, the number of preterm infants surviving until adolescence and adulthood continued to increase. Therefore, the long-term consequences of preterm birth, as well as the special medical needs of preterm adults, became more apparent. Numerous surveillance programs for formerly premature infants continue to focus on neurodevelopmental disorders, while long-term assessment of the impact of preterm birth and low birth weight on child growth and the associated risk of cardiovascular disease in young adults is equally necessary.This literature review will discuss the impact of prematurity and low birth weight on childhood growth and cardiovascular risk in children, adolescents and young adults.Papers investigating growth trajectories from infancy through adolescence to early adulthood in all categories of preterm children were taken into consideration in our review. We researched papers that assessed those parameters for groups of not only children born preterm, including extremely preterm-born infants, but also children born LBW, VLBW and ELBW. We found the recent original papers assessing the growth outcomes  extremely interesting. Papers describing the impact of long-term growth alterations on the risk of obesity and cardiovascular consequences, such as elevated blood pressure, lipid profile and the risk of death were also investigated.We took into consideration data from large prospective cohorts assessing children born in the era of modern neonatal intensive care, as well as data derived from national medical registers.Preterm-born children and LBW children with congenital diseases, including congenital heart diseases, were excluded from the analysis, owing to the fact that the presence of inborn anomalies affects the growth pattern negatively and is an independent risk factor for neurological sequelae and the risk factor for early death.Preterm birth, FGR and exposure to serious complications during hospitalization in the Neonatal Intensive Care Unit (NICU) can have an essential impact on long-term health problems later in life . The firThis is relevant especially to extremely preterm or ELBW children who have experienced in- and ex-utero growth restriction, which influences the risk of overweight, obesity, elevated blood pressure, stroke, heart events and metabolic syndrome in adulthood.Several studies have shown a strong epidemiological relationship between prematurity and low birth weight with adult hypertension. Preterm birth and FGR detain renal development, resulting in a decreased number of nephrons and smaller kidneys . InhibitLong-term adaptive changes that occur in a developing fetus in response to an insecure in-utero environment affect maternal–placental–fetal (MPF) cross-talk with short- and long-term effects on brain development . The resThe causes of premature birth are complex. Many factors influence gene-environment interactions from conception. Various obstetric problems altering the maternal–placental–fetal (MPF) triad can negatively affect the course of pregnancy and delivery.Origins of developmental and life course theories emphasize the importance of fetal and neonatal neurological programming on the onset of various diseases later in life. Maladaptive interactions of the MPF triad impair progenitor neuronal and glia populations in the transitional structures of the fetal brain by means of maternal immune activation, placental ischemic syndromes and fetal inflammatory reaction. Life-long developmental neuroplasticity is more likely to occur during critical periods of brain maturation within the first 1000 days. Preterm birth may also modify the programming of the hypothalamic–pituitary–adrenal axis (HPA), contributing to psychiatric disorders later in life. The HPA overactivity can also explain a cluster of features such as increased abdominal fat contents, insulin resistance, increased blood pressure, shorter adult stature and behavioral problems . In mostSeveral studies have shown that infants born preterm and with LBW may present significantly lower growth achievement in young adulthood than their peers born at term ,25. In tDue to numerous complications occurring after preterm birth up to 40 weeks postmenstrual age, many preterm babies, even those who were AGA, experienced dramatic growth failure and became SGA around the term corrected age. At the expected date of delivery, the majority of these infants were smaller compared with the full-term neonates ,24. DespHead circumference growth is the indicator of nutritional status and is independently related to long-term neurodevelopmental outcomes. Being born either very or extremely preterm and SGA contributes to abnormal head size in adolescence and young adulthood. However, it seems that lower GA at birth is associated with poorer catch-up in head circumference .Studies classifying preterm participants by birth weight have shown that growth outcomes in children with FGR significantly differed from the growth pattern