Elevated MMA and homocysteine were observed among 73.6% and 6.1% of the women, respectively. We found B6 levels were significantly associated with birth weight (β(SE) −0.002(0.0), p = 0.001) after adjusting for age, parity, adiposity, gestational diabetes, and socioeconomic status of the mother. Those with impaired folate deficiency were twice at risk , p = 0.002) of low birth weight. Vitamin B6 levels and impaired folate status were associated with low birth weight in the MAASTHI birth cohort.Vitamins B12 and B6 and folate are known to have implications for pregnancy outcomes. We aimed to describe B6, B12, and folate status in pregnancy and investigate their associations with low birth weight and preterm delivery in mothers recruited from public hospitals in urban Bengaluru. Pregnant women between 18 and 45 years were included in the MAASTHI prospective cohort study. Each participant’s age, socioeconomic status, and anthropometry were recorded during baseline and followed up after delivery. Blood samples were collected between the 24th and 32nd weeks of gestation and stored at −80° for analysis. B6, B12, folate, homocysteine, and methylmalonic acid (MMA) levels were analyzed in the stored samples. We found low plasma vitamin B12, folate, and B6 levels in 48.5%, 42.0%, and 10.4% of the women ( In 2015, 20 million children 14.6%) were born with low birth weight, and nearly half were born in Southern Asia . However.6% were Mothers’ nutritional status is the most important determinant of newborn children’s birth weight. Women with low hemoglobin values, low body mass index, and height less than 150 cm are more likely to give birth to low-birth-weight babies. Pregnancy-induced physiologic changes and the growing fetus increase the micronutrient demand. Studies have shown that micronutrient deficiency is strongly associated with low birth weight; mothers not receiving supplementation are at higher risk of delivering a low-birth-weight child [Water-soluble B vitamins folate, vitamin B6, and vitamin B12 play key roles as enzyme cofactors or substrates in one-carbon metabolism (OCM), a process whereby folate transfers one-carbon groups in a series of biological processes. These processes encompass DNA synthesis, methylation, and metabolism of homocysteine. Therefore, disturbance of OCM due to altered nutrient status is associated with aberrant DNA methylation patterns and several adverse outcomes such as birth defects, cancer, metabolic disorders, and cardiovascular disease . HoweverNationwide data on the prevalence of multiple micronutrient deficiencies during pregnancy are not readily available in India. Vitamin B12 deficiency is highly prevalent among Indians, as many vegetarians lack access to foods rich in this vitamin. The Comprehensive National Nutrition Survey 2016–18) showed that 26.8% and 34.1% of female adolescents had vitamin B12 and folate deficiencies  showed t,10. VitaInvestigating the role of nutrients influencing OCM in India is important. Moreover, very little is known about the relationship between micronutrient status and birth outcomes in women attending public health facilities. We explored vitamin B6, B12, and folate levels in pregnancy and investigated their association with low birth weight and preterm delivery.n = 230). The sample size for studying the association between vitamins B12 and B6, folate, and low birth weight was estimated based on a prevalence of 18% low birth weight [The study is nested within an ongoing study, the ‘Maternal Antecedents of Adiposity and Studying the Transgenerational Role of Hyperglycaemia and Insulin’ (MAASTHI) cohort, a prospective pregnancy cohort in public hospitals of Bengaluru. Women are recruited during pregnancy and followed up from delivery until the child is four years old. MAASTHI was set up to understand the effect of maternal nutritional and psychosocial environment on the child’s noncommunicable disease risk factors. Around 2962 pregnant women were recruited from public hospitals from 14 to 32 weeks from 2016 to 2019; after obtaining consent, a baseline questionnaire was administered. Blood samples were collected between 24 and 32 weeks in a subsample of randomly selected pregnant women  were collected from pregnant women during the baseline visit between 14 and 32 weeks by administering a questionnaire. Data were collected only once during pregnancy. Socioeconomic status was assessed based on the Kuppuswamy scale of classification using education, occupation, and income, into Upper, Upper middle, Lower middle, Upper lower, and Lower. For analysis purposes, only two main categories of lower  and middle  were created.In pregnant women, height in centimeters was measured to the nearest 0.1 cm using a portable stadiometer (SECA 213). Weight was measured to the nearest 0.1 kg using digital weighing. BMI was classified as Normal (18.5–22.9), Underweight (<18.5), Overweight (23–24.9), and Obese (≥25). At birth, infants’ age, gender, weight, length, and circumferences were measured. Weight was recorded to the nearest 10 g using the SECA 381 baby weighing scale. Infants’ birth weight of less than 2.5 kg was categorized as low birth weight.Between 24 and 32 weeks of gestational age, an oral glucose tolerance test was conducted among pregnant women, and hemoglobin was estimated on an automated analyzer. Based on the WHO criteria, a hemoglobin concentration of 110 g/L or higher is classified as nonanemic, and less than 109 g/L is classified as anemic . The oraThe vitamin B12 cut-offs are as follows: >221 pmol/L is vitamin “B12 adequacy”, between 148 and 221 pmol/L is “low B12”, and lower than 148 pmol/L is “B12 deficiency” .Folate was considered as low if <10 nmol/L (4 ng/mL) .Homocysteine was analyzed using the chemiluminescence method, and vitamin B6 and methylmalonic acid were analyzed through serum/ultra-high-performance liquid chromatography–tandem mass spectrometry. Homocysteine was elevated if it was >10 μmol/L, and MMA above 0.26 μmol/L was considered high. MMA (>0.26 μmol/L) was used to reflect depleted vitamin B12 status. Vitamin B6 >30 nmol/L was considered adequate, 20–30 nmol/L suboptimal, and <20 nmol/L was B6 deficiency.Combined vitamin B12 (cB12), a composite indicator of vitamin B12 status, modified for three biomarkers , was calculated using the formulas developed by Fedosov et al. .The normality of variables was tested using a histogram and the Shapiro–Wilk test. Quantitative variables are described as mean ± standard deviation (SD). Nutritional markers are also reported as median and IQR, and qualitative variables are reported as percentages. Respondents were divided into two groups: LBW children and normal-weight children.We performed univariable linear regression and multivariable linear regression analysis models adjusted for confounders in the association between LBW, preterm delivery, and maternal characteristics.We created a composite variable termed ‘Impaired folate status’ (high Hcys and low folate) to identify women with confirmed folate deficiency. Associations between the composite exposure variables and the prevalence of low birth weight were analyzed using a causal model with inverse probability treatment weighting using propensity scores. Propensity scores were calculated using predicted probabilities from logistic regression models of composite exposure variables against the confounding variables.Based on a priori knowledge, maternal age, parity, BMI and socioeconomic status, maternal adiposity and gestational diabetes mellitus, and sex of the child were included as confounders. Maternal age ≤20 years, nulliparity, and low socioeconomic status are known causative factors for the high incidence of LBW. Male gender has a protective effect against LBW, and so does maternal adiposity and gestational diabetes mellitus.All analyses were performed using SPSS software version 20  and R software version 4.0.The mean age of the participants in the study was 24.2 years. The baseline assessment was conducted at around 22.5 weeks, and the blood sample was drawn between 24 and 32 weeks. Most of the women had attended pre-university college (41.9%). Around one-third of the children, 65 (28.1%), were born with low birth weight in this population. Among women who delivered low-birth-weight children, 53.8% of their husbands were unskilled employees , but the differences were not statistically significant .Women delivering low-birth-weight children had higher median values of B6, B12, folate, and homocysteine but lower MMA compared to women who delivered normal-weight children. Women who delivered babies with LBW had a lower sum of skinfold. .We found a significantly weak negative correlation between homocysteine, vitamin B12 (−0.30), and homocysteine and folate (−0.132). There was a weak correlation between MMA and vitamin B12 levels (0.03).  Low plasp = 0.02). No such association was seen between B12 or folate levels with birth weight , h weight .p = 0.002) (We found that those with impaired folate status (high homocysteine and low folic acid levels) were twice at risk of low birth weight  = 0.002) .In this study, we investigated the effects of vitamin B6, B12, and folate deficiency on neonatal birth weight. Our findings reveal a significant association between vitamin B6 levels and impaired folate levels with low birth weight.In our study, B12 status was not associated with birth weight. There have been several other studies that have not found any association between B12 and birth weight . ConsideIn our study, methylmalonic acid, a functional marker for B12 deficiency, was not associated with birth weight. In vitamin B12 deficiency, increased concentrations of methyl malonyl-CoA are hydrolyzed and lead to increased amounts of MMA. However, our study did not find a negative correlation between vitamin B12 and MMA. This has been the case in some recent studies where patients with a decreased serum B12 concentration still had normal MMA concentrations . There hp = 0.09). We found a significant association between low birth weight and impaired folate status (low folate and raised homocysteine). Two well-established cohorts in South India, the Pune Maternal Nutrition Study (PMNS) and Parthenon Cohort Study, found that offspring birth weight was inversely related to maternal homocysteine concentration [Our analysis showed a significant negative correlation between folate and homocysteine. Homocysteine levels were negatively associated with the child’s birth weight  [Another important finding of our study is that low vitamin B6 levels were significantly associated with low birth weight; however, there was no negative correlation between B6 and homocysteine. Studies investigating the effect of B6 on LBW are scarce. An epigenetics study showed that higher maternal B6 concentrations were associated with offspring DNA methylation levels at the MEG3 DMR ( < 0.01) . Supplem < 0.01) . In a me < 0.01) .The majority of our participants had poor vitamin B12 status and folate levels. Low B12 levels in mothers perpetuate low B12 levels in infants, which are further triggered by a diet low in B12 levels. The National Nutritional Anemia Prophylaxis Program advocates folate treatment for pregnant women, and yet we found low folate levels in our participants. Vitamin B12 deficiency and folate deficiency increase homocysteine levels and are associated with adverse fetal development. This could be attributed to one-carbon metabolism (OCM), which is essential for cell proliferation, differentiation, and development, and folate, vitamins B12 and B6 play a key role in OCM. Further studies using standardized cut-offs and large numbers of participants are needed to elucidate the impact of B6, folate, vitamin B12, MMA, and homocysteine on neonatal outcomes.Thus, individual micronutrient deficiency may not hold the key to problems related to low birth weight. The answer would be an integration of solutions. Katre et al. examined the effect of multiple nutrient deficiencies on parameters of one-carbon metabolism in Indian women and compared these with US women. Indian women had lower plasma levels of B12, folate, and B6 and lower plasma levels of essential amino acids and glutathione. The concentration of amino acids, serine, glycine, and homocysteine in the plasma was higher in the Indian subjects. They concluded that the observed changes in amino acids and markers of one-carbon metabolism were likely the result of marginal protein intake and lower B12, folate, and B6 status . Hence, The strengths of our study include its prospective study design and the use of a sensitive and specific diagnostic method. In addition, we used both direct and functional biomarkers of B12 and folate. We assessed the concentration of appropriate functional markers, such as homocysteine and methylmalonic acid for vitamin B12, which provide greater sensitivity than standalone assays. Some of the limitations of the study are that we did not analyze some important contributors such as dietary intake or dosage and duration of folic acid supplements that the pregnant women may have consumed during pregnancy; these factors might have a confounding effect on the nutrient status of mother and the birth outcomes as well.There is a growing need to counsel pregnant women on the right diets to ensure adequate vitamins B12 and B6 and folate are consumed. Vitamin B6 levels and impaired folate status were associated with low birth weight in our study. It is essential to conduct large-scale studies investigating the combined role of nutrients involved in OCM to guide the development of intervention. Such steps can ensure intake of folate and micronutrients during preconception and pregnancy to prevent low birth weight.


