There is limited evidence to support the use of customised centile charts to identify those at risk of stillbirth and infant death at term. We sought to determine birth weight thresholds at which mortality and morbidity increased and the predictive ability of noncustomised  and partially customised centiles  to identify fetuses at risk.This is a population-based linkage study of 979,912 term singleton pregnancies in Scotland, United Kingdom, between 1992 and 2010. The main exposures were noncustomised and partially customised birth weight centiles. The primary outcomes were infant death, stillbirth, overall mortality (infant and stillbirth), Apgar score <7 at 5 min, and admission to the neonatal unit. Optimal thresholds that predicted outcomes for both non- and partially customised birth weight centiles were calculated. Prediction of mortality between non- and partially customised birth weight centiles was compared using area under the receiver operator characteristic curve (AUROC) and net reclassification index (NRI).p < 0.001). We were unable to fully customise centile charts because we lacked data on maternal weight and ethnicity. Additional analyses in an independent UK cohort  suggested that lack of data on ethnicity in this population  and maternal weight would have misclassified ~15% of the large-for-gestation fetuses.Birth weight ≤25th centile was associated with higher risk for all mortality and morbidity outcomes. For stillbirth, low Apgar score, and neonatal unit admission, risk also increased from the 85th centile. Similar patterns and magnitude of associations were observed for both non- and partially customised birth weight centiles. Partially customised birth weight centiles did not improve the discrimination of mortality  compared with noncustomised birth weight centiles  and slightly underperformed in reclassifying pregnancies to different risk categories for both fatal and non-fatal adverse outcomes  are increasingly being adopted by many maternity units. However, whether they can identify term fetuses at risk of death more accurately than noncustomised centiles is unknown.n = 10,515).We examined data on 979,912 term singleton pregnancies over a 19-y period in Scotland. With external validation of our findings on an independent UK cohort  with stillbirth, infant mortality, admission to the neonatal unit and Apgar score <7 at 5 min. In addition, we assessed whether partially customised centiles perform better in predicting adverse outcomes compared with noncustomised centiles. We were unable to assess fully customised centiles as we did not have data on maternal ethnicity and weight.We found that birth weight ≤25th or ≥85th centile  are associated with greater risk of adverse outcomes. Partially customised centiles did not identify more fetuses at risk of death compared with noncustomised centiles.Adverse outcomes frequently occur in term fetuses. Closer surveillance or earlier delivery of those fetuses with a predicted birth weight ≤25th or ≥85th centile may reduce adverse outcomes.Replication of the analysis with fully customised birth weight centiles is required. Infants who are born at the extremes of birth weight have a higher risk of adverse perinatal outcome . In deveThe aims of this study were (1) to determine the shapes and magnitudes of the associations between birth weight centile and infant death, stillbirth, infant mortality and stillbirth combined, Apgar score <7 at 5 min, and admission to the neonatal unit and (2) to compare the accuracy of predicting mortality  using noncustomised  birth weight centile charts versus partially customised  birth weight centile charts.www.isdscotland.org). All data were nonidentifiable, and individual informed consent from participants was not required.The Privacy Advisory Committee of the Information Services Division (ISD) of the National Services Scotland awarded ethical approval for access to and linkage of the datasets  guidelines .http://www.adls.ac.uk/nhs-scotland/maternity-inpatient-and-day-case-smr02/?detail). The data can be accessed from the National Services Scotland (www.isdscotland.org) following approval.We linked four Scotland-wide databases: the Scottish Morbidity Record 02 (SMR02), the National Records of Scotland (NRS), the Scottish Stillbirth and Infant Death Survey (SSBIDS), and the General Registrar for Scotland’s death certificate database, to provide comprehensive obstetric, neonatal, infant, and mortality data for all women discharged from Scottish maternity hospitals. Details of the datasets and the quality assurance procedures are provided in Supporting Information , stillbirths (intrapartum or antepartum deaths), combined stillbirth and infant mortality, low Apgar score (<7) at 5 mins, and admission to neonatal unit .http://www.gestation.net/GROW_documentation.pdf. Customised centile charts typically also adjust for maternal weight and ethnicity. However, this information was not available in the routine data sources employed. White British ethnicity was assumed for all pregnancies since only 2% of babies were born to women in ethnic minority groups  in Scotland over this period. Weight was assumed to be 66 Kg for all women . Given the lack of adjustment for maternal weight and ethnicity, we refer to the adjusted percentiles as "partially customised." Noncustomised percentiles were internally standardized for gestational age (in weeks) and sex. Gestational age has been confirmed by ultrasound in the first half of pregnancy in more than 95% of women in the UK since the early 1990s [The exposures were noncustomised birth weight centiles (sex and gestation specific) and partially customised birth weight centiles  . Transfoly 1990s .We considered that year of delivery, parity, and diabetes  might be effect modifiers of the relationships between birth weight and outcomes. Data on year of delivery and parity were obtained from SMR02. The ICD codes recorded on the SMR02 record were used to ascertain gestational diabetes: 6488 (ICD9) O244, O249 (ICD10) and pre-existing diabetes: 250, 6480 (ICD9) E10-14, O240-1, O243 (ICD10). Any associations between birth weight and fatal outcomes might differ in those who die after delivery as a result of delivery complications . We, therefore, repeated all main analyses with deaths related to these causes only.In addition to the procedures and audits used to ensure high-quality data on mortality, we explored the face validity of these data further by assessing associations of known risk factors, such as a previous history of infant/fetal mortality or morbidity and smoking.On being granted data access, all authors agreed on the statistical analysis plan prior to commencing the main analysis. The analysis of the ALPSAC cohort was undertaken in response to comments from peer reviewers. All analyses were performed using Stata  and R version 3.2.3 .We used multivariable cubic regression splines to model the associations between birth weight centiles  and each outcome using the mvrs command in Stata. The mvrs command uses a closed-test approach to select the most appropriate spline model from a number of competing spline models . BrieflyDifferences in associations of birth weight with mortality (stillbirth or infant) by parity, year of delivery, and diabetes were examined by presenting stratified results—two categories of parity (nulliparous and multiparous), four categories for year of delivery , and two categories for diabetes —and by testing for statistical interaction between these categories and birth weight in their association with outcomes, using a likelihood ratio test.Complete data were available on over 99% of the cohort for all variables included in the main analyses, with the exception of maternal height . Maternan = 10,378 following exclusions similar to the analyses completed in the main study) and then recalculated these first with all weight values removed (so that each woman would be given the default 66 Kg) and then additionally with the 2% who were not white British changed to white British. We calculated the proportions of those defined as SGA, normal for gestational age and LGA birth weight, with missing weight and ethnicity data to the gold standard of full-customisation, using both the 10th and 90th centiles and 25th and 85th centiles to define SGA and LGA, respectively.We undertook additional analyses in an independent UK Cohort—the Avon Longitudinal Study of Parents and Children (ALSPAC), which has data on all of the variables