of full-term appropriate-weight babies. In the group of infants with FGR, after an initial marked decline in weight, height and head circumference, the rapid weight gain exceeding percentiles was reported at school age. However, they remained lighter and shorter than adults, and their final height attainment was lower than the predicted mid-parental height ,34. SimiOverweight and obesity have been identified by the World Health Organization as one of the five leading risk factors for noncommunicable disease (NCD), particularly cardiovascular disease (CVD) and diabetes mellitus . In receMetabolic syndrome is a combination of clustering risk factors, including increased waist circumference, low level of high-density lipoprotein (HDL), high triglycerides (TG), elevated blood pressure and impaired fasting glucose, which may lead to CVD and diabetes ,42. SomeAn initial analysis of children aged 6 years in the EPICure cohort, assessing their height and BMI at the age of 6 years, has shown that they were smaller, shorter and had a lower BMI and low fat mass. Therefore, they were not considered to have an increased risk of obesity or CVD . HoweverSeveral studies have reported cardiometabolic outcomes for both extremely preterm and ELBW without adjusting for the effect of size at birth on cardiometabolic health ,44. A FiControversy exists about whether parameters such as glucose and insulin levels, serum total cholesterol and low-density lipoprotein (LDL) levels and HDL cholesterol are altered in extremely preterm survivors ,47,49. USeveral studies have shown a positive correlation between rapid weight gain and elevated blood pressure in extremely preterm and ELBW subjects ,44,47,51Much of the recent evidence derives from national-based registers. Large national cohorts have the advantages of complete birth and health data and long-term follow-up . Data frAmong participants from the ESTER cohort born before the 1990s, hypertension was 2- to 3-fold more frequent in ex-preterm adults, and this effect diminished with increasing GA. However, the late preterm infants also had increased both systolic and diastolic blood pressure, although not significantly . Other sThe global burden of CVD continues to increase worldwide and is responsible for 30% of all deaths. CVD includes the following disorders: ischemic heart disease, stroke, hypertensive heart disease, heart failure, cardiomyopathy and others. The known risk factors for CVD/NCD are physical inactivity, poor diet and smoking, which may lead to overweight and obesity, dyslipidemia, raised blood pressure, raised blood glucose and diabetes, i.e., components of the metabolic syndrome . Newly eVascular abnormalities may be evident as an elevated pulse-wave velocity, reduced endothelium-dependent brachial artery flow-mediated dilation and increased carotid intima-media thickness ,60. CardAnalyses of former cohorts have reported a greater cardiovascular risk related to the length of gestation. Evaluation of preterm singletons born in Upsala in 1915–1929 has shown the connection between lower GA at birth and an increased rate of death from cerebrovascular disease, but not from ischemic heart disease. The risk of stroke diminished for patients born at GA < 36 weeks . SimilarThe association between prematurity and the increased risk of heart failure from childhood to adulthood has been confirmed in recent registry-based studies. The risk of heart failure increased with decreasing GA, with the highest risk being 12- and up to 17-fold greater for individuals born at GA < 28 weeks. However, late preterm subjects also had a 2.2-fold higher risk than full-term peers ,70. OverOptimal nutrition during the critical postnatal period is vital for the growth and development of preterm children. Early introduction of enteral nutrition reduces the risk of unfavorable consequences and improves cognitive function and metabolic outcomes later in life .Nutritional practices in neonatal intensive care units have changed with advances in neonatology. In the late 20th century, it was common to feed concentrated formula to ensure adequate caloric intake, while nowadays human milk is recommended as the first choice for all newborns, including preterm infants ,74,75. HHuman health is notably regulated by the human genome. However, environmental non-genetic factors, such as radiation, infectious agents, chemical and environmental pollutants, lifestyle habits , occupation and medical interventions also play a pivotal role in regulating one’s health. This non-genetic effect complements the human genome by mediating various vital processes, such as metabolism, hormones, lipids profile, inflammation and gut microbiota modulating physical activity, oxidative stress and aging. This idea, known as the exposome concept, was first suggested by C. Wild in 2005. Nutrition is one of the environmental factors, influencing human health during the whole life course from conception onwards, contributing