This study looked at the magnitude of anaemia and its associated factors among preterm infants at 6 weeks chronological age in a paediatric clinic of Muhimbili National Hospital (MNH).this was a hospital based cross-sectional study conducted among preterm infants at 6 weeks chronological age attending follow-up clinic at MNH from October 2019 to March 2020. Parental interviews, medical records reviews and haemoglobin assessment was done during the clinic visits. Logistic regression was used to determine the association between studied factors and anaemia.the proportion of preterm infants with anaemia at 6 weeks chronological age was 38.4% (142/370) with 74% of these infants having moderate anaemia. Morphological types of anaemia were normocytic (56.3%) and microcytic anaemia (4.9%). Two-thirds of preterm infants (62%) were on haematinics supplementation. Moderate preterm born at gestation age 32 to <34 weeks , two or less phlebotomies  and more than two phlebotomies  were significantly associated with anaemia.the proportion of preterm infants with anaemia at 6 weeks chronological age is high despite two-thirds being on haematinics supplementation. Moderate preterm and multiple phlebotomies significantly contributed to the occurrence of anaemia. Screening preterm infants for anaemia, appropriate management, and close follow-up are recommended to reduce its burden. Globally, around 15 million babies are born prematurely each year with more than 60% of preterm deliveries occurring in Africa and South Asia -6. In ruFactors that contribute to the occurrence of anaemia in preterm infants include lower birth weight and gestation age at birth, rapid increase in body weight, blood loss due to phlebotomy, infections and inadequate nutrition ,10. HoweDespite the high rate of premature delivery in Tanzania, long-term negative impacts of anaemia to growing infants and the fact that premature infants are more vulnerable, the magnitude of anaemia among these infants is not well documented in our setting. Therefore, this study was conducted to determine the magnitude of anaemia among preterm infants at 6 weeks post-natal age as well as associated factors to detect early and prioritise those at risk of developing anaemia.Study design and setting: this is a hospital based cross-sectional study conducted at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania at the Paediatric Outpatient Department between October 2019 and March 2020.Study population: preterm infants at 6 weeks of chronological age attending follow-up clinic at MNH during the study period were enrolled into the study. However, those with obvious congenital anomalies or who denied consent to participate were excluded. The age group of 6 weeks was chosen in order to capture the true picture of the proportion of the infants with anaemia because the physiologic decrease of haemoglobin content in premature infants is noticed approximately at 6 weeks [ 6 weeks .Sample size determination: the sample size was calculated using Kish Leslie formula, and the estimated minimum sample size was 354. Data collection was done by using a pre-tested researcher administered, standardized structured questionnaire. Data collected included socio-demographic and clinical information for each study participant.Study variables: socio-demographic parameters were gestation age at birth based on last normal menstrual period obtained from mothers' antenatal clinic card and for infant variables including birth weight and gender were obtained from Reproductive and Child Health (RCH) card 1. Maternal variables including maternal age, education level, occupation status and parity were obtained from the interviews.Clinical parameters were haematinics supplementation, type of feeding, palmar pallor, nutritional status , haemoglobin level, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH), blood transfusion and phlebotomy history (assessed by counting the number of times the blood samples had been recorded in the computer system by dates). The frequency of blood investigations recorded was used to estimate the amount of blood that was drawn per investigation. This was established since our hospital central laboratory accepts a minimum of approximately 2 mls per blood test, thus if blood was drawn > 2 times, we estimated blood loss to be a minimum of 4 ml. The anticipated recall bias was mitigated by cross-checking with computer records. The outcome (anaemia) was assessed using a portable haemoglobinometer (HemoCue 301) and a cut-off point was haemoglobin levels below 11g/dl according to WHO guideline. Severity of anaemia was classified as mild anaemia (10.0-10.9g/dl), moderate anaemia (7.0 to 9.9g/dl) and severe anaemia (<7g/dl) .Sample collection and testing: a blood sample of approximately 10 microlitre (heel prick) was drawn into the cavity of microcuvette by capillary action and inserted in the haemoglobinometer. Additionally, a sample of one millilitre of venous blood was aseptically drawn from antecubital of each premature infant found to have anaemia and blood was placed into EDTA tube that was properly labelled and immediately sent to the haematology laboratory for full blood picture (FBP) analysis. This was done according to the hospital standard of care and preterm infants who had anaemia were referred to the attending paediatrician immediately for further management.Data management and analysis: data entry and cleaning was done using Statistical Package for Social Science (SPSS) version 25. Description of means, medians, frequencies, and proportions of the given data of each variable was calculated. Contingency tables were constructed for bivariate analysis to explore factors associated with anaemia. To determine associations between dependent and independent variables, Chi-square test and where applicable Fischer's exact test were used for categorical variables while Student's t-test and Mann-Witney U test were used for continuous variables. The level of significant association was set at p <0.05. Binary logistic regression model was used to determine Odds ratios and 95% confidence interval as well as p-values for the factors associated with anaemia. Only factors with p-values <0.2 on univariate analysis were used in multivariate analysis. Adjusted Odds ratios with p-value <0.05 on multivariate analysis were considered significant. For the missing data, case deletion approach was used.Ethical approval: to conduct the study, it was obtained from the Ethics Review Committee of the Muhimbili University of Health and Allied Sciences and MNH (Ref.No.DA.287/298/01A).There were a total of 1278 premature infants who attended the follow-up clinic during the study period. A total of 370 premature babies met the inclusion criteria and were enrolled into the study and their data were included in the final analysis . Out of The overall proportion of anaemia among preterm infants at 6 weeks of age was 38.4% (142/370) and majority  had moderate anaemia. Morphological type of anaemia was normocytic (56.3%) and microcytic anaemia (4.9%).The mean birth weight of study participants with anaemia was approximately 0.1 kg lower compared to those without anaemia (p=0.031) on bivariate analysis. Other factors that were significantly associated with anaemia included gestation age at birth and phlebotomy status . PretermIn this study, we found a high proportion of preterm infants 38%) with anaemia; with nearly three-quarters having moderate anaemia. Anaemia was prevalent among moderate preterm infants (born at gestation age 32 to <34 weeks) and those with multiple phlebotomies. Birth weight, maternal age, parity and haematinics did not influence the occurrence of anaemia in these infants. A high burden of anaemia found in this study could be due to the physiological post-natal haemoglobin drop which occurs in new-borns during the first weeks of life and reaches nadir level at approximately 4-6 weeks in preterm infants. However, other studies in Brazil , South A8% with aIn addition, other studies have reported much higher proportions, for instance, 58% in Cardiff, Wales  among veAmong the factors studied, multiple phlebotomies were associated with the occurrence of anaemia in the current study. These findings are in keeping with what has been reported by a study done in Iowa, U.S.A -17 whererd trimester of gestation are deprived of most of the iron transported from the mother and a great deal of in utero foetal erythropoiesis.We also found higher proportion of anaemia among moderate preterm infants compared to late preterm infants. These findings were similarly reported by other studies done in Cameroon , China  and Waleet al. [In our study, more than half of the preterm infants were on haematinics supplementation. This is contrary to what has been found by Kasasa et al.  years aget al. . Similaret al. ,21. ScreThere were few limitations; like inability to assess comorbid conditions such as sepsis as one of the contributing factors for anaemia both related to its effect through hemolysis and necessity for frequent blood work ups. Moreover, it was difficult to quantify the exact amount of blood loss due to phlebotomy, instead number of blood draws was used as a proxy. Despite the limitations, the study opens our eyes on the burden of anaemia in these children.Burden of anaemia among preterm infant at our setting is high with majority presenting with moderate anaemia. Multiple phlebotomies and moderate preterm were significantly associated with anaemia. Screening of the preterm infants especially those at risk should be emphasized. Further, minimizing the number of phlebotomies will be invaluable for preventing anaemia in preterm infants.Anaemia is associated with delayed neurodevelopment in preterm infants;Anaemia is a significant public health problem in children;Anaemia is among the complications of prematurity.The magnitude of the anaemia in preterm infants at our setting is high;Multiple phlebotomies and moderate gestation age are associated with anaemia in preterm infants.