required for customisation and an ethnic distribution similar to that of the main Scottish population used here, with 98% being of white British origin ,20. We uBetween 1 January 1992 and 31 December 2010, there were 1,062,390 deliveries in Scotland. After pre-specified exclusions, the analysis cohort included 979,912 term deliveries . Among tp for interaction < 0.001) and fatal events increase with increasing birth weight centile (linear association) in infants of mothers with diabetes, whereas in those without diabetes the 25th and 85th centiles knot points were still evident  (p < 0.001) , compared with a noncustomised birth weight centile  . The mod< 0.001) .Expediting delivery for an anticipated birth weight of ≤25th noncustomised centile rather than <10th , would result in pre-emptive delivery of 159,025 additional women to prevent 377 fatal events (stillbirth and infant deaths). Hence, to prevent one death, 422 (95% CI 381 to 468) additional pregnancies below this new threshold would require to be delivered. If the equivalent ≤25th threshold was used for the partially customised centiles, intervention in an additional 463 (95% CI 417 to 516) pregnancies would be required to prevent one fatal event. Adopting the threshold of ≥85th centile for defining large for gestation babies rather than >90th centile and delivering them earlier, assuming 69% effectiveness of intervention, would require an additional 721 (95% CI 598 to 947) or 826  pre-emptive deliveries, respectively for noncustomised and partially customised centiles, to prevent one fatal event.In the ALSPAC cohort partially customised centile charts that did not adjust for maternal weight accurately identified SGA in comparison with fully customised charts, with 97% of those identified as SGA with full-customisation being identified with partial (weight removed) customisation when either the 10th  or 25th Being born too small or too large is associated with an increased risk of mortality and morbidity ,5,7. Desrd percentile, the risk was doubled. Hence, interventions focused on improved care of poorly grown fetuses could potentially have longer term benefits in childhood.Prior to term, fetal biometry is used to detect abnormal growth trajectories, with the overall clinical management of ongoing fetal health and timing and mode of delivery guided by evidence-based guidelines . This is+6 wk for those in the >95th centile reduces shoulder dystocia [Our results also support considering earlier delivery of those fetuses ≥85th centile at term, with a recent randomised controlled trial suggesting that induction of labour at 37–38dystocia . But thedystocia . Randomidystocia .The clinical utility of routine second and third trimester ultrasound for the detection of fetuses with abnormal growth and at increased risk of neonatal complications has recently been reported . An addin = 20,486) indicated that ethnicity had a minimal effect on fetal growth in healthy women [n = 1,737) suggested that Hispanic, Asian, and black ethnicities are associated with differential growth and up to 245 g lower median estimated fetal weight than white Europeans by 39 wk gestation [The process of customisation of birth weight centiles has an additional major difference to the conventional approach, over and above accounting for maternal characteristics. The growth reference used is the distribution of weight at a given gestational age based on ultrasonic estimation of fetal weight, rather than actual birth weight. This is important preterm, as previous studies have shown that preterm birth is associated with fetal growth restriction . A consehy women , though estation . HoweverOur study included around one million deliveries. We included all eligible deliveries in Scotland over a 19-y period, thereby avoiding selection bias. We linked four national datasets to maximise data completeness. The routine data sources are subject to quality assurance checks and perform well in terms of completeness and accuracy. The detail provided by these datasets allowed us to examine a range of different outcomes and we used robust methods to calculate the RR of the outcomes of infant mortality, stillbirth, Apgar score <7 at 5 min, and neonatal admission for birth weight at term. Measurement of birth weight was not subject to quality control measures, but represents routine clinical practice, and is not subject to the error that can occur in research assessments of birth weight taking place within the first few days  because of the large decrease in weight observed during the first two days of life . We wereIn conclusion, term fetuses remain at substantive risk of infant death, stillbirth and neonatal morbidity. Birth weight identifies those at greatest risk, and our results support consideration of early delivery, increased surveillance or additional testing for those with an anticipated birth weight ≤25th centile or ≥85th centile  proposed to reduce adverse outcomes. Replication of our results in other independent large datasets is warranted. A clinical trial looking at morbidity outcomes  will clarify whether early term intervention at the proposed thresholds of birth weight will be beneficial. In Scotland, and similar countries, there is no evidence that partially customised charts perform better at identifying those term infants at risk than noncustomised charts.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Tablen = 10,378).Analyses undertaken in the ALSPAC cohort ((DOCX)Click here for additional data file.S5 Tablen = 10,378).Analyses undertaken in the ALSPAC cohort ((DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


To investigate the association between fetal growth between first and early second trimester ultrasound scan and the risk of severe small for gestational age (SGA) birth.rd centile) was calculated using multivariable logistic regression analysis and presented as adjusted odds ratio (aOR).This cohort study included 69 550 singleton pregnancies with first trimester dating and an early second trimester growth scan in Stockholm and Gotland Counties, Sweden between 2008 and 2014. Exposure was difference in biparietal diameter growth between observed and expected at the second trimester scan, calculated by z-scores. Risk of birth of a severe SGA infant . The risks of preterm severe SGA (birth before 37 weeks) and term severe SGA (birth 37 weeks or later) were at similar levels, and risk of severe SGA were also elevated in the absence of preeclampsia, hypertensive diseases or gestational diabetes.Fetuses with slow growth of biparietal diameter at ultrasound examination in early second trimester exhibit increased risk of being born SGA independent of gestational age at birth and presence of maternal hypertensive diseases or diabetes mellitus. Impaired fetal growth is a major pregnancy complication and determinant of perinatal morbidity and mortality. , 2 IncreIt is biologically plausible that early discrepancy in fetal biometry is a result of placental dysfunction, with impaired fetal growth, resulting in IUGR. Early recognition of fetuses at risk of IUGR enables more appropriate surveillance and management, which has been shown to reduce risks of adverse fetal outcomes. , 13 PrevWe conducted this study to evaluate whether slow growth between the first trimester and the early second trimester based on ultrasound measurements of BPD is associated with increased risks of overall SGA birth, preterm and term SGA birth.Data from the population-based Stockholm-Gotland obstetric database was used for the study. The database obtains information from all antenatal, ultrasound, delivery, and postnatal care units in the counties of Stockholm and Gotland, Sweden. From the first antenatal visit, midwives record information about maternal reproductive history, smoking habits, height, weight, and state of health. Biometric measurements, obtained at the ultrasound examinations were collected from all ultrasound units in the region, and information about infant birth weight, maternal diabetes, hypertension and preeclampsia was obtained from standard delivery charts and diagnoses at discharge from the delivery hospital.The study population included all singleton deliveries in Stockholm and Gotland between January 1st, 2008 and October 22nd, 2014 (n = 167 695). Data on maternal, delivery and infant characteristics was available in of all deliveries. In 72 309 (43%) the pregnancies, biometric measurements were performed both in the first and early second trimesters. We excluded 2 495 pregnancies with infant malformations (3.4%), 198 stillbirths (0.2%) and 66 pregnancies with missing information on infant birth weight. First trimester  ultrasound scan is recommended to pregnant mothers older than 35 years to examine the risk for chromosomal disorders (combined ultrasound and biochemistry [CUB] examination). The examination is also available to mothers younger than 35 years on request. All women are offered an early second trimester  ultrasound scan in order to calculate the expected date of delivery and to detect multiple pregnancies or fetal malformations. The ultrasound examinations are free of charge and in 2014, 57% of all mothers in Stockholm region, underwent first trimester scans, while 98% underwent early second trimester scans. [The exposure was slow fetal growth defined as the difference between observed and expected BPD at second trimester ultrasound scan. We related the estimated fetal size to the expected size on the basis of the first trimester scan. At both first and second trimester ultrasound examinations, gestational age was estimated by fetal BPD according to the formula by Selbing  **2).  