to the appearance of some diseases, especially noncommunicable diseases.Environmental factors, such as inappropriate nutrition, lack of physical activity and obesity causing chronic inflammation, as well as environmental pollutants and social interactions, contribute to unfavorable cardiovascular outcomes. Scientific efforts should be applied to the development of the concept of the exposome. Advanced research on the influence of nutrition on the development of noncommunicable diseases may be helpful in determining their etiology and may contribute to the implementation of preventive methods ,78.Due to modern neonatal and pediatric care, approximately 95% of extremely preterm subjects survive until NICU discharge and beyond infancy. Therefore, the first generation of people born prematurely and with extremely low birth weight in the 1990s is now entering adulthood.Findings from registry-based studies have reported that preterm and LBW children are at risk of growth impairment in early childhood, which may lead to obesity and, later, blood pressure alterations and other chronic cardiometabolic complications throughout childhood and adolescence to adulthood. Therefore, an early, long-term clinical follow-up for preterm-born patients is necessary for the early detection and monitoring of disorders contributing to the development of the metabolic syndrome and CVD in later life. Health practitioners should aim to reduce modifiable risk factors through dietary counseling, encouraging breastfeeding and monitoring blood pressure, glucose and lipid levels. These interventions should be supported by public health strategies and implemented from birth, through preschool and school age, and into adulthood.Owing to the fact that elevated blood pressure appears to be strongly associated with prematurity, intensive research into the causes and effects of prematurity is needed to discover new early intervention approaches to prevent both preterm birth and prematurity-related cardiovascular sequelae.


This narrative aims to evaluate the efficacy of point-of-care ultrasound (POCUS) in the early diagnosis and management of postprocedural arterial pseudoaneurysms in the emergency department (ED). We hypothesize that POCUS can be used as the first line of imaging to distinguish vascular from non-vascular causes and diagnose a pseudoaneurysm if present. A comprehensive review of cases involving postprocedural pseudoaneurysms was conducted. We focus on patients who underwent endovascular procedures, including transfemoral and transradial arterial access for cardiac interventions, or received laceration repair after blunt head trauma. We analyzed each case's clinical symptoms, POCUS findings, and subsequent management. POCUS demonstrated high efficacy in early diagnosis by detecting pseudoaneurysm sacs with characteristic bi-directional flows (yin-yang sign) and, in some cases, partial thrombosis. The early identification of potential arterial complications allowed for efficient planning of further imaging and expedited surgical consultation, leading to timely and definitive management. Our study emphasizes the significance of using POCUS as the primary imaging modality for early detection and diagnosis of postprocedural arterial pseudoaneurysms. Incorporating POCUS into the initial assessment of patients presenting with pain and swelling at the site of arterial access or laceration repair can streamline consultation and potentially reduce the need for additional imaging, optimizing patient care in the ED setting. The growth of arterial endovascular access is specifically focused on interventions targeting cardiac and neurovascular diagnosis, cardiac support, and extracorporeal circulation. This procedure involves the insertion of sterile catheters into blood vessels, notably the femoral or radial arteries. The shift towards these minimally invasive endovascular interventions for therapeutic purposes has subsequently increased access site complications. Post-intervention complications can range from site discomfort and hematomas to more severe issues such as the formation of pseudoaneurysms, arteriovenous fistulas, and dissections.Pseudoaneurysm is a well-known iatrogenic arterial complication that can be accurately detected using point-of-care ultrasound (POCUS). Although radial and femoral arterial access is frequently obtained in the emergency department (ED), few studies have described the role of POCUS in the ED evaluation of pseudoaneurysms. In this case series, we illustrate that POCUS can be used as a first-line imaging modality for the detection of pseudoaneurysms following arterial endovascular interventions.Pseudoaneurysms tend to develop with direct arterial trauma and differ from true aneurysms in that they are contained by only one or two of the three arterial wall layers , as opposed to all three in a true aneurysm. Iatrogenic injury due to arterial access in percutaneous procedures is the