Z-scores for weight and length did not differ but the benefits of STENA for head circumference persisted until the age of 2 years (p = 0.034). Concerning the psychomotor outcome, we neither found any statistically significant differences in the mental developmental index (MDI) (p = 0.738), norin the psychomotor developmental index (PDI) (p = 0.122). In conclusion, our data adds important insights on the topic of rapid enteral feeding advances and confirms the safety of STENA with respect to somatic growth and psychomotor outcome measures.The importance of nutritional supply for somatic growth and neurodevelopmental outcome in very-low-birthweight infants is an established medical strategy for reducing long-term morbidities. Our cohort study on rapid enteral feeding advances using a standardized protocol (STENA) previously demonstrated a 4-day reduction of parenteral nutrition. STENA did not impede the success of noninvasive ventilations strategies but significantly less infants required mechanical ventilation. Most importantly, STENA resulted in improved somatic growth at 36 weeks of gestation. Here, we evaluated our cohort for psychomotor outcomes and somatic growth at 2 years of age.  Tria = 3864) . The rec = 3864) . Concern = 3864) .Another point of discussion is whether or not to evaluate gastric residuals before application of the next feeding volume. Prefeeding gastric residual evaluation has been introduced into clinical routine to identify clinical precursors of NEC and other severe morbidities early on. The actual Cochrane meta-analysis comprising two randomized controlled trials as well as a more recent systematic review and meta-analysis of 6 randomized studies on this topic both concluded that routine prefeed gastric residual aspiration does not reduce the incidence of NEC but is associated with a prolonged duration until full enteral feeds are reached ,29. Of cp-value of 0.16 and of 0.152 for the most severely affected infants fulfilling the severe BPD criterion [The limitation of all the previous publications on this topic remains the heterogeneity between studies and the mostly small sample size, the heterogeneous background of high- and middle-income countries and the type of feeding applied that was not separated for breast and formula feeding ,27. Furtriterion . Here, wn = 363 infants were available for analysis, of which n = 70 were excluded . Group sizes before and after implementation of STENA were nearly equivalent with n = 145 and n = 148 infants available for analysis respectively. Here, we provide the 2-year outcome data concerning somatic growth and psychomotor development. Ethical approval was obtained from the ethics committee of the Justus-Liebig-University of Giessen (Az. 98/2014) prior to the start of the analyses. All patient data were retrieved from the electronic patient management system as described previously. Baseline characteristics included birth weight and z-scores at delivery, gestational age, gender, multiple birth and provision of antenatal corticosteroids which was counted when at least one dosage was given 24 h prior to delivery , 500 g < BW ≤ 1000 g (n = 102) and 1000 g < BW ≤ 1500 g  protocol in preterm infants <1500 g BW including daily milk increments of 20–30 mL/kg of body weight . Originadelivery . SGA sta n = 75, , we had  n = 75, . Analogon = 105, .p value of < 0.05.The absolute and relative frequencies of parameters are given for counted data. Comparisons were carried out using Wilcoxon rank-sum test for metric data and Pearson’s χ2 with continuity correction for categorical data. The demographics in n = 218) were smaller and more immature than those not available for analyses in both groups . There was no need to control for possible confounders because there were no differences between infants followed-up in the pre-STENA and STENA implementation group regarding baseline demographics and perinatal characteristics including the outcomes determining parameters of birth weight, gestational age, SGA status, sex, multiple birth and provision of antenatal corticosteroids (p = 0.092) and equal proportion of infants born small for gestational age . Frequency of multiples  and the use of antenatal corticosteroids  did not differ between both groups, as well as the z-scores for the auxologic parameters birth weight, length and head circumference at birth  and in the psychomotor developmental index (PDI)  (p = 0.170), proportion of infants with severe hearing impairment  or blindness  did not diverge significantly  underlining the benefit particularly to this high-risk population (n = 4 vs. fast group n = 7) for a meaningful analysis (n = 24 vs. n = 35) was quite low   . Furtherficantly . Separatpulation  while thanalysis . As SGA analysis . We furtuite low .All main results of our STENA cohort study on respiratory outcomes, somatic growth and psychomotor outcome are summarized in n = 3635), 90.3% had used follow-up services, and 27.3% were still doing so at 5 years of age. Never using follow-up services was associated with maternal sociodemographic characteristics  and lower perinatal risk including higher GA . Our follow-up data is in line with the results from the large multicenter SIFT-trial and supports their results of no significant impact of rapid enteral feeding advances on survival without moderate or severe neurodevelopmental disability at 24 months in very-low-birth-weight infants [Our follow-up data adds important new insights on the compatibility of rapid enteral feeding advances and in parallel successful stabilization of preterm infants <1500 g on noninvasive respiratory support. Our results display that the effects of rapid enteral feeding advances on birth weight and body length were transient, but infants remained within the expected range defined as physiologic development with median z-scores not below −1.0. Of clinical importance, the persistent improved head circumference may hint towards improved brain growth although the data on the psychomotor outcomes did not reveal any advantage of STENA. Even if the results of our study suggest equal findings for psychomotor outcomes, we suggest to be careful in interpreting and drawing conclusions. We need to acknowledge, that the retrospective data collection, the restriction to 2-year follow-up outcomes and the nonavailability of nutritional supply data during follow-up prohibit more detailed insights into the relationship between nutritional supply and psychomotor outcomes. Although countless other factors influence preterm brain development, most notably the familiar educational and socioeconomic background, and these adversities can have substantial impact on the awareness of the important role of adequate nutritional supply with respect to the quantity but as well to the quality of nutrition that deserves particular attention during the first two years of life and undergoes several changes from exclusive milk feeding to table nutrition. The on average better somatic growth at discharge may led to less attention to further somatic growth or resulted in reduced total caloric intake, lower quality of nutritional supply including the duration of breast milk provision or less support of psychomotor development in the STENA group infants as these infants appeared more robust. Vice versa, the pre-STENA cohort could have been followed up more intensively due to the somatic growth deficits at discharge that resulted in catch-up of somatic growth parameters in weight and length until 2 years of age. In that direction, our results on Δz-score median for weight suggest variations in caloric intake between nonSGA and SGA infants but that did not result in catch-up growth for length and head circumference. The fact that our lost-to follow-up cohort was less immature and probably more stable after discharge probably made the families and pediatricians think that medical aftercare or final outcome testing was not required. This is also reflected by the data from the population-based prospective EPICE cohort study evaluating the routine follow-up of very preterm infants < 32 weeks of gestation . Of all  infants . In this infants ,50,51. Tp = 0.160), the study was underpowered to detect significant effects on BPD but the association between better somatic growth and reduced risk for BPD was established within other observational studies on this topic and the data from our STENA cohort on somatic growth and BPD as well point into this direction [Our focus on the birth weight subcategories and results are in line with the conclusion from the actual Cochrane meta-analysis which constituted that results of rapid enteral feeding advances are equally applicable to the categories <1000 g and 1000 to 1499 g of birth weight . The treirection . Considep = 0.160), the study was underpowered to detect significant effects on BPD but the association between better somatic growth and reduced risk for BPD was established within other observational studies on this topic and the data from our STENA cohort on somatic growth and BPD as well point into this direction [One strength of our study is the high follow-up rate and the fact that we only had 25% of infants lost to follow-up. Furthermore, the two groups were highly comparable concerning their baseline demographics. That is why risk adjustment for confounders was not required. On the other hand, the limitations of our study need to be listed: Due to the retrospective nature of our study and the legal restrictions of follow-up only until the age of 2 years by the GBA in Germany we will not be able to provide later follow-up data and outcomes on higher-level skills that cannot be tested at the age of 2 years. However, these functional impairments constitute the predominant limitations of psychomotor function in former preterm infants that outreach gross motor function and mental development at 2 years of age. As parental auxiologic parameters were not recorded during clinical routine, we cannot describe potential variations between our two groups that might have impacted the outcome for head circumference. Furthermore, we cannot exclude carry-over effects between one and the other medical measure. From the large multicenter study COT  it is knirection . ConsideIn conclusion, our follow-up results are in line with the previous observations on this topic  and conf


Epidermoid cysts are rare benign lesions that originate from remnants of ectodermal epithelial tissue, particularly infrequent in the pediatric population. They exhibit characteristic imaging features, with occasional variations leading to the development of a “white” epidermoid cyst. This transformation results from the presence of protein and lipid material within the cyst, causing intrinsic hyperintensity in T1-weighted images, signal hypointensity in T2-weighted images, and a bright signal in diffusion-weighted imaging.We describe the case of a 5-year-old Latina pediatric patient initially diagnosed with a typical epidermoid cyst. After 13 years of follow-up, this typical epidermoid cyst underwent a transformation, becoming a “white” epidermoid cyst.Epidermoid cysts are rare intracranial lesions. The term “white epidermoid cyst” does not denote a variant; it represents a distinct transformation within an epidermoid cyst due to liquid and protein accumulation. This transformation should be considered in cases with specific imaging characteristics. Epidermoid cysts are lesions that originate from remnants of ectodermal epithelium during the closure of the neural tube between the third and fifth weeks of pregnancy ; these aIn this report, we present a rare clinical case of a pediatric patient who was initially diagnosed with a typical epidermoid cyst in the prepontine region. Subsequent imaging follow-up revealed the evolution of the cyst into a white epidermoid cyst.The patient is a female with a history of headaches and a single seizure episode at the age 5 years old. She underwent contrast-enhanced head magnetic resonance imaging (MRI), which revealed the presence of a prepontine extraaxial mass with predominantly hypointense signal intensity in T1, similar to cerebrospinal fluid (CSF) in T2. Additionally, there was heterogeneity in fluid attenuated inversion recovery (FLAIR) imaging, giving the appearance of “dirty FLAIR.” The mass appeared bright in diffusion weighted imaging (DWI) and did not show enhancement after the administration of contrast medium, findings consistent with an epidermoid cyst , and hyperintensity in DWI , leadinget al. described this as an atypical representation of dense epidermoid cysts in 1977, attributing their etiology to areas of saponification and calcifications [It is important to note that in brain computed tomography (CT), an epidermoid cyst typically appears hypodense. However, it is crucial to understand that the presence of hyperdensity in CT does not necessarily indicate a “white” epidermoid cyst, as there is not always a correlation between hyperdensity in CT and hyperintensity in MRI in T1 sequences. Braun ications .Conservative treatment has demonstrated promising results with minimal complication rates, while surgical excision is the preferred treatment for symptomatic cases. However, complete resection of epidermoid cysts poses a significant challenge for neurosurgeons and may carry a high risk of morbidity and mortality . It can Epidermoid cysts are infrequent benign intracranial lesions. It is important to clarify that the term “white epidermoid cyst” does not refer to a variant of an epidermoid cyst; rather, it signifies a specific transformation that can occur within an epidermoid cyst due to liquid and protein degeneration. Therefore, it is essential to consider the possibility of this transformation in cases where well-delimited extraaxial lesions exhibit hyperintense behavior in T1 with decreased signal intensity in T2, along with a bright intensity in DWI.