ExpectedThe ultrasound examinations were performed by specially trained midwives according to a standardized protocol. The Swedish Association for Obstetrics and Gynecology (SFOG) recommends that the fetal BPD should be measured from the outer edge of the proximal parietal bone to the inner edge of the distal parietal bone at the level of thalami and septum pelucidi. rd percentile according the sex specific national reference curves for gestational age. [th and ≥ 3rd percentiles.The primary outcome measure was severe SGA birth, defined as a birth weight less than the 3nal age.  The secoMaternal and pregnancy characteristics, categorized as in th centile for gestational age.We investigated the association between slow fetal growth at early second trimester ultrasound scan and risk for severe SGA birth. A Z-score was calculated for each fetus by subtracting observed BPD and mean of expected BPD and dividing by the standard deviation (SD) of the BPD for this group: Z-score = (observed BPD − expected mean BPD) / (group BPD SD). Slow growth was defined as a BPD measurement at early second trimester less than the 2.5th centile, 97th to > 90th centile, 90th to 10th centile, 3rd to < 10th centile and < 3rd centile. The associations between severe SGA (< 3rd percentiles) and slow BPD growth at early second trimester scan, were investigated using class variables: > 90th centile, 90th to 10th centile (reference), 2.5 th to < 10th centile and < 2.5rd centile. Mothers with preeclampsia, gestational hypertension or diabetes mellitus, where excluded in the restricted analyses. The analysis of risk of preterm severe SGA was performed in the cohort of all pregnancies. The risk of being born severe SGA at term (≥ 37 weeks) was estimated in the group of term (≥ 37 weeks) pregnancies.Unconditional logistic regression analysis was used to calculate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age, BMI, parity, smoking, IVF and maternal pre-pregnancy diabetes and hypertension. Infants were categorized into five groups based on centiles according to birth weight for gestational age and sex: > 97The statistical software package SAS 9.4  was used for analysis.The regional ethical committee of Karolinska Institutet, Stockholm, Sweden approved the study protocol.The regional ethical review board of Karolinska Institutet, Stockholm, Sweden approved the study protocol. No written informed consent for participation in the study was obtained from participants since data was depersonalized prior to the analysis. This study was supported by grant from the Swedish research council th centile at the second trimester ultrasonic scans. In 55 518 (79.8%) of the fetuses, the growth was between 10th and 90th centile, while 10.2% of fetuses had a BPD growth larger than expected (> 90 th centile).In total, 69 550 pregnancies were eligible for the study. Based on the information on biometric measurements, 6 950 (10%) of the fetuses had BPD growth less than 2.5rd percentile) at birth. Compared to infants with appropriate birth weight for gestational age (between 90th and 10th percentile), severe SGA infants were more likely slow growing during the early pregnancy. Compared to women delivering infants with normal birth weight for gestational age, mothers delivering severe SGA infants were more likely to be younger (24 years old and younger), lean (BMI ≤ 18.4), cigarette smokers, pregnant after IVF, to deliver preterm, and to have hypertension or preeclampsia.The characteristics of the study population according to birth weight for gestational age are presented in th -90 th centile), the risk of being born severe SGA (<3rd percentile) increased by 70% in infants who had a slow early pregnancy fetal growth (th centile) had a lower risk of severe SGA than the reference group. These risks were also present in the analysis restricted to pregnancies without preeclampsia, gestational hypertension or diabetes mellitus (th centile did not significantly influence risk of intermediate SGA (3rd—<10th percentiles)  th centile at early second trimester scan and preterm severe SGA (< 37 weeks) and severe SGA in term pregnancies (≥ 37 weeks)  and maternal age 35 years and older . .th centile at an early second trimester scan.In this large cohort study, we found that the risk of severe SGA at birth increased with slow fetal growth between a first trimester and an early second trimester scan. The risks of preterm (before 37 weeks) and term (37 weeks or later) severe SGA were at similar levels and highest for fetuses with fetal growth below 2.5The main strengths of this study are the prospectively recorded information and the large cohort size, which makes it possible to predict the risk for rare outcomes such as preterm severe SGA. The study is population based, antenatal and obstetric care is free of charge in Sweden, and standardized ultrasound examinations in early pregnancy are commonly performed in the region. Because ultrasound measurements were collected from a large number of units, there might by a variation of performance and interpretation of ultrasound examination. However, all included ultrasound units follow the professional standards for equipment specifications and training, set by Swedish technology assessment in health  and by tth percentile for gestational age. [rd percentile. Severe SGA might have several causes such as structural or chromosomal abnormalities that affect fetal growth, be constitutionally small or exposed to fetal malnutrition. [rd percentile), we were better able to study fetuses that were truly growth restricted.The terminology for classifying fetuses and newborns who have failed to achieve normal weight is inconsistent. In Sweden, SGA is defined as birth weight of two standard deviations or less the average weight for gestational age and sex. However,nal age.  Since wetrition. , 11 We etrition. , 29 We bth centile at an early second trimesters was an independent risk factor for severe SGA. Our findings support the hypothesis that IUGR and preeclampsia, that are presumed to share the same etiology, might be two different entities and IUGR can be present without clinical signs of gestational hypertension or preeclampsia. [Fetuses with IUGR do not achieve their growth potential because of environmental factors that influence placental function.  Hypertenlampsia. , 31–33In previous studies, first trimester predictions of severe term SGA have been less strong than predictions of early SGA.  ExplanatThe increased risk of adverse neonatal outcome in fetuses smaller than expected at early second trimester ultrasound scan has previously been based on comparison of early fetal size in relation to LMP, , 36–38 dIn summary, growth discrepancy in early pregnancy is indicative of a subgroup of slow-growing fetuses that are at increased risk of severe SGA. Our method, based on two sequential ultrasound measurements of the BPD using the same dating formula, should be more reliable than previously described methods., 20, 21 th centile during early pregnancy increases the risk of preterm and term severe SGA birth, also in pregnancies without hypertensive diseases. These findings may be used to identify pregnancies at risk and thereby optimize prenatal management.Fetal growth below the 2.5 S1 Table(DOCX)Click here for additional data file.