most frequent cause of femoral and radial artery pseudoaneurysms . The incWith increasing rates of ultrasonography, some society guidelines state that the acceptable rate of pseudoaneurysms post-procedural arterial endovascular access should be under 0.2% . In a laCase 1: iatrogenic radial artery pseudoaneurysmAn 81-year-old female presented to the ED with arm pain approximately one week after right radial artery catheterization for a scheduled percutaneous cardiac procedure. Her medical history was notable for atrial fibrillation on warfarin, chronic kidney disease, and aortic stenosis status post valve replacement. The patient initially experienced mild pain at the catheterization site that had steadily improved in the days following the procedure. However, on the day of presentation, the patient had acute sharp pain and increased swelling to the right wrist approximately eight hours before arrival in the ED. She had an uncomplicated recovery until this point, with no fever, chest pain, or changes to the sensation of the hand. She reported compliance with all medications, including warfarin.Physical examination was notable for ecchymosis and pulsatile swelling, but there was no noticeable erythema or warmth along the volar aspect of the distal right forearm. Sensation was intact, but the patient could not fully range her wrist due to pain and swelling. Capillary refill in all five digits was less than one second. The emergency physicians performed a POCUS, revealing a pseudoaneurysm sac connected to the radial artery with a distinct neck Figure . The DopClinical Implication and Learning Points1. Even standard procedures, like radial artery catheterization, can lead to complications such as pseudoaneurysms. Emergency medicine physicians should remain vigilant for delayed complications.2. Patients on anticoagulation, such as warfarin, may be at higher risk for developing post-procedural pseudoaneurysms. This case emphasizes the importance of early detection of vascular complications in a patient on anticoagulation.3. POCUS can quickly and non-invasively identify pseudoaneurysms. In this case, a rare two-chambered pseudoaneurysm with partial thrombosis is visualized by POCUS. In most cases, CTAs can give more details in preparation for surgical intervention.Case 2: Iliofemoral arterial pseudoaneurysm following iliofemoral thrombectomyA 75-year-old female with a history of peripheral vascular disease managed with two prior right inguinal cutdowns and thrombectomies presented with several days of progressively worsening right groin pain and bleeding. In the past year, the patient had two presentations for acute right limb ischemia requiring emergent right groin cutdown and thrombectomies of iliofemoral, profunda femoris, and superficial femoral arteries. She was discharged on aspirin and apixaban, with routine healing at follow-up appointments several weeks ago.Her physical exam was notable for a small area of bluish discoloration over the right groin with mild bleeding just below the previous puncture site. Strength and sensation were intact in the bilateral lower extremities with 2+ distal pulses and good capillary refill bilaterally. A POCUS was performed with a linear transducer showing a right common femoral artery pseudoaneurysm measuring approximately 2.2 x 2.8 x 2 cm  is ideal, though a lower-frequency transducer (2-5 MHz) may be required for patients with edema or certain body habitus. Use an arterial or vascular preset for optimal frame rate and focus, adjusting the gain on B-mode.When scanning the radial artery, progress from proximal to distal; for the femoral artery, move from distal to proximal. It is vital to ensure the transducer's pressure does not distort the pseudoaneurysm's diameter and avoid excessive pressure on a thin wall pseudoaneurysm.A complete POCUS examination includes the evaluation of the focal or palpable abnormality concerning pseudoaneurysm. Once identified, slide the probe transversely from the adjacent artery toward the abnormality to visualize a pseudoaneurysm. Follow the artery and pseudoaneurysm transversely to view the connection and neck, and then rotate for a longitudinal view. If walls are unclear, use color Doppler for measurements. Measure the sac diameter using B-mode and color Doppler, and evaluate the pseudoaneurysm walls for flow defects and thrombosis.In B-mode, pseudoaneurysms appear as anechoic fluid-filled structures with thin walls, distinct from the impacted artery, often showcasing swirling flows. They might exhibit thrombosis of varying echogenicity based on the thrombosis age. Record the dimensions of the pseudoaneurysm in anteroposterior, craniocaudal, and transverse orientations using the POCUS machine's caliper.Apply color Doppler to observe pulsatility and connections, which is especially useful for detecting flow disturbances and potential AV fistulas. Pseudoaneurysms often exhibit a "yin-yang" bidirectional flow pattern. Partially