The persistent burden of chronic hepatitis B among ≤5-year-old children in Africa suggests missed opportunities for controlling mother-to-child transmission (MTCT) of the hepatitis B virus (HBV). This scoping review maps the evidence base on the risk of HBV MTCT, the status of HBV MTCT mitigation strategies including hepatitis B birth-dose vaccination, and the role of systems complexity on the suboptimal adoption and performance of hepatitis B birth-dose vaccination programs in Africa. Overall, 88 peer-reviewed and grey literature sources published between 2000–2022 were included in this review. The growing evidence base consistently argues for a heightened risk of HBV MTCT amidst the HIV co-epidemic in the region. Without universal HBV screening programs integrated within broader antenatal care services, current selective hepatitis B birth-dose vaccination is unlikely to effectively interrupt HBV MTCT. We underscore critical health systems-related barriers to universal adoption and optimal performance of hepatitis B birth-dose vaccination programs in the region. To better conceptualize the role of complexity and system-wide effects on the observed performance of the program, we propose an adapted systems-based logic model. Ultimately, exploring contextualized complex systems approaches to scaling-up universal hepatitis B birth-dose vaccination programs should form an integral part of the regional research agenda. Chronic hepatitis B caused by persistent infection with the hepatitis B virus (HBV) is a major public health threat in endemic regions like the World Health Organization (WHO) Africa region . ChronicWhile the WHO Western Pacific region has more chronic HBV carriers  4.9–7.3] vs. 82 million or 7.5% [95% UI 5.7–10.5] of the population in the WHO Africa region), the highest proportion of children younger than 5 years of age living with HBV are in Africa, estimated at 2.5%, which surpasses the global prevalence of 0.9% [95% UI 0.7–1.6] ,17. ThisGlobal Health Sector Strategy (GHSS) on Viral Hepatitis 2016–2021, which aims to eliminate viral hepatitis as a global public health threat by 2030 .,41.40,41http://www.who.int/ (accessed on 15 August 2022)), United Nations International Children’s Fund ) and Gavi, the Vaccine Alliance (http://www.gavi.org/ (accessed on 15 August 2022)). Supplementary searches for peer-reviewed and grey literature were sourced by reviewing bibliographies and performing additional internet searches on Google Scholar. Developed with guidance from an information specialist, the search strategy included synonyms of keywords and terms like hepatitis B, hepatitis B vaccines, birth dose, and birth dose vaccine . Additionally, grey literature was sourced from organizational websites like WHO  was sourced. This spans the period before and after the WHO recommendation on universal hepatitis B birth-dose vaccination in 2009. All search yields were imported to Mendeley Reference Manager®  and, aft® [® . Here, tA total of 991 records were retrieved from all the databases searched. After deduplication and screening of abstracts, titles, and full-text, 72 unique records were identified. Of the 72 records, 46 reported on relevant research conducted in the WHO Africa region. Additional published literature sources were identified through supplementary searches and judged to be eligible for inclusion. Overall, 88 literature sources were included in this scoping review . These vimmaturity of the neonatal immune system increases the risk of viral replication and is suggested as the reason for delayed clearance of HBeAg [Areas of high endemicity are defined as having an HBsAg prevalence of ≥8%, moderate endemicity between 2–7% and low endemicity of <2% in the general population . In Afriof HBeAg , whereasof HBeAg . In a meof HBeAg . Among tof HBeAg . TherefoIt is established that HBV MTCT depends on the presence of increased maternal infectiousness, correlating with HBeAg positivity or high HBV DNA viral loads . HistoriIn a 2016 situational report compiled by the WHO Africa regional office, the scarcity of evidence on chronic HBV infection and the risk of perinatal transmission in Africa were identified by 6 countries as one of the barriers to hepatitis B birth-dose introduction . Since tAccompanying the high burden of HBV infections in the region is the simultaneous burden of HIV infection . It is eSafe and effective strategies are available for prevention of HBV MTCT to neonates and infants from as early as the in-utero stage, as shown in Antiviral prophylaxis offered in the third trimester to at-risk pregnant women has been proven to suppress maternal viral loads and decrease the likelihood of HBV MTCT ,15,20. TFor neonates born to women living with chronic HBV infection, hepatitis B immunoglobulin (HBIG) offers further benefit in preventing HBV MTCT by providing passive immunization to HBV-exposed neonates, particularly when administered within 24 h of birth . AccordiAlthough all strategies have proven effective ,58, univDespite the lack of region-wide adoption of hepatitis B birth-dose vaccination, universal hepatitis B infant vaccination programs have been successful at reducing the incidence of horizontally transmitted HBV infection in under-5-year-olds, leading to a significant reduction in the burden of the disease worldwide . The WHOThe growing evidence presented so far argues for a substantial risk of HBV MTCT in Africa. The 2017 Global Hepatitis Report emphasizes the fact that hepatitis B birth-dose vaccination remains the cornerstone of preventing vertical transmission  due to iKey barriers to the adoption of hepatitis B birth-dose vaccination in countries within the region are cited in the 2016 WHO African regional situational report . As repoIn countries that have universal hepatitis B birth-dose vaccination programs in place, coverage estimates consistently show suboptimal and disparate uptake of the hepatitis B birth-dose vaccine . For exaLimited access consistently emerges as a common thread across these reported barriers, whether it be due to the inability of national governments to secure necessary, sustainable financing mechanisms to procure hepatitis B birth-dose vaccines, limited access to information on birth-dose vaccination, geographical access barriers including limited access to immunization clinics, or, as frequently mentioned, poor access to the birth-dose vaccine for home births. In relation to the challenges associated with home births, expert opinions have reiterated the importance of encouraging institutional delivery, as the coverage of hepatitis B birth-dose vaccination is correlated with the rate of skilled birth attendance and institutional delivery, globally . In a prA priority concern facing hepatitis B birth-dose vaccination programs in Africa is the poor adherence to the recommended time of administration ,84. The Observations on other birth-dose vaccines in the region could offer further insights into the performance of programs with the same overall specification. In Africa, coverage of all three recommended birth-dose vaccines, namely, BCG, OPV, and hepatitis B birth-dose vaccines, were estimated by the WHO/UNICEF at 75%, 70%, and 17% in 2021, respectively . In compGlobal agencies have recognized well-functioning health systems as crucial to the optimal performance of so-called vertical health programs and in attaining global health targets ,86,87. DThe country context has a considerable influence on the capabilities of the health system to effectively support the performance of health programs. Accordingly, barriers to the adoption and optimal performance of universal hepatitis B birth-dose vaccination programs in the region may be unique to the health systems that deliver them. For example, it has been previously suggested that countries with prolonged civil unrest and unstable governance, as observed previously in countries like Uganda and South Sudan, experience negative implications in the functioning of their health programs including hepatitis B birth-dose vaccination . FurtherAccording to the WHO, a health system encompasses “all organizations, people and actions whose primary intent it is to promote, restore and maintain health” . This deEven though the WHO framework is effective in clarifying essential functions of the health system , it has Though it is established that not all interventions will benefit from a systems-thinking approach, complex interventions are likely to have profound effects across the system, and more so in weak health systems . Among aWe propose a systems-based logic model for understanding the role of complexity within hepatitis B birth-dose vaccination programs and the health systems that deliver them . This moBox 1Intervention—theory, design, and/or delivery elementsIntervention theory refers broadly to the description of implicit or explicit ideas on how an intervention works including the overall aims of the intervention.Intervention design is descriptive of the “What?” of the intervention. The ‘execution’ provides a detailed prescription of intervention; elements of timing (when), duration (how long), dose (how much), and intensity (how often) are described.Intervention delivery describes the “How?” (delivery