Suboptimal prenatal and early postnatal growths are associated with obesity in later life, but the underlying mechanisms are unknown. The aim of this study was to systematically review the literature that reports on the longitudinal association of (i) birth size or (ii) infant growth with later (i) energy intake, (ii) eating behaviors, (iii) physical activity or (iv) sedentary behavior in humans.A comprehensive search of MEDLINE, EMBASE, PsycINFO and The Cochrane Library was conducted to identify relevant publications. We appraised the methodological quality of the studies and synthesized the extracted data through a best-evidence synthesis.Data from 41 publications were included. The quality of the studies was high in three papers, moderate in 11 and low in the large majority (n = 27) of papers appraised. Our best-evidence synthesis indicates that there is no evidence for an association of birth weight with later energy intake, eating behavior, physical activity or sedentary behavior. We found moderate evidence for an association of extreme birth weights (at both ends of the spectrum) with lower physical activity levels at a later age. Evidence for the association of infant growth with energy balance-related behavior was generally insufficient.We conclude that current evidence does not support an association of early-life growth with energy balance-related behaviors in later life, except for an association of extreme birth weights with later physical activity. There is now an abundance of literature highlighting the importance of early life growth on adult-onset disease risk. Low birth weight, as a marker of suboptimal prenatal growth, is strongly linked to central obesity, cardiovOne of the hypothesized mechanisms underlying the association of pre- and early postnatal growth with later obesity and cardiovascular disease is the alteration of energy balance-related behaviors, including eating behavior, physical activity (PA) and sedentary behavior (SB). Several studies in rodents have shown that impaired prenatal nutrition followed by increased postnatal growth causes excessive intake and diminished PA in the offspring, preceding the development of obesity.–8 The hyHuman data on the association of pre- and early postnatal growth with energy balance-related behaviors are limited and show conflicting results. For example, some studies found a positive association of birth weight with PA, whereaset al. reviewed the literature on the relation of perinatal growth with accelerometer-assessed PA in children and concluded that there is no evidence for an association of birth weight with childhood PA based on a formal meta-analysis. Of  Of 26] OThe included studies were very heterogeneous, especially with regard to the type and measurement of behavior, the categorization of subjects and type of statistical analysis. Therefore, statistical pooling by means of a formal meta-analysis was not feasible, and we performed a best-evidence synthesis. A best-evidence synthesis is a systematic qualitative summarization of available evidence, which helps to reduce the chance of conflicting results and conclusions. We stratThe literature search generated a total of 7,907 references: 3,724 in PubMed, 3,061 in EMBASE.com, 577 in PsycINFO and 545 in The Cochrane Library. We consecutively removed duplicates that were selected from more than one database, excluded non-relevant articles by screening the titles and abstracts, and reviewed the remaining articles in full text. see  EventualThirty-one (76%) of the 41 studies were prospective cohort studies, nine were retrospective studies and one study combined prospective and retrospective cohorts in a meta-analysis. Four artThe sample size ranged from 84 to 43,48In 39 (95%) of the included studies, birth weight was the primary determinant, expressed as absolute weight, birth weight ratio  or gestational age-adjusted SD-score. Five studies additionally reported other birth size measures besides birth weight , 48, 49,Eight studies reported energy intake as only primary outcome, 38, 61,Thirty-one (76%) of the 41 studies adjusted for a variety of covariates in the analysis. Eleven studies controlled for confounding by gestational age, which was the criterion for moderate quality in the dimension ‘potential confounding’.The methodological quality of the included studies is presented in The results for the various associations of birth weight and infant growth with energy balance-related behavior are summarized in According to the best-evidence synthesis, we found no evidence for an association of birth weight with energy intake. This is based on three moderate-quality studies, 29, 33 We found no evidence for an association of birth weight with eating behaviors, based on two moderate-quality studies, 42 and No evidence was found for an association between birth weight and PA in humans. This is based on the results of two studies of high quality, 62, fivThere is no evidence for an association of birth weight with SB in humans, based on three moderate-quality and two low-quality studies., 52, 55 There is inconsistent evidence for the association of extreme birth weights with SB, as the association with low birth weight was absent in one study and posiThis review represents the first synthesis of all the available human data on the association of birth weight and infant growth with the spectrum of behaviors that collectively encompass energy balance-related behavior, while accounting for the methodological quality of the studies. We identified 41 eligible studies, of which the large majority focused on the association of birth weight with PA. Overall, there is no evidence for an association of birth weight with PA, SB, energy intake or eating behaviors, although the largest study addressing SB found that a kilogram increase in birth weight was associated with 4 more minutes of daily SB. There waDespite evidence supporting the idea that postnatal weight gain is more important than birth weight for later obesity risk, the humWe found moderate evidence for the association of extreme birth weights with later PA levels, as studies in very low birth weight, 56 and et al. the relatively small sample size of 88 children may have compromised the study’s ability to detect an association of birth weight with PA.[We conducted a best-evidence synthesis to summarize all the available evidence on the association of pre- and early postnatal growth with energy balance related behavior. This has the additional advantage that it accounts for the methodological quality of the studies: low- and moderate-quality studies are disregarded if sufficient high-quality evidence is available. However, this approach does not consider the size of the studies involved. Many of the studies were relatively small, particularly if samples were stratified by age or sex. For example, in the study of Salbe  with PA. But in t with PA. This lat with PA. The clin with PA. and the  with PA., have beet al. previously reviewed the literature on the association of birth weight with PA, but their review was limited to studies in children and to studies with PA assessed by accelerometry.[A second limitation of the best-evidence synthesis is that it does not give an estimated overall effect size. For this, a meta-analysis would have been preferable, but this requests statistical pooling. Pooling was only possible for the continuous association of birth weight expressed in kg with PA expressed in accelerometer counts per minute, which was reported in three publications., 48, 49 erometry. They conerometry., 55 ThisAs with any systematic review, this review is limited by the quality of the included studies. The quality of the included studies was generally low, with the exception of 11 studies judged to be of moderate quality, and three studies of high quality. The most common shortcoming in the methodological quality of the included studies was that the required information to assess the validity and reliability of the behaviors was often lacking or unclearly reported. Reliability and validity of the data may be of particular concern in studies where data were based on recall or self-report albeit using validated instruments. These meSystematic reviews are subject to publication bias. Publication bias typically biases the association away from null, so this might particular be relevant for the (positive) association of extreme birth weights with PA.Our review was restricted to the association of birth weight and postnatal growth with energy balance-related behaviors as primary outcomes. Therefore, studies focusing on other potentially relevant factors such as basal metabolic rate, its regulatory systems, such as the autonomic nervous system, or closely related pathways, such as the timing of the ‘obesity rebound’. Birth weight has been associated with resting metabolic rate, and infIn conclusion, the studies included in our best-evidence synthesis indicate that there is no evidence for an association of birth weight with PA, SB, energy intake or eating behaviors. Also, there is no evidence that other birth sizes or infant growth are associated with PA in later life. However, there is moderate evidence for an association of extreme birth weights with lower PA. There is insufficient evidence on the associations of infant growth, other birth size measures and extreme birth sizes with energy intake, eating behavior or SB.Our study leads to important recommendations for future research. First, as a relatively high number of studies found no association of birth weight with any energy balance-related behavior, shifting focus to the effects of infant growth or trimester specific fetal growth on theseObesity prevention and treatment programs may be helped with better identification of mechanisms that underlie relationships between early life growth and adult obesity, but current evidence does not allow inferences about the relation of early-life growth with energy balance-related behavior in later life. First, there is a need of high-quality studies on this topic that overcome the methodological limitations in participation, measurements and attrition rate that almost invariably accompany existing birth cohorts.S1 File(DOC)Click here for additional data file.S2 File(PDF)Click here for additional data file.