thrombotic pseudoaneurysms often reveal blood flow through the thrombus, showing a false arterial lumen. Obtain spectral Doppler waveforms at a 45-60 degree angle, typically displaying a to-and-fro flow in the pseudoaneurysm neck.Pseudoaneurysms, although relatively rare, with incidence generally reported under 4% in the literature ,11, can Though conventional angiography continues to be the gold standard in pseudoaneurysm diagnosis , POCUS iOur study underscores the significance of utilizing POCUS as the primary imaging modality for the early detection and diagnosis of postprocedural arterial pseudoaneurysms. In these four cases, POCUS demonstrated high efficacy in providing early diagnosis by detecting pseudoaneurysm sacs with characteristic bi-directional flows (yin-yang sign) and, in some cases, partial thrombosis. The early identification of potential arterial complications allowed for efficient planning of further imaging and expedited surgical consultation, leading to timely and definitive management. Although pseudoaneurysms are a relatively rare complication of arterial access and percutaneous interventions, they can result in significant morbidity. Thus, emergency physicians should be prepared to identify, diagnose, and initiate management of these severe complications in the ED. We believe that POCUS can be used as the first line of imaging to distinguish vascular from non-vascular etiologies and diagnose a pseudoaneurysm if present. In support of this, we demonstrated that the incorporation of POCUS can be used in early diagnosis of arterial pseudoaneurysm post arterial endovascular interventions or trauma.Institution specific protocols for the incorporation of POCUS could include methods to identify the characteristic features of pseudoaneurysms, including an anechoic mass adjacent to the artery with swirling color flow and a bidirectional Doppler waveform in the pseudoaneurysm neck. With this knowledge, emergency physicians can effectively diagnose pseudoaneurysms in the ED. The incorporation of POCUS into the initial workup of such patients could streamline surgical consultation and the need for additional imaging. Future studies could evaluate whether POCUS can decrease the time to diagnosis, surgical evaluation, or the need for CT angiography in the ED. The cases presented above demonstrate that there could be a larger role for POCUS when it comes to this uncommon, though potentially severe, iatrogenic complication of obtaining arterial access for diagnostic or therapeutic purposes.


Adverse (poor or excessive) fetal growth “programs” an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids.In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age , large-for-gestational-age  and optimal-for-gestational-age  infants, we measured cord blood concentrations of FABP4 and lipids .P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL  and HDL  in LGA infants only.Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11–0.77) per log unit increment in FABP4, FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth. Fatty acid binding protein 4 (FABP4) is an adipokine that binds to saturated and unsaturated fatty acids . FABP4 iFABP4 regulates cellular lipid metabolism and the reception of lipid signals relevant to the atherogenic processes . FABP4-dPoor or excessive fetal growth “programs” an elevated risk of obesity and type 2 diabetes in later life . It remaThe goals of this study were to determine whether FABP4 is associated with poor or excessive fetal growth, and whether FABP4 is correlated with fetal lipids (cholesterols) in normal, poor or excessive fetal growth.This was a nested matched case-control study in the Shanghai Birth Cohort (SBC) . The SBCThere were 3,692 singleton live births in the SBC. Infants were classified as SGA (birth weight <10th percentile), appropriate-for-gestational-age  and large-for-gestational-age  according to the 2015 Chinese sex- and gestational age-specific birth weight standards . Among tThe nested case-control fetal growth study is a random sample of 60 trios of SGA, LGA and OGA (control) singleton infants matched by sex (the same) and gestational age at birth (within 1 week) in the SBC as has been described recently . EligiblCord blood serum (without anticoagulant) and EDTA plasma samples were obtained by centrifugation at 4°C, 4,000 rpm for 10 min, and stored in multiple aliquots at −80°C until assays. The assay technicians were blinded to the clinical status  of study subjects.Cord plasma FABP4 was measured by an enzyme-linked immunosorbent assay (ELISA) kit . Cord serum levels of TG, LDL and HDL and total cholesterol (TC) were determined using a Hitachi 7600 Automatic Biochemistry Analyzer.As reported previously , cord plThe minimal detectable concentrations were 0.007 ng/ml for FABP4, 0.011 mmol/L for TG, 0.026 mmol/L for LDL, 0.026 mmol/L for HDL, 0.026 mmol/L for TC, 3.5 pmol/L for insulin, 1.7 pmol/L for proinsulin, 25 ng/ml for