mechanisms), “Who?” (delivery agents), and “Where? (setting)” of the intervention. Delivery agents, as individuals, form the basis of every organization and the potential for organizational change. Their knowledge, skills, motivation, and beliefs are vital for the success of intervention delivery.Outcomes are categorized into those short, intermediate, and long term. Outcomes should include both desired/positive outcomes and potential undesired/negative outcomes.Process outcomes are described quantitatively and/or qualitatively and include elements of participation, implementation fidelity, reach, experience of barriers, contamination by study or non-study interventions of the comparison group, and description of experiences of participants and intervention providers. Behavior outcomes include participant behaviors such as adherence or compliance, which are important for the success of the intervention but may extend to include intended or unintended behavioral outcomes.Intermediate outcomes can be divided into process, behavior, and surrogate outcomes. Health outcomes include specific clinical outcomes, and may refer to broader outcomes, such as well-being and life expectancy.Non-health outcomes include relevant societal impacts of the intervention.context and implementation section highlights the importance of a broader range of factors influencing the effectiveness of complex interventions.The This scoping review maps the growing body of evidence on HBV MTCT in the WHO Africa region. The findings affirm the need for hepatitis B birth-dose vaccination programs in order to effectively interrupt HBV MTCT in Africa. Barriers to adoption and implementation of hepatitis B birth-dose vaccination programs underscore important gaps in broader health systems functioning. While previous reviews have applied a systems-thinking lens, both at a global  and regiIn 2012, the WHO Immunization, Vaccines, and Biologicals Department summarized and appraised implementation evidence from 65 studies using the WHO health systems framework to categorize barriers and facilitators . RecommePersistent barriers identified demonstrate the need to evade perceiving hepatitis B birth-dose vaccination programs as a simple intervention, especially when introduced and implemented in resource-constrained settings. With this perspective, a complex explanation should be sought in order to plan for successful vaccination programs. It is not only the complexity found in the timing requirements of the intervention but the way this interacts across the health system  that affects its success. Further exploration is needed to uncover what the sources of complexity are, and how we can use this information to mitigate persistent barriers encountered, as reiterated extensively in this review. Considering this, and the fact that previous reviews have not explored the systems complexity perspective, we propose the use of the systems-based logic model tailored to hepatitis B birth-dose vaccination programs. We further emphasize the need for research that is contextualized to the African setting in order for its application to African health systems.Building on the findings of previous reviews, we contribute critical system-wide evidence underpinning the weak adoption and performance of hepatitis B birth-dose vaccination programs in this region . Taken tThe dearth of synthesized evidence needed to inform health system strengthening efforts to support hepatitis B birth-dose vaccination programs within Africa creates challenges in the adoption and effective performance of this pivotal intervention. Through well-funded health system strengthening efforts, it is possible to achieve optimal service delivery and, ultimately, improved health outcomes within the population. Such efforts will have to be informed by robust, context-specific evidence. Future research directions should include the exploration of contextualized complex systems approaches to scaling-up hepatitis B birth-dose vaccination programs within the African region.


This systematic review aimed to identify the benefits and possible harms of tocolytic therapy for preterm labour management in the context of pregnant women with extremely preterm birth, multiple gestations, or growth-restricted foetuses. A comprehensive search using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINAHL, and the WHO Global Index Medicus databases was conducted from 10 to 15 July 2021. We included randomized controlled trials and non-randomized studies that assessed the effects of tocolysis compared with placebo or no treatment. We found 744 reports and, finally, nine studies  pertaining to women with <28 weeks of gestation were included. No eligible studies were identified among women with a multiple pregnancy or a growth-restricted foetus. A meta-analysis of the trial data showed that there were no clear differences in perinatal death nor for a delay in birth. Non-randomized evidence showed that tocolysis delayed birth by 7 days, though there was no clear difference for preterm birth. In summary, it remains unclear whether tocolytic therapy for inhibiting preterm labour is beneficial for these subgroups of women and their newborns. Further well-designed randomized controlled trials and observational studies are needed to address the lack of evidence regarding tocolytic agents in these populations. The World Health Organization (WHO) defines preterm birth as a live birth that occurs before 37 weeks of gestation . In 2014While some interventions—such as midwife-led continuity of care models, screening for lower genital tract infections, zinc supplementation, and cervical cerclage—can reduce the likelihood of preterm birth in some subgroups of women, the majority of women who experience a preterm birth do not have a clear risk factor or causative agent ,9. For wSeveral Cochrane systematic reviews have been published on the effects of different tocolytics on maternal and newborn outcomes ,12,13. TThe Cochrane Handbook, Chapter IV, recommends updating the review in such cases .,29.27,29In the non-randomized evidence, a cohort study suggested that tocolysis provided benefits for delaying birth for 7 days, although the certainty of evidence was very low   35]. On. On35]. For the review’s secondary outcomes, data were available from four cohort studies  for women at risk of imminent preterm birth to improve newborn outcomes . While say birth ,37,38,39ay birth . Delayinay birth .In the current, contemporary meta-analysis, we identified no definitive evidence as to whether tocolytic treatments are effective or safe for women giving birth at <28 weeks of pregnancy. While some outcomes were suggestive of benefits, the certainty of the evidence was assessed as low to very low as these estimates were derived from small sample sizes and thus must be interpreted with considerable caution. It remains unclear whether using tocolytic drugs improves preterm birth outcomes in women at <28 weeks of pregnancy. There is no evidence available to assess the potential benefits and harms of tocolytic therapies for women with multiple gestations and growth-restricted foetuses. Further trials are needed before specific conclusions can be drawn on the use of tocolytic therapy for delaying preterm birth and improving preterm birth outcomes in these populations.The Cochrane Handbook in order to ensure that all potential biases were identified and addressed. At least two review authors carried out the screening and data extraction, and assessed the risk of bias independently. The findings of this study increase our understanding of the effects of tocolytic therapy on women with pregnancies < 28 weeks of gestation. However, the review has some limitations. First, the results of the meta-analysis were from limited data; thus, it is likely that conclusions may change when additional evidence comes to light in the future. Second, we included one study that included infants who received magnesium sulfate for any indication. It is possible that the magnesium sulfate was used for indications such as pre-eclampsia or foetal neuroprotection.The strengths of this review include its adherence to the standards of Further well-designed studies are needed to evaluate the effects and possible harms of tocolytic agents to improve preterm birth outcomes, particularly for women with multiple gestations or with growth-restricted foetuses. The range of maternal and newborn mortality and morbidity outcomes, as well as maternal outcomes  and harms  should be reported to obtain meaningful data for clinical decision-making. Acknowledging that randomized trials involving these women can be challenging to implement, well-conducted retrospective observational studies would nonetheless provide useful evidence to guide clinical decision-making internationally.The current body of evidence is inadequate to establish the impact of tocolytics on women who have less than 28 weeks of gestation, women who are carrying multiple pregnancies, and women who have a growth-restricted foetus. Further well-designed studies, including randomised controlled trials and retrospective observational studies, are needed to evaluate the effects and possible harms of tocolytic agents to improve preterm birth outcomes.