In the musculoskeletal and peripheral nerve systems, DTI has been mostly used in experimental settings, with still few indications in clinical practice. In this review, we describe the potential use of DTI to evaluate different musculoskeletal and peripheral nerve conditions, emphasising the translational aspects of this technique from the experimental to the clinical setting.Magnetic resonance imaging (MRI) is a well-established imaging modality which is used in all districts of the musculoskeletal and peripheral nerve systems. More recently, initial studies have applied multiparametric MRI to evaluate quantitatively different aspects of musculoskeletal and peripheral nerve diseases, thus providing not only images but also numbers and clinical data. Besides  Diffusion tensor imaging (DTI) is feasible in the musculoskeletal and peripheral nervous systemsMost studies on musculoskeletal DTI were performed in experimental settingsClinical data on DTI in the musculoskeletal system are still sparseStandardisation of protocols in musculoskeletal DTI is a major issueQuantitative evaluation of musculotendinous damage is the most promising clinical application1H and 31P magnetic resonance spectroscopy have been used for soft-tissue lesion characterisation [Magnetic resonance imaging (MRI) is a well consolidated modality in all districts of the musculoskeletal system. Until a few years ago, most musculoskeletal and peripheral nerve disorders were qualitatively assessed with MRI using standard morphological sequences . More rerisation  and to erisation . Diffusirisation . Blood orisation .Diffusion tensor imaging (DTI) is a relatively new MRI-based technique relying on principles of DWI, which has traditionally been used mainly for evaluating the central nervous system to track fibre course . In the In this review, we describe the potential use of DTI to evaluate different musculoskeletal and peripheral nerve conditions, emphasising the translational aspects of this technique from the experimental to the clinical setting.2. The amount of water molecule diffusion is quantified by the apparent diffusion coefficient (ADC)—obtained by interpolating the results given with different applied b-values—which provides indirect information also about the arrangement of the surrounding structures.The principle of water molecule diffusion evaluated using MRI in the human body was firstly reported in 1985 . MoleculMolecular mobility in human tissues is usually non-isotropic, which means that diffusion does not occur equally in all directions; protein fibres, cell membranes and myelin sheath tend to hinder water diffusion .The effect of diffusion anisotropy can be easily detected by evaluating variations in the diffusion measurements when the direction of gradient pulses is changed . FractioDTI is derived from the concept of water molecule diffusion. In DTI, it is possible to calculate FA and evaluate the preferred spatial movement of molecules. Hence, since structural arrangement makes the water diffusion prevalent along the major axis of fibrillary tissues, DTI can be used for fibre tractography. To calculate the diffusion tensor, we need to acquire DWI with high b-values along at least six non-collinear directions in addition to a low b-value DWI or a T2-weighted sequence . The hig3, short TE, b-values in the range of 400–500 s/mm2 and at least ten gradient directions [0 magnetic field strength, the higher the SNR [To optimise the study protocol, the spatial complexity of the structure under investigation should be considered. Acquisition time is largely variable, as standardised protocols are still lacking. As an example, six directions may be enough for the median nerve, about 15–25 vector directions are needed for the brachial plexus, while 10–12 different vector directions are needed for muscular structures . Regardirections . Clearly the SNR . However the SNR .Tractography represents an application of DTI  that allFirst applications of DTI in the evaluation of muscle architecture were validated on small animals . Damon eFeasibility of DTI in the evaluation of normal muscle tissue has been widely demonstrated, with high reproducibility . In diffAfter physical exercise, the contractile complex of muscle, composed of actin and myosin, increases in size and density. This hypertrophic response of muscular tissue determines an increase in the thickness of endomysium muscle wrap and sarcoplasmic reticulum . OkamotoUnder the name of muscular dystrophy, a group of genetic, progressive and degenerative muscular diseases is included, whose primary symptom is muscle weakness . These pDuchenne muscular dystrophy (DMD) is the most common form of inherited muscular dystrophy in children. It is caused by mutations in the X-linked dystrophin gene and is characterised by systemic muscle weakness due to the progressive destruction of skeletal muscle . In thisArthroscopic grafting for ligament tears is common in active population  and MRI Cervical spondylotic myelopathy (CSM) is the most common spinal cord disorder in patients aged > 55 years and it is seen in as many as 95% of men and 70% of women aged 60–65 years . It is dEvaluation of brachial plexus abnormalities represents a diagnostic challenge due to anatomical complexity and to overlapping presentation of both benign and malignant conditions. There is a wide range of disease which may involve the brachial plexus, including tumours, radiation fibrosis, trauma and inflammatory processes. MRI is the imaging modality of choice for the evaluation of the brachial plexus . To dateCubital tunnel syndrome is the second most common peripheral compression neuropathy after carpal tunnel syndrome (CTS) . It is rCTS is the most common compressive peripheral neuropathy, affecting 3–4% of the general population . It is cp < 0.001), even though it always needs to be correlated with clinical symptoms.Conventional MRI of CTS gives variable qualitative results . DTI maySciatic neuropathy is a common cause of lower extremity pain, which can be related to several causes affecting any level of the nerve and resulting in different symptoms . The diaPiriformis syndrome (PS) is a not easily recognisable disorder, characterised by buttock and leg pain due to compression of the sciatic nerve through or around the piriformis muscle in patients with usually normal neurological examination . ManoeuvPrevious studies reported higher frequency of destruction or massive fibre disorganisation in malignant peripheral nerve tumours, whereas benign tumours are often associated with dislocation or partial interruption of fibres. Chhabra et al. reported that tractography may provide three-dimensional visualisation of fibre dislocation or destruction. On the other hand, FA and MD show low values that indicate malignancy extension in neural structures .DTI and tractography may provide useful additional information allowing a quantitative analysis of healthy and pathological nerves, myelin sheaths, and muscles. To date, these tools are mainly applied in experimental settings and are uncommonly translated to clinical practice.Since application of DTI and tractography in the musculoskeletal and peripheral nerve systems is different from application in the central nervous system, some issues still need to be addressed, such as: standardisation of acquisition protocols with optimised parameters and duration times; optimisation of post-processing software for DTI to be used in the musculoskeletal system; investigation of the possibility of using DTI around metallic implants, used in clinical practice more and more frequently; and analysis of reproducibility of DTI quantitative measurements .At any rate, DTI and tractography seem to be promising tools and are able to provide useful quantitative information about muscular tissue and peripheral nerves as an adjunct to morphological MRI sequences. The definition of the real clinical added value of this approach requires well designed studies on large population samples, possibly with clinical end-points potentially showing a benefit to the patients which is not limited to diagnostic performance.