IGF-I and 1.88 pg/ml for IGF-II, respectively. The intra-assay and inter-assay coefficients of variation were in the ranges of 3.4%–12.7% for FABP4, 0.5%–2.0% for TG, LDL, HDL and TC, 2.0%–6.5% for insulin and IGF-I, 0.3%–5.0% for proinsulin and 2.4%–9.3% for IGF-II, respectively.z score was calculated according to the 2015 Chinese sex- and gestational age-specific birth weight standards .Continuous variables are presented as mean ± SD. Biomarker data were log-transformed in correlation and regression analyses. Birth weight tandards . Cord bltandards . Pearsonhttp://powerandsamplesize.com/Calculators/), we estimated that with the study sample sizes  and type 1 error  at 2.5%, the study had a power of 94% to detect a 0.7 SD or greater difference in cord plasma FABP4 concentration (the primary outcome) comparing SGA or LGA to OGA infants. P < 0.025 was considered statistically significant in assessing the differences in cord plasma FABP4 concentration comparing SGA or LGA vs. OGA infants (Bonferroni correction for 2 tests). P < 0.05 was considered statistically significant in assessing the correlations between cord blood FABP4 and cholesterols, and in exploring the predictors of SGA and LGA in order to capture all potentially important predictors.Using an online sample size and power calculator (2), and were more frequently delivered by cesarean section (58% vs. 20%) than OGA newborns. SGA infants had lower maternal pre-pregnancy BMI (mean: 20.1 vs. 21.2 kg/m2), but did not differ from OGA infants in other maternal characteristics. The mothers of OGA infants more frequently drank alcohol during pregnancy than the mothers of SGA infants (13.0% vs. 1.7%). Maternal fasting glucose concentrations at 24–28 weeks of gestation were higher in LGA vs. OGA groups (mean: 4.6 vs. 4.4 mmol/L) . Br. Br18). P = 0.0002), and TG concentrations lower , while there were no differences in cord blood LDL, HDL and total cholesterol concentrations.Comparing cesarean section vs. vaginal deliveries, cord blood FABP4 concentrations were higher , and were significantly lower in SGA vs. OGA infants (P = 0.02), but did not differ significantly between LGA and OGA infants (P < 0.01). Cord blood HDL concentrations were lower in SGA vs. OGA infants (P = 0.02), but did not differ between LGA and OGA infants. There were no significant differences in cord blood total cholesterol concentrations between SGA or LGA vs. OGA infants. Cord blood glucose-to-insulin ratios [higher values indicating better insulin sensitivity (P < 0.01).Adjusting for pre-pregnancy BMI, primiparity and cesarean section (other factors did not affect the comparisons), cord blood FABP4 concentrations were progressively higher from SGA to OGA to LGA infants , and negatively correlated with gestational age in the total study sample (z score) were positively correlated in LGA infants , but towards negatively correlated in SGA infants  . Cord blood FABP4 was positively correlated with LDL , HDL  and TC  in LGA infants only.Adjusting for gestational age at delivery, cord blood FABP4 was positively correlated with proinsulin, birth weight  . Cord blIn the fully adjusted model including pre-pregnancy BMI, primiparity, cesarean section and cord blood TG, HDL and LDL , the ORsWe observed that higher cord blood FABP4 concentrations were associated with a lower odds of SGA, while higher cord blood TG concentrations were associated with a higher odds of SGA. Cord blood FABP4 was positively correlated to HDL and LDL cholesterols in LGA infants, but not in SGA or OGA infants. This novel observation suggests an impact of FABP4 on fetal cholesterol/lipid metabolism exclusively in subjects with excessive fetal growth.n = 40) to appropriate-for-gestational-age  to LGA (n = 33) infants  in Boston (n = 20 each) relative to AGA (n = 40) infants in Athens, Greece  or excessive fetal growth (LGA) to normal fetal growth, we selected OGA infants (birth weight between 25th and 75th percentiles) rather than AGA infants (birth weight between 10th and 90th percentiles) as the reference. We defined fetal growth status using the 2015 Chinese sex- and gestational age-specific birth weight standards, and the birth weight cutoffs are in general higher than the Intergrowth birth weight standards , but lowOur study has some limitations. The study sample size was modest, and was powered to detect moderate to large differences (≥0.7 SD), but not powered to detect small differences. All participants were Chinese, and more studies in other ethnic groups are warranted to understand the generalizability of the study findings. The study is observational in nature. We could not draw firm inference regarding causality.Cord blood FABP4 was inversely associated with the odds of being born SGA, suggesting that low FABP4 may be a biomarker of poor fetal growth. FABP4 was positively correlated with HDL and LDL cholesterol exclusively in LGA subjects, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.