Objective To analyze the agreement, in relation to the 90th percentile, of ultrasound measurements of abdominal circumference (AC) and estimated fetal weight (EFW), between the World Health Organization (WHO) and the International Fetal and Newborn Growth Consortium for the 21stCentury (intergrowth-21st) tables, as well as regarding birth weight in fetuses/newborns of diabetic mothers.Methods Retrospective study with data from medical records of 171 diabetic pregnant women, single pregnancies, followed between January 2017 and June 2018. Abdominal circumference and EFW data at admission (from 22 weeks) and predelivery (up to 3 weeks) were analyzed. These measures were classified in relation to the 90th percentile. The Kappa coefficient was used to analyze the agreement of these ultrasound variables between the WHO and intergrowth-21sttables, as well as, by reference table, these measurements and birth weight.Results The WHO study reported 21.6% large-for-gestational-age (LGA) newborns while the intergrowth-21streported 32.2%. Both tables had strong concordances in the assessment of initial AC, final AC, and initial EFW  and almost perfect concordance in relation to final EFW (Kappa = 0.91). Regarding birth weight, the best concordances were found for initial AC  and with the final EFW .Conclusion The initial AC and final EFW were the parameters of best agreement regarding birth weight classification. The WHO and intergrowth-21sttables showed high agreement in the classification of ultrasound measurements in relation to the 90th percentile. Studies are needed to confirm whether any of these tables are superior in predicting short- and long-term negative outcomes in the LGA group. Our aim was (i) to analyze the level of agreement of these two LGA classifications in a population of diabetic pregnant women and (ii) to compare the birth weight results in relation to the ultrasound variables during the third trimester of pregnancy, to determine whether there was any disagreement between these results.Given the divergences observed in the clinical practice between the LGA classifications by the WHO's and intergrowth-21This is a retrospective cohort study based on a survey of medical records of 171 diabetic pregnant women followed up by the Obstetrics and Endocrinology Services of one tertiary Hospital from Belo Horizonte, in the state of MG, Brazil. The participants received care between January 2017 and June 2018. Data were collected between August and November 2018. This study was approved by the Research Ethics Committee (CAAE: 50724015.3.0000.5149), and all participants signed the informed consent form.st's studies. The inclusion and exclusion criteria are shown inFirst, we obtained the record from all the patients representing 310 diabetic and non diabetic pregnant patients. Then, we applied the exclusion criteria: a) non diabetics; b) patients lost to follow-up; c) missing data on patient medical records to include in the study. We excluded 139 patients. All the other 171 participants were included in the present study and attended the following inclusion criteria: pregnant women diagnosed with pregestational or gestational diabetes, with single pregnancies, aged ≥18 years, regularly monitored during the previously mentioned period, with available ultrasound measurements , and those women who consented to participate in the research. Twin pregnancies were excluded because they were not represented in the WHO's and intergrowth-21The clinical variables reported were maternal age (years), type of diabetes , classification of pregestational diabetes cases , gestational age at birth (weeks), and birth weight (g). Gestational age was calculated by the Obstetrics Service based on the date of women's last period or the first ultrasound scan available, as recommended by the American College of Obstetricians and Gynecologists.All pregnant women who had no previous diagnosis of diabetes were screened with a fasting glucose test up to 20 weeks of gestation. When the initial fasting blood glucose was < 92 mg per deciliter [5.11 nmol per liter], the diagnosis of GDM was based on the IADPSG recommendations, endorsed by the American Diabetes Association (ADA), using the 75G-OGTT  at 24 to 28 weeks of gestational age (fasting ≥ 92 mg per deciliter [5.1 nmol per liter] or 1 hour post dextrosol ≥180 mg per deciliter [10 nmol per liter] or 2 hours post dextrosol ≥ 153 mg per deciliter [8.5 nmol per liter]).thpercentile (p90) was considered LGA. During the newborn assessment, LGA was applied to birth weight, according to gestational age, as ≥ p90.st's  studies.During prenatal care, EFW ≥ 90p = 0.0099; for gestational age at birth: W = 0.79,p < 0.0001; and for birth weight: W = 0.96;p = 0.0001). Since none of them had a normal distribution, these variables were reported as median and interquartile range (p25–75).A statistical analysis was performed using MedCalc version 19.1 . The Shapiro-Wilk normality test was applied to quantitative variables to verify normality distribution  in relation to birth weight. The Kappa coefficient between 0 and 0.2 is considered weak; between 0.21 and 0.4, reasonable; between 0.41 and 0.6, moderate; between 0.61 and 0.8, strong; and between 0.81 and 1, almost perfect.Estimated fetal weight, AC, and birth weight were categorized as < p90 or ≥ p90 and reported as proportions. The Kappa coefficient was used to analyze clinimetric evidence considering the agreement of results in relation to ultrasound measurements between the WHO's and intergrowth-21n = 14) were T1D, 46.2% (n = 30) T2D, 30.8% (n = 20) overt diabetes, and 1.5% (n = 1) had other cause of DM (pancreatic). The median gestational age at birth was 38 weeks (37–38 weeks). The median birth weight was 3,185 g . Considering the LGA outcome according to the WHO classification, 37 cases (21.6%) were detected; according to the intergrowth-21stclassification, 55 cases were detected (32.2%).We analyzed data from the medical records of 171 pregnant women who met the inclusion criteria. Of this total, 65 (38.0%) participants had pregestational DM and 106 (62.0%) GDM, with a median age of 33 years (29–37 years). Regarding the pregestational DM group, 21.5% (The first ultrasound scans were performed at a median of 30 weeks (21–36 weeks), and the final ultrasound scans at a median of 35 weeks (26–39 weeks). Descriptive analysis comparing the two reference tables used in this study regarding AC, EFW and birth weight is shown instclassification. The best agreement results were obtained for the initial AC and final EFW parameters, both in the WHO and intergrowth-21stclassifications, and they are considered reasonable. However, the Kappa value was higher in relation to the reference measurements obtained by the intergrowth-21stclassification.Considering birth weight as a reference measurement, we analyzed the agreement of this measure with the ultrasound parameters, AC and EFW.st's LGA classifications, which have representativeness of Brazilian pregnant women. We found a high agreement between the two studies regarding the measurements of initial AC, final AC, and initial EFW, and an almost perfect agreement with the final EFW. This study was justified because it approaches a population at risk of excessive fetal growth, and it is based on the observation of the alarming number of referrals of LGA cases based on the first fetal ultrasound scan, even though glycemic control and other lifestyle changes can positively affect the reduction of negative gestational and neonatal clinical outcomes.This unprecedented study analyzed—in a sample of 171 diabetic pregnant women treated in a Brazilian public tertiary care service—the agreement between ultrasound parameters (AC and EFW) and birth weight, comparing of WHO's and intergrowth-21st). Barel et al.The EFW measurement is extremely important in clinical practice, especially for the management of high-risk pregnancies, such as diabetic pregnant women.In addition to weight extremes, late gestational ages and obesity itself can reduce the accuracy of ultrasound results in diabetic pregnant women compared with low-risk pregnant women.st). In a Chinese prospective multicenter study of 8,272 DM cases and 729 pre-gestational DM cases, Yan et al. showed that the growth rates assessed by means of AC were higher in the GDM and pre-gestational DM groups with macrosomic babies than in non-macrosomic groups, with statistically significant differences between groups older than 22 weeks of gestation (p = 0.001).p < 0.001), regardless of BMI (body mass index).Another measurement that showed one of the best agreement regarding birth weight percentiles was the initial AC  were detected by the WHO and 32.2% (n = 55/170) by intergrowth-21st. With a population similar to the one investigated in the present study, the WHO used Hadlock's formula to calculate EFW, while intergrowth-21stcreated its own formula to calculate the EFW using only AC and head circumference. Further, starting at 25 weeks, EFW's p90 cutoff in intergrowth-21st's is lower than in WHO's . Concerning AC, this difference can be observed as early as 14 weeks .Differences between the WHO's and intergrowth-21In addition, the populations included in the studies were different. The WHO's study included 1,387 healthy pregnant women with good socioeconomic, environmental and nutritional status, aged 18 to 40 years, in single pregnancies, and from 10 countries . In Brazil, the University of Campinas  was the center that participated in the study, with a total of 148 women. The pregnancies had an average duration of 39 weeks. Significant differences were observed in EFW among countries, both in the lowest (3.5%) and the highest percentiles (4.5%). Maternal age, weight and parity contributed to these differences. These variations between countries and the number of countries represented in it were limiting conditions for the widespread use of this scale, according to the authors.st's study included, for the purpose of generating growth tables, 1,556 healthy, well-nourished pregnant women with low risk of maternal and perinatal adverse events, between 14 weeks of gestation and with babies up to 2 years of age, from 8 countries . Brazil was represented by the Federal University of Pelotas . This study, like WHO's, worked as the prescriptive concept of growth, in which healthy populations have similar growth patterns, but did not perform statistical analysis between the populations of the different countries included.The intergrowth-21stand reference tables generated by population studies in different countries. In an Australian retrospective hospital-based cohort study with 2,966 unselected pregnant women, 16.5% of newborns were classified as LGA after 33 weeks of gestation using intergrowth-21st's p90.st, with 5 to 10% of gestational diabetes cases. The authors reported 16.7% of AC cases ≥ p90 according to intergrowth-21st, compared with 7.1% of cases according to French population's specific growth curves. These findings, however, were similar between unselected population and low-risk cases, both in the second and third trimester.Some studies have compared LGA and AC detection rates above p90 between the intergrowth-21There are several limitations to our work. This is a retrospective study based on medical record data, with a limited number of participants, some data loss, and a poor description of the procedures and results that could contribute to a more complete analysis. In addition, patient admission was not homogeneous and, sometimes, even late, limiting the early appropriate execution of interventions and even ultrasound measurements, especially in pregnant women with pregestational DM. As a research agenda, future studies may investigate, prospectively and in a multicenter way, the Brazilian population to determine whether the differences between these two studies, regarding LGA detection, affects neonatal outcomes, such as complications and mortality, so they can be safely inserted into clinical practice.st's studies, with a tendency to overestimate weight based on the first ultrasound scans. The initial AC and EFW at the last ultrasound scan were the best agreement parameters for birth weight, as corroborated by other studies in the international literature, with a better agreement obtained by the intergrowth-21stclassification. Higher LGA detection rates were observed in intergrowth-21st's tables. Further studies are needed to define the study that better applies to our population, objectively analyzing outcomes such as short and long-term neonatal and postnatal complications in relation to LGA fetuses.In a Brazilian population of diabetic pregnant women, we found strong agreement for ultrasound measurements of AC and EFW between the WHO's and intergrowth-21


Maternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children’s development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality.We used data from randomized–controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019–2020. Newborns of mothers aged 13–19 years (adolescents) and 20–40 years (adults) were enrolled in the study 8–27 days after birth and followed for 6 months. Measurements of child’s anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES).Babies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months  compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect  towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null .Our findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age. Key MessagesBabies born to adolescent mothers on average had lower weight at birth and lower weight, shorter length, lower mid-upper arm circumference, lower Length-for-Age Z Score, Weight-for-Age Z Score and Weight-for-Height Z Score at enrolment compared with babies of adult mothers.Infants born to adolescent mothers had similar growth outcomes to infants born to adult mothers, suggesting that catch-up growth reduces some of the anthropometric disparities in early childhood.Infants born to adolescent mothers had twice the risk of mortality by 6 months of age compared with infants of adult mothers.Delaying childbirth from adolescence to adulthood can improve birth outcomes and reduce mortality of neonates.Whereas the effect of biases on the point estimate for infant mortality is substantial, under all scenarios correcting for selection bias and unmeasured confounding, the odds of mortality in 6 months was higher for babies born to adolescent mothers compared with adult mothers. Changes in estimates in quantitative bias analysis show the importance of considering the role of biases in examining effects of interest.,Maternal age is increasingly recognized as a predictor of birth outcomes. Studies show that pregnancies in the extremes, at ages <17 and >40 years, are at a higher risk of negative birth outcomes than other age groups.,,,,Previous studies show that babies born to young mothers have a greater risk of very-pre-term and pre-term delivery, low birthweight, small for gestational age and neonatal mortality.,Although some studies show that young maternal age has negative birth outcomes, there is limited evidence regarding the influence of maternal age on anthropometric measures at birth and within the first few months of life, particularly in developing countries where the rates of adolescent childbearing are high. The effect of maternal age on growth outcomes is also not clear. Whereas some studies show that under-five morbidity may still be higher in children born to younger mothers and that the effect of poor birth outcomes may persist in early childhood,Using data from a large randomized–controlled trial of neonates in Burkina Faso,This analysis used data from a randomized–controlled trial of azithromycin vs placebo conducted to establish the efficacy and safety of administration of a dose of azithromycin during the neonatal period.At baseline, trained field workers collected information of the infant and mother via a questionnaire. Child information included birthweight, type and timing of breastfeeding initiation and whether the child was born at a health centre. Maternal information collected included age, education level, number of previous pregnancies, number of prenatal care visits, region of residence and pregnancy type (single vs multiple). The vital status of each infant enrolled was assessed by field workers at 28, 90 and 180 days after enrolment. Anthropometric measurements were made at baseline and at 6 months, and included weight in kilograms (kg), length in centimetres (cm) and mid-upper arm circumference (MUAC). Weight was measured using a digital scale that was standardized each morning before measurement. Length was measured using a Shorrboard to the nearest cm. At both visits, three consecutive measurements for length were taken and the median was used for analysis. MUAC was measured using a standard MUAC tape. Birthweight data were extracted from government-issued health cards of babies enrolled in the trial.n = 7) and those aged >40 years (n = 270). This is because of data-quality issues, as those aged >40 years were in some cases the grandmother of the baby as opposed to the mother and due to the non-linearity in the effect as pregnancies in older age may also result in negative birth outcomes.For this analysis, maternal age was dichotomized as adolescent (13 to <20 years) and adult (20–40 years). We excluded babies born to mothers for whom maternal age was missing (Outcomes at enrolment/birth included birthweight (in g), weight (in kg), length (in cm), MUAC (in cm), Length-for-Age Z Score (LAZ), Weight-for-Age Z Score (WAZ) and Weight-for-Length Z Score (WLZ), which are measures of stunting (LAZ < –2 SDs), underweight (WAZ < –2 SDs) and wasting (WLZ < –2 SDs), respectively. All outcomes mentioned above except birthweight were also measured and analysed at 6 months as growth outcomes, i.e. as change from enrolment to 6 months of age. All-cause mortality was determined based on the vital status assessment at 180 days.To assess the effect of maternal age on birth and growth outcomes, we used simple and multivariable linear regression. The changes in outcomes between maternal age groups were expressed as beta coefficients.IJE online) and based on previous literature on this topic. Covariates that were adjusted in multivariable models include region  and maternal education. We did not adjust for prenatal care visits as they occur after maternal age and can thus potentially mediate the effect of maternal age on birth and growth outcomes.Potential confounders of the association between maternal age and birth and growth outcomes and mortality were selected a priori using a directed acyclic graph (DAG)To determine the effect of maternal age on mortality, we used logistic regression models with estimates expressed as odds ratios (ORs). Complete case analysis was conducted. For 6-month anthropometry measures, which had some missing outcome values ; factorsepisens command in STATA statistical software  to conduct multidimensional deterministic and probabilistic analysis to correct for differential selection and unmeasured confounding by SES, respectively.,For the quantitative bias analysis (QBA), we used the At baseline, babies born to adult mothers had a slightly higher birthweight in g, weight in kg, length in cm, MUAC, LAZ, WAZ and WLZ. At 6 months, all these measures were similar among babies born to teenage and adult mothers . Among bIn multivariable models, compared with babies born to adult mothers, babies born to adolescent mothers on average weighed 161 g less (95% CI –178.8 to –146.7) at birth and weighed 0.18 kg less (95% CI –0.20 to –0.16), were 0.56 cm shorter (95% CI –0.64 to –0.48) and had 0.29 cm narrower (95% CI –0.33 to –0.25) MUAC at enrolment . At baseIJE online).At 6 months, there were very small decreases in weight, length, MUAC, LAZ and WAZ for babies born to adolescent mothers compared with those born to adult mothers. Overall, at 6 months, there were only narrow and negligible differences in anthropometric measures between babies born to adolescent vs adult mothers . Estimatn = 5827), the estimates for baseline outcomes were attenuated but similar to the unrestricted analyses except for the difference in length and LAZ, which were no longer substantial. At 6 months, in adjusted models, the mean growth outcomes were consistently lower for babies born to adolescent mothers compared with those born to adult mothers but were not substantial (IJE online). These differences in growth outcomes were negligible.In a sensitivity analysis restricting to first-born children (IJE online). For the sensitivity analysis adjusting for baseline measures, we found that including them in the models weakened the association between maternal age and 6-month growth and mortality outcomes, consistently with baseline measures being mediators (IJE online).For the sensitivity analysis using maternal age as a continuous variable, we found that an increase in maternal age was associated with higher/better baseline measures and very small increases in 6-month anthropometric measures (IJE online). In the sensitivity analysis in which maternal age was a continuous variable, each 5-year increase in maternal age was associated with a 21% decrease in the odds of mortality .For the association between maternal age and infant mortality, in the model adjusted for region and maternal education, babies born to adolescent mothers had 2.17 (95% CI 1.35 to 3.47) times the odds of death by 6 months compared with babies born to adult mothers . In sensFor the QBA, the observed unadjusted OR of the maternal age–infant mortality association was 2.24 (95% CI 1.41 to 3.57). For the selection bias analysis, the bias-corrected (adjusted ORs) for probability of selection of adolescent mothers with child mortality at 6 months (exposed case) of 0.90, 0.85, 0.80 and 0.75 were 2.37 (95% CI 1.49 to 3.77), 2.51 (95% CI 1.58 to 3.99), 2.67 (95% CI 1.67 to 4.24) and 2.84 (95% CI 1.79 to 4.52), respectively . The ORsIn this study, babies born to adolescent mothers had poorer birth and neonatal outcomes as seen in baseline anthropometric measures and a higher risk of all-cause mortality by 6 months but similar growth outcomes at 6 months compared with those born to adult mothers.,,,,,IJE online). This may again be explained by factors above and beyond birthweight that have previously been associated with risk of infant mortality.Similarly to findings of previous studies, babies born to adolescent mothers had lower weight, height, MUAC, LAZ, WAZ and WLZ at baseline and higher odds of mortality by 6 months.,,,IJE online). Poor birth outcomes have been previously associated with higher risk of infant mortality and morbidity.,At 6 months, there were very small differences between babies born to adolescent and adult mothers in most anthropometric outcomes in fully adjusted models. This may be due to the smaller babies gaining weight more quickly. Previous studies show that there may be a faster weight-gain ‘catch-up growth’ among infants who are of low birthweight compared with those who are not.,In sensitivity analysis restricting to first-born children to account for confounding by birth order, our results were mostly similar but attenuated in magnitude. Babies born to adolescent mothers had poorer birth outcomes and higher mortality but similar 6-month growth outcomes. This attenuation of effect may be partly explained by differences related to birth order. Studies show that independently of maternal age, a child’s birthweight increases with birth order.IJE online). This is because being born to an adolescent mother is associated with infant survival in the first week and having a lower weight at birth,,There was potential for selection bias in this study because neonates had to weigh >2500 g (be of sufficient weight) and be ≥8 days old (survive their first week of life) to be enrolled in the trial. If babies born to adolescent mothers more often died during the first week or were of lower weight, this could lead to differential selection into the study cohort. This would bias the results towards the null as a higher proportion of the well (survivors with higher weight) babies from adolescent mothers would be represented in the study. This is similar to our finding from the QBA in which the adjusted OR went further away from the null as the difference in the selection probability of adolescent and adult mothers with child mortality at 6 months increased from 0% to 5%, 10%, 15% and 20%. When considering the causal structure, this is similar to collider stratification in which we restrict the study to babies who survived their first week of life and are of sufficient weight, therefore opening the back-door path from maternal age to infant mortality (IJE online). Second, the generalizability of the findings may be limited to low- to middle-income countries. Third, there were other important factors that were not measured or retrospectively collected such as gestational age at birth, as it required ultrasound, which was not available in the context the study was conducted. Additionally, smoking during pregnancy as well as maternal or paternal height and weight were not measured and may be potential confounders that could contribute to residual confounding.This study has some limitations. First, there were some missing values for 6-month anthropometric measures/outcomes (12–15%) and babies born to adolescent mothers were more likely to have missing outcomes (15.3% vs 11.5% of those born to adult mothers). However, estimates obtained from inverse probability of censoring weighting for growth outcomes were very similar to complete case analysis from unweighted analyses  in Ouagadougou, Burkina Faso (protocol 2018–10-123) and the University of California, San Francisco Institutional Review Board (protocol 18–25027). Written informed consent was obtained from the caregiver of each enrolled child.dyac236_Supplementary_DataClick here for additional data file.