The objective of the two case reports was to discuss the pathogenesis, origin, and therapeutic options for vallecular cysts. Method of Study. 2 children diagnosed in our department were treated by transoral endoscopic surgery, using cold instruments, suspension laryngoscopy and the operating microscope. Results. Both cases presented breathing and deglutition problems at diagnosis. The surgery aimed the complete excision, with cold instruments, via transoral access. No complications occurred and the postoperative healing was uneventful. No recurrences were observed on the long-term follow-up. Conclusion. Clinical, imagistic, and surgical data support the thyroglossal duct origin of vallecular cysts (base of tongue variant) and the complete excision is required to obtain long lasting cure. From an anatomical point of view, there are laryngeal cysts  and base of tongue cysts . These lesions could have a different pathogeny and, hence, different therapeutical approaches [2]. Due to the paucity of cases presented in the literature, the incidence of the disease is unknown. It can determine respiratory obstruction and stridor or dietary intake difficulties with failure to thrive in neonates [3]. Their origin is debatable, most of the theories being malformative [4]. The reason for discussing the pathogenesis of such cysts is linked to the best therapeutical option and the investigation taken into consideration when approaching these cases. Their diagnosis is relatively easy, using nasopharyngeal laryngoscopy (NPL). Treatment techniques include: marsupialization [5] and surgical excision (with/ without CO2 laser) [6]. Some authors described the use of coblation for the excision of the cyst [7].Vallecular cysts have been described in the literature for some time [Fig. 1). Ultrasonography (US) verified the presence of the normal thyroid gland in the cervical region. CT-scan was performed to verify the dimensions of the cyst and its relations with the surrounding structures. Cold instrument excision was performed under general anesthesia (GA) and suspension laryngoscopy, followed by the local cautery of the wound. Healing occurred uneventfully, with analgesics and antibiotics administered postoperatively. The histologic exam revealed a cystic tumor lined by stratified cuboidal epithelium and moderate lymphocytic infiltration. The 2-year follow-up showed no sign of local recurrence .A ten-year-old boy presented in our department with deglutition problems, intermittent odynophagia, and subtle dysphony. NPL and physical exam showed a median lump at the base of tongue, covered by normally colored mucosa . Cervical US showed a normal thyroid gland. CT-scan was performed in order to demonstrate the cyst dimensions and its position . The cyst was completely excised under GA and by using suspension laryngoscopy. No suture of the remaining wound was applied. Histological sections showed the presence of a cystic cavity lined with cuboidal stratified epithelium and minor inflammatory infiltrate. Healing recorded no complications. The patient was seen at 1-year follow-up with no recurrence of the cyst . A second case involved a girl aged 1 year and 8 months, who presented with frequent food aspiration into her lower airways, needing prolonged and recurrent hospital admission. Minor respiratory stridor was sometimes present when supine. Neurological problems were suspected but no other handicap was obvious. NPL and physical exam revealed a median tumor at the base of the tongue . There was no unique hypothesis upon their origin. Some considered the possibility of a large mucous gland located into the thickness of the lingual tonsil. We considered this a less likely origin because the region was mainly lymphoid in its histology, with few secretory glands. Moreover, the existence of constant local, mechanical trauma/ pressure (from food/ deglutition) did not favor the blockage of local mucinous glands but their drainage. That is why we considered this kind of cyst a form of thyroglossal duct remnant. That would also explain the perfect median location, as seen on the CT-scan images and the observed tendency to develop towards the anterior muscular region of the tongue and the hyoid bone. The normal appearance of the cyst covering mucosa and the close adherence of the cyst lining to the muscular fibers of the tongue, with no preexisting dissection plane, were also noticed during surgery. The CT-scan also showed the profound muscular and the strict median position of the cyst. All the data from imagistics and surgery suggested the thyroglossal duct/ cyst theory as a valid one, even if no proofs of active thyroid tissue could be histologically found inside the cysts. Treatment options in the literature consider marsupialization but mention the risk of recurrence. That is also quite possible if a thyroglossal duct cyst is considered and treated. In addition, that is why an excision was decided to be performed in both cases, although endoscopically. Along with suspension laryngoscopy, the operating microscope can offer the tools to safely remove all cyst lining and, as such, prevent recurrences.Vallecular cysts are different from laryngeal cysts. The term pseudocyst is more likely to reflect this condition and explains the lack of a real epithelial lining of the cyst. Their most likely origin is thyroglossal duct remnants. Consequently, their treatment should be guided by the same principles, complete surgical removal. The lack of a complete excision can explain recurrences. We believe that surgical excision should be the standard method, with an endoscopic approach, which yields the best results. We do not believe that the nature of the used instruments (cold instruments vs. laser) influences the outcome and rate of recurrence. Preoperative CT-scan is useful in verifying the adherence of the cyst to the hyoid bone. Those cases would better benefit from a cervical approach.FundingNone. DisclosureNone. Conflict of interestThe authors declare that there is no conflict of interest regarding the publication of this paper. AcknowledgementNone.