Background and Objectives: This study aimed to compare maternal complications, perinatal outcomes, and neurodevelopment 1 year after the birth between concordant and discordant twins in monochorionic and dichorionic twins. Materials and Methods: This retrospective study included twin pregnancies delivered between 24 + 1 and 38 + 2 weeks of gestation between January 2011 and September 2019. Chorionicity was confirmed by ultrasonography and was categorized into monochorionic and dichorionic. Each was then divided into two groups (concordant and discordant) according to birth weight discordancy. Maternal complications and neonatal outcomes, including neurodevelopmental delays, were compared between the two groups. Results: A total of 298 pairs of twin pregnancies were enrolled, of which 58 (19.26%) women were pregnant with monochorionic diamniotic twins and 240 (80.54%) with dichorionic diamniotic twins. In both monochorionic and dichorionic twins, the discordant twins had a greater incidence of emergency deliveries because of iatrogenic causes than the concordant twins. Among dichorionic twins, discordant twins had lower birth weight rates and higher hospitalization rates and morbidities than concordant twins. Among monochorionic twins, discordant twins had a lower birth weight and higher neonatal mortality than concordant twins. The neonatal size was not a predictor of neurodevelopment in this group. Based on the logistic regression analysis, male sex, respiratory distress syndrome, and bronchopulmonary dysplasia were risk factors for the neurodevelopmental delay; birth weight discordancy was significant only in dichorionic twins. Conclusions: Perinatal outcomes in discordant twins may be poor, and neurodevelopment 1 year after birth was worse in discordant twins than in concordant twins. Discordancy in twins can be a risk factor for neurodevelopmental delay. Approximately 1–3% of all pregnancies are multiple pregnancies. As the use of artificial reproductive techniques (ART) continues to increase with advanced maternal age, the number of twin pregnancies is also increasing. The rate of twin pregnancies increased by 76% (from 18.9 to 33.3 per 1000 births) from 1980 to 2009 ,5. In twIn discordant twins, chorionicity is an independent factor for neonatal outcomes ,13. TherThe primary aim of this study was to compare the maternal outcomes of discordant and concordant twins according to chorionicity and compare the neonatal outcomes of large and small discordant twins with those of concordant twins. The secondary aim was to determine the effect of discordancy on neonatal neurodevelopment 1 year after birth.In this study, we retrospectively reviewed the medical records of 350 women with twin pregnancies who delivered between 24 + 1 and 38 + 2 weeks of gestation at Chilgok Kyungpook National University Hospital in Daegu, South Korea, between January 2011 and September 2019. Weight discordancy was calculated using the following formula:  × 100/birth weight of the larger twin. According to the consensus of ACOG and ISUOG, values >20% define cases of discordant twins, whereas those <20% define cases of concordant twins . Discordwww.r-project.org (accessed on 24 April 2020)). Data were compared using the Mann–Whitney U-test for continuous numerical data and the chi-square test for binary categorical data. After performing a normality test, the mean ± standard deviation was used to present continuous variables with normal distributions, whereas numbers (percentage) were used for binary categorical data. Variables with a p-value < 0.05 based on the Mann–Whitney U-test or chi-square test were used. A logistic regression analysis was conducted to identify the independent variables predictive of developmental delay according to chorionicity. Odds ratios and 95% confidence intervals (CIs) were calculated, and p-values of <0.05 were considered statistically significant.All data were analyzed using IBM SPSS version 26.0  and R version 4.0.0  of Chilgok Kyungpook National University Hospital . Informed consent was not obtained from the study participants because of the retrospective nature of the medical record review. The informed consent waiver was approved by the IRB of Chilgok Kyungpook National University Hospital.In total, 298 sets of twins were included in this study. Of these, 58 (19.46%) sets of twins were MC diamniotic (MCDA) twins, and 240 (80.54%) sets of twins were DC diamniotic (DCDA) twins. Among MCDA twins, 47 (81.03%) sets of twins were concordant, and 11 (18.97%) were discordant, whereas among DCDA twins, 190 (79.17%) sets of twins were concordant, and 50 (20.83%) were discordant.p = 0.011), a higher frequency of placenta previa , and a higher incidence of PPH  than concordant twins. In DC twins, no significant differences were observed in maternal age, placenta previa, PPH, or threatened preterm labor, regardless of discordancy. However, more nulliparous women , higher frequency of ART , and a higher incidence of preeclampsia  were observed in DC discordant twins than in concordant twins. Overall, concordant twins had a higher frequency of elective delivery than discordant twins , and delivery due to iatrogenic reasons was relatively low  in both MC and DC twins.p = 0.032) and higher neonatal mortality  than MC concordant twins. However, they did not differ in terms of the frequency of NICU admission and the composite morbidity of RDS, IVH, PVL, NEC, and sepsis. On the contrary, DC discordant twins had lower birth weight , higher frequency of NICU admission , higher composite neonatal morbidity , and a more frequent neurodevelopmental delay at 1 year after birth  than DC concordant twins.p < 0.001) and higher incidence of neonatal death  than concordant neonates. Notably, when comparing concordant neonates and discordant large neonates among DC twins, significant differences were observed in PVL incidence  and neurodevelopmental delay . Discordant large neonates were more prevalent among males  than discordant small babies. The 1- and 5-min Apgar scores of ≤7 and the incidence of neonatal death were not statistically significant between the two groups; however, NICU admission was higher in small neonates .p = 0.001) and a lower birth weight  than those without. Furthermore, male sex was common , and the NICU hospitalization frequency was also high  in this subgroup. The presence of placental infection, such as chorioamnionitis, was higher in the group with neurodevelopmental delay, but this difference was not statistically significant . Among those with neurodevelopmental delays, discordant twins  and composite morbidity  were more common. MC twins with neurodevelopmental delay had a lower birth weight  than those without. No statistically significant differences were observed in NICU admission, composite morbidities, or weight discordancy.p = 0.062); the presence of BPD, 25.645 ; and RDS, 3.708 . Moreover, weight discordancy was confirmed as a predictor of neurodevelopmental delay, with an odds ratio of 6.805 .Birth weight discordancy was related to obstetrical complications and poor neonatal outcomes, and it can be a risk factor for neurodevelopmental delay in twin pregnancies.In a twin pregnancy, the uterus, which can provide an adequate blood supply to one fetus, has to sustain two fetuses. In the process of adapting to this, maternal complications and fetal problems such as FGR arise . IntertwDiscordancy can influence maternal obstetrical complications and neonatal outcomes; however, the prognosis according to chorionicity has only been studied to a limited extent. Breathnach et al. reported that the discordancy of MC twins had a worse prognosis at every level of discordance compared with DC twins . HoweverMany studies have tackled the relationship between discordancy and subsequent neurodevelopment, but the results have been inconsistent ,21,22. HBirth weight discordancy was related to obstetrical complications and poor neonatal outcomes, and it can be a risk factor for neurodevelopmental delay in twin pregnancies.