Various definitions of very severe (VS) tricuspid regurgitation (TR) have been proposed based on the effective regurgitant orifice area (EROA) or tricuspid coaptation gap (TCG). Because of the inherent limitations associated with the EROA, we hypothesized that the TCG would be more suitable for defining VSTR and predicting outcomes.2) and then according to the TCG (≥10 mm). The primary endpoint was all-cause mortality and the secondary endpoint was cardiovascular mortality.In this French multicentre retrospective study, we included 606 patients with ≥moderate-to-severe isolated functional TR  according to the recommendations of the European Association of Cardiovascular Imaging. Patients were further stratified into VSTR according to the EROA (≥60 mmR2 = 0.22), especially when the size of the defect was large. Four-year survival was comparable between patients with an EROA <60 mm2 vs. ≥60 mm2 . A TCG ≥10 mm was associated with lower four-year survival than a TCG <10 mm . After adjustment for covariates, including comorbidity, symptoms, dose of diuretics, and right ventricular dilatation and dysfunction, a TCG ≥10 mm remained independently associated with higher all-cause mortality  and cardiovascular mortality , whereas an EROA ≥60 mm2 was not associated with all-cause or cardiovascular mortality The relationship between the EROA and TCG was poor (The correlation between the TCG and EROA is weak and decreases with increasing defect size. A TCG ≥10 mm is associated with increased all-cause and cardiovascular mortality and should be used to define VSTR in isolated significant functional TR. Tricuspid regurgitation (TR) is a frequent valvular condition that affects approximately 0.8% of the general population . Its preVarious definitions of VSTR have been proposed since, using EROA or tricuspid coaptation gap (TCG) –15. BecaThis retrospective study was conducted in seven French tertiary centers  and included consecutive patients with a diagnosis of significant (≥moderate-to-severe) isolated TR between 2013 and 2020. Isolated functional TR was defined by structurally normal tricuspid valves with no overt organic cause of TR, no >mild left-sided valvular heart disease, no pulmonary hypertension, preserved (>50%) left ventricular ejection fraction (LVEF), and no previous cardiac surgery . Baselin2  recommendations using the integrative multiparametric approach, including morphological , semi quantitative , and quantitative (EROA and regurgitant volume) parameters . Patient2  and then2 –21 but tber view . Moderat 10 cm/s . Tricusp 10 cm/s .During follow-up, events were collected based on hospital chart reviews, direct patient interviews and/or repeated follow-up letters, questionnaires, and telephone calls to physicians, patients, and (if necessary) family members. The primary endpoint was all-cause mortality and the secondary endpoint cardiovascular mortality, including sudden death, Heart failure related death and deaths attributable to other cardiovascular causes . Decisions on medical or surgical management were made by each heart team based on European Society of Cardiology guidelines and patient comorbidities .t test. The χ2 or Fisher exact test were used to compare categorical variables between groups. The significance between the referent group (moderate-to-severe TR) and the other groups was examined when a significant difference between categories was observed. Individual differences were compared using Mann–Whitney U-tests (with a Bonferroni correction for multiple comparisons) and Tukey tests for normally distributed data. The presence of VSTR was assessed in each centre, prior to that study, by the physician's overall judgement of the regurgitation severity and consequences. After integration of all these parameters, the echocardiographer graded TR as severe or VSTR. Using ROC curve analysis, we compared the ability of the TCG and the EROA to diagnose VSTR as defined above. The correlation between EROA and TCG was tested by linear regression. Interobserver reproducibility for EROA and TCG measurements was evaluated using Pearson correlation coefficient and intraclass correlation coefficient (ICC) analysis using a randomly chosen subset of 20 patients with severe TR. Event rates ± standard errors were estimated using the Kaplan-Meier method and compared by two-sided log-rank tests. Multivariable analyses for all-cause and cardiovascular mortality in the overall study population and in patients with a tricuspid coaptation gap ≥10 mm, were performed using Cox proportional hazard models. Clinical and echocardiographic covariates considered to have a potential prognostic impact were tested in univariate analysis. All significant variables in univariate analysis with p < 0.1 were included in the multivariate cox analyses. The limit of statistical significance was p < 0.05 and all tests were two-tailed. Data were analyzed using SPSS 25.0 .Baseline continuous variables are expressed as means ± standard deviations and categorical variables as numbers and percentages. The differences between the three groups  based on baseline continuous variables were explored using the Student n = 104, 17%) was the best cutoff with a sensitivity of 83% and a specificity of 100% to predict VSTR whereas an EROA of 0.6 cm2  had a sensitivity of 75% and a specificity of 52% to predict VSTR. Interobserver reproducibility was quite good for the EROA measurement (ICC: 0.89. TR was graded, using a multiparametric approach, as moderate-to-severe for 212 patients (35%) and severe for 394 patients (65%). The area under the curve (AUC) to predict VSTR graded using a multiparametric approach was only 0.74 for EROA and 0.95 for TCG . A TCG wncreased . Among pp < 0.05) (p < 0.001) than patients with moderate-to-severe TR  are presented in  < 0.05) . Patientevere TR .In terms of echocardiographic parameters, the area of the left and right atria, TR EROA, and tricuspid annulus diameter increased with TR severity, whereas the TR peak jet velocity decreased. Patients with severe and VSTR were more likely to have inferior vena cava and subhepatic vein dilatation and subhepatic vein flow reversal than patients with moderate-to-severe TR .2 to define VSTR, estimated four-year survival rates were 70 ± 4% for moderate-to-severe TR, 65 ± 5% for severe TR, and 64 ± 5% for VSTR (Log rank p = 0.289), with no significant difference between patients with an EROA <60 mm2 and those with an EROA ≥60 mm2  (p = 0.022), with a significant difference between patients with a TCG <10 mm and those with a TCG ≥10 mm   deaths occurred during follow-up , of which 100 were attributed to cardiovascular causes (58%). When using an EROA ≥60 mm= 0.899) . When a < 0.001) .p < 0.1, p = 0.186 per mm2 increase), whereas the TCG was . After adjustment to the same variables, a TCG ≥10 mm remained independently associated with all-cause mortality , whereas an EROA ≥60 mm2 did not   after adjustment for the all variables associated with cardiovascular mortality on univariate analysis  . The resanalysis .p = 0.004), NYHA class III–IV , and a Charlson comorbidity index >2 , whereas those associated with cardiovascular mortality were male sex , NYHA class III–IV , and ascites   .p = 0.010) was associated with all-cause mortality in multivariate analysis. A LVEF between 50% and 60%  and moderate or severe RV dilatation  were independently associated with cardiovascular mortality ; ortality .2 was not associated with excess mortality. Therefore, a TCG ≥10 mm should be used to define VSTR in isolated functional TR.The prevalence of VSTR in patients with significant isolated functional TR was variable, ranging from 17% to 35% of patients, depending on the parameter used to define it. In our population of significant TR, the correlation between EROA and TCG was poor and decreased with increasing TCG. Risk stratification was significantly improved using the TCG but not EROA. Indeed, after adjustment for established prognostic factors, a TCG ≥10 mm was associated with a >2.1-fold increase in the relative risk of cardiovascular death, whereas an EROA ≥60 mm2, the mean residual EROA 30 days after treatment was 0.63 ± 0.29 mm2 , especially for patients with a large TCG. Indeed, among patients with a TCG ≥10 mm, those with the lowest EROA (<40 mm2) had the largest TCG (mean 17.9 mm). Conversely, TCG measurements are relatively easy to perform when TCGs are present. We found a better reproducibility for the TCG measurement than for the EROA probably because the TCG requires only one measurement whereas the calculation of the EROA by the PISA technique requires several parameters , which increases the risk of error and is more technically challenging to obtain. Thus, to summarize, the shape of the regurgitant orifice as well as the frequent not flat surface due to the tethering of the leaflets and the fact that the PISA method is less reliable due to greater variability are our main hypotheses to explain the superiority of TCG over PISA EROA in very severe TRs. Rapid developments in three-dimensional transthoracic echocardiography will soon allow routine measurement of anatomical EROA, which will certainly be more accurate because it will assess the true coaptation defect in all three dimensions but will require clinical validation. Pending the widespread adoption of these new techniques, the two-dimensional measurement in end-systole in the view where the TCG is the largest is simple and present good interobserver reproducibility   . We founS′ measurements, despite the limitations of these parameters in the presence of severe TR. Nevertheless, although normal RV systolic function cannot be determined with certainty when the values are normal, the presence of a dysfunction is clear when these parameters are altered. While the extent of TCG is a reflect of the anatomic ERO, TCG might also reflect RV enlargement and/or dysfunction and tricuspid annular dilatation especially when RV dilatation contributes significantly to the severity of TR. However, in isolated functional  TR, RV dilatation is not the cause of the disease but rather a late consequence of the regurgitation (R2 = 0.17 and 0.19 respectively). We did not include the laminar character of the TR and the inversion of the hepatic vein flow in the definition of VSTR, contrary to our previous study (Va) were not collected in our database and we cannot multiply the calculated flow rate by Vmax/(Vmax − Va) to yield the correct regurgitant flow rate (Our study had several limitations. First, it was retrospective and suffered from the inherent limitations of this type of analysis. Echocardiograms were not analysed in a central corelab but at each institution separately. The assessment of RV dimensions is challenging due to its complex geometry and the lack of specific right-sided anatomic landmarks to be used as reference points. Unfortunately, we did not dispose of right ventricular surface or 3-dimensional volume data which is a limitation and, in our study, RV dilatation was defined by a diameter >42 mm. The definition of RV dysfunction was based on TAPSE and gitation , 33. Actus study  because us study . We belilow rate . Howeverlow rate . The TCGThe correlation between the TCG and the EROA is weak in significant TR and decreases with increasing defect size due to limitations inherent to the PISA technique. A TCG ≥10 mm is associated with a significant increase in all-cause and cardiovascular mortality and should be used to define VSTR in isolated significant functional TR.