We carried out a study to determine the impact of prematurity on renal development. The primary outcomes measured were nephrinuria and albuminuria; renal volume and glomerular filtration rate were the secondary outcomes.Preterm neonates born at less than 28 weeks of gestation, with birth weight between 10th and 90th centile , were recruited and underwent assessments at 28, 32 and 37 weeks postmenstrual age (PMA).3 at 28 weeks PMA to 19.2 (3.7) cm3 at 37 weeks PMA (P = 0.0001). TKV at 37 weeks PMA was significantly smaller compared to term neonates (19.2 (3.7) vs 26.3 (7.0) cm3; P = 0.0001). However, there was no significant difference in estimated glomerular filtration rate (eGFR) between premature neonates (at 37 weeks PMA) and term neonates (control) . There was a statistically significant decline in nephrin-creatinine ratio and albumin-creatinine ratio from 32 to 37 weeks PMA.Fifty-three premature neonates and 31 term neonates (control) were recruited. The median gestational age of the premature neonates was 26.4 [24.7–27.4] weeks, with a mean birth weight of 886 (179) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g. The median age of the term neonates was 6.5 [3.0–12.5] days. The total kidney volume (TKV) almost doubled from 10.3 (2.9) cmDespite having a smaller renal volume (and fewer nephrons), extremely premature neonates achieve similar eGFRs at corrected term as term-born neonates, likely through single nephron hyperfiltration. Extremely premature neonates also show evidence of glomerular injury. There are more than 15 million preterm (birth before 37 completed weeks of gestation) births globally per year, and the number is increasing . PrematuCurrently, microalbuminuria is used as an early indication of glomerular pathology . MeasuriWe carried out a study to determine the impact of prematurity on renal development in a cohort of extremely premature neonates. The primary outcomes were nephrinuria and albuminuria; renal volume (a surrogate for nephron number) and glomerular filtration rate were secondary outcomes.This prospective case-control study was conducted in the Department of Neonatology, Townsville Hospital, Queensland, Australia. The hospital is a tertiary perinatal centre that caters for a region with more than 10,000 births each year. The study was conducted from August 2014 until October 2016. The neonates recruited in this study are part of a larger ongoing study that investigates the relationship between prematurity, retinal vascularisation and renal development in preterm and low birth weight neonates. Preterm neonates at less than 28 weeks of gestation (extremely premature neonates), with birth weights between the 10th and 90th centile ), admitted to the neonatal department during the study period were eligible to participate in this study. Neonates with congenital abnormalities or syndromes were excluded. Preterm neonates were recruited and followed until discharge. Once recruited, the preterm neonates underwent their first assessment at 28 weeks postmenstrual age (PMA) and a second assessment at 32 weeks PMA and a final evaluation was undertaken at 37 weeks PMA. PMA for the preterm neonates was defined as follows: PMA = gestational age at birth (weeks) + postnatal age in weeks. A cohort of term neonates admitted to the neonatal unit with minor neonatal conditions such as jaundice or feeding problems were recruited into the control group.During each assessment, the neonates underwent renal ultrasonography and venepuncture for cystatin C (CysC) measurements with a concurrent random urine analysis for albumin-creatinine (ACR) and nephrin-creatinine (NCR) ratio measurements.Analysis of microalbumin was performed on randomly collected urine samples using the Beckman Coulter microalbumin immunoturbidimetric assay on the automated Unicel DxC analyzer . The assay was calibrated using the SYNCHRON Systems MA calibrator specifically for urine assays , and this calibrator is traceable to the International Federation of Clinical Chemistry reference.Analysis of human nephrin was performed on randomly collected urine samples using the Exocell Human-Nephrin ELIZA assay . The range of the assay is 0.031 to 2.0 μg/mL. The intra- and inter-assay coefficients of variation for samples with concentrations in this range have been found to be < 10%, and this was confirmed under our experimental conditions . The NepGFR (ml/min per 1.73 m2) = 75.94/[serum cystatin C1.17]) ) .L), anteroposterior diameter (AP) and transverse diameter (W) were measured for both kidneys. Kidney volume  was calculated according to the following formula: KV = (π ∕ 6 × L × W × AP)  weeks, with a mean birth weight of 886 (179) g. At 37 weeks PMA, the mean weight of the premature group was 2416 (328) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g.P = 0.028). However, there was no significant difference between NCR at 37 weeks PMA and levels in term neonates . There was also a statistically significant in decline of ACR from 32 to 37 weeks PMA . ACR at 37 weeks PMA was however significantly higher compared to controls .There was a statistically significant decline in NCR from 32 to 37 weeks PMA  cm3 by 37 weeks PMA (P < 0.0001). TKV at 37 weeks PMA was significantly smaller compared to term control (19.2 (3.7) vs 26.3 (7.0) cm3; P < 0.0001). Figure P = 0.07). There was also no statistically significant difference in the eGFR in premature neonates at 37 weeks PMA when compared with term infants . Table The TKV almost doubled from 10.3 2.9) cm.9 cm3 atPremature neonates in our cohort have smaller renal volumes (hence reduced nephron number) compared to term neonates. Despite this, their eGFRs were the same as those measured in term neonates. We postulate that preterm babies, despite having fewer glomeruli, achieve a similar eGFR to their term counterparts by single nephron hyperfiltration. This sets them on a trajectory for chronic renal diseases in due course, as proposed by Brenner et al. .Urinary NCR was elevated in preterm neonates in early postnatal life, but subsequently, it declined and by 37 weeks PMA, there was no significant difference between premature and term neonates in NCR. To the best of our knowledge, this is the first time urine nephrin-creatinine ratio has been measured in preterm and term neonates. Previous studies have investigated nephrin excretion in adults and in women with preeclampsia . NephrinAbnormal extra uterine glomerular development may be the result of ischaemia of the outer still developing nephrons, which are the most immature. Pappenheimer and Kinter proposed that cell-free blood is “skimmed” from the periphery of the intralobular arteries to enter the afferent arterioles of deeper glomeruli . Animal Renal toxicity from antibiotics is an additional potential cause of impaired renal function in preterm infants. In our department, a combination of beta-lactam antibiotic (penicillin) and aminoglycoside (gentamicin) is often used as first-line antibiotics for 5 to 7 days to treat early-onset sepsis. This combination is the preferred choice based on the microbial profile observed in our department . The secThe presence of albumin in the urine could indicate either immaturity of renal glomerular function, tubular function or both. Studies designed to investigate this show that unlike their term counterparts, preterm neonates show high variability in urinary albumin levels between individuals . TsukahaThe main limitation of our study is that our recruitment rate is approximately 50%. The predominant reason is that nearly half of our admissions are neonates from regional areas, who are often transferred back to health facilities nearer to home after 32 weeks PMA for ongoing care. This limits the availability of the neonates for full participation in our study. There is approximately 3 weeks in gestational age difference between term (control) and premature (at term corrected) groups. Term birth is defined at any birth after 37 weeks of gestation, up to 42 weeks. To recruit term neonates at the exact same gestation will be ideal, but more challenging in clinical practice. Furthermore, nephrogenesis is complete between 34 and 36 weeks of gestation ; hence, Despite having smaller renal volume (and reduced nephron number), premature neonates achieve a similar eGFR as term neonates through glomerulo-hyperfiltration. They also show evidence of glomerular injury in the early neonatal period as demonstrated by nephrinuria and albuminuria. This may be due to a combination of abnormal glomerular development, ongoing ischaemia and the use of potentially nephrotoxic antibiotics. By term equivalence, nephrinuria returns to normal but albuminuria remains abnormal. Calculated glomerular filtration rate in the preterm infants is also normal at term equivalence in spite of the relatively small kidneys, strongly suggesting the presence of single nephron hyperfiltration. The hyperfiltration in preterm born infants may predispose them to continuing loss of additional nephrons and a higher risk of earlier-onset renal failure.


Submental dermoid cysts are uncommon midline cysts which occur due to entrapment of ectoderm between the second and third branchial arches during embryogenesis. Most dermoid cysts of the head and neck are benign, but rarely malignant transformation may occur. To the best of our knowledge, this is the first report of a carcinosarcoma arising in a submental dermoid cyst.A 42-year-old Sri Lankan Tamil man presented with a large cystic swelling in his submental region which was diagnosed as an extensive submental dermoid cyst. The cyst had been asymptomatic for 11 years but there was sudden enlargement and pain during the past 2 months. On surgical removal, a primary carcinosarcoma arising from part of the cyst wall was identified. After completion of radiotherapy, the disease was well controlled and he was disease free at 18 months.Although extremely rare, a dermoid cyst of the submental region can undergo malignant transformation. It can be successfully treated with surgical excision and radiotherapy. Dermoid cysts are ectodermal inclusion cysts which arise in many parts of the body. Dermoid cysts are most frequently seen in the coccyx 44.5%) and ovaries 42.1%), followed by the head and neck %, follow. Accordi4.5% and Clinically, dermoid cysts expand slowly over many years. Although congenital, DCFM may occur at any age after birth (average 15 to 35 years). Gender distribution is almost equal . DCFM arA 42-year-old Sri Lankan Tamil man presented with a large cystic swelling in his submental region. There were no obvious intra-oral extensions. The cyst had enlarged gradually over 11 years but there was rapid enlargement over the last 2 months. Apart from discomfort and pain, which was of recent onset, he was asymptomatic.A computed tomography (CT) scan showed a well-demarcated cyst in his submental region measuring 4×5.4×6 cm. A solid mass of 1.4×2.9 cm was also noted at the medial margin of the cyst wall and appeared suspicious. The adjacent soft tissues and his lymph nodes were uninvolved.The lesion was surgically removed under general anesthesia using a submental approach Fig. . On macrThe lesion was completely excised by surgery. Radiotherapy was started 4 weeks and 3 days after surgery, following complete healing of the surgical wounds. An equal dose of radiotherapy was administered to the primary site and bilateral neck to include level I to III . Concomitant chemotherapy was not administered considering the microscopic nature of the primary disease, absence of distant metastasis in CT scan (neck and lungs), and potential side effects. Radiation-induced mucositis and dry mouth were the most significant complications of radiotherapy and were managed conservatively. He was free of recurrences at review at 18 months.Malignant transformation in a dermoid cyst is rare (less than 2 %) and is usually seen in ovaries and testes . SquamouThe pathogenesis of a carcinosarcoma is explained by multiclonal or monoclonal hypotheses. The multiclonal hypothesis describes the origin of the two forms of malignancies from separate epithelial and mesenchymal cell lines . In contThe exact cause for malignant transformation within the cyst wall is uncertain. A diameter more than 10 cm, age more than 45 years, rapid growth, thickening of the cyst wall, and adherence to an adjacent structure are considered risk factors for malignant transformation in dermoid cysts and teratomas in the ovaries , 12. In Malignant transformation was clinically suspected due to the sudden increase in size and associated pain. Therefore, we recommend that clinicians be vigilant of malignant change in cases of rapid enlargement of a dermoid cyst. Surgery and radiotherapy helped to control the disease and our patient is disease free at 18 months. Due to the rare nature of the disease, a treatment protocol cannot be recommended. Furthermore, a long-term follow up of at least 5 years is required to comment on the success of treatment.


Using register data from the Finnish Census Panel, this paper studies the relationship between the use of the child home care allowance and second and third births among women aged 20–44 in Finland during the period 1992–2007. Discrete-time event-history analysis is applied to examine (i) whether women taking up the child home care allowance while their previous child was under the age of 3 have a higher risk to proceed to subsequent childbearing, (ii) whether these women proceed to a further birth more quickly, and (iii) whether the risk to proceed to a subsequent birth is related to educational level. The results show that women using the allowance have a higher risk of having a second and a third birth than women not using it. The risk of having a second birth is higher than that of having a third birth. Also, women using the allowance get their subsequent child sooner than women not using the allowance. No large educational differences in the effect of allowance use are found for second or third births. Although Finland, as the other Nordic countries, has higher fertility than many other Western countries, its fertility rate is below the replacement level [defined as a total fertility rate (TFR) 2.1]. Therefore, Finland, like many of its Western counterparts, will face problems with an aging population—accompanied by a decrease in the share of people in working ages implying future difficulties in maintaining social services associated to a welfare state. Still, the relatively generous family policies, including paid parental leaves and publicly subsidized childcare, are likely to be, at least partly, a reason for Finland not being one of the European countries with lowest-low fertility (defined as a TFR at or below 1.3) Adsera .Child home care allowance is an important component of Finland’s family policy. It is a benefit paid to a parent with a child under the age of 3 who does not use publicly financed childcare services. The purpose of the allowance is to increase parents’ flexibility in combining paid work and childcare as well as to allow them to spend more time with their children. The policy may, however, also lead to increased childbearing. Although the policy was intended to be gender neutral, the allowance is used almost exclusively by mothers. Hence, mothers’ labor market attachment is reduced which may decrease the opportunity costs of having another child.Based on a 10% sample from population registers, this paper explores the relationship between second (third) birth and the uptake of the home care allowance in Finland during the period of 1992(3)–2007. This study examines whether the users of the allowance have a higher risk of proceeding to subsequent childbearing—second and third births—than those not using the allowance. The study also looks at timing differences, i.e., whether the allowance users proceed to a subsequent birth more quickly than non-users. As both fertility patterns, i.e., transition to second and third births, and the use of home care allowance are assumed to differ by education, also potential differences by education in the effects of the allowance on subsequent births are investigated. The overall effects and the timing differences are studied separately. However, as selection effects may exist, the analysis cannot demonstrate any causality between allowance use and subsequent childbearing.There has been an ongoing debate in family politics on how to increase fertility while not decreasing female employment. A lot of research has looked at fertility and labor market outcomes. This study focuses on the relationship between a specific family policy that involves a cash transfer, encouraging women to stay at home instead of being active in the labor market, and the transition to second and third births. To date, there is only one Finnish study Vikat  on this Finland followed the trend typical of many Western European countries implying a high TFR after World War II and a subsequent decrease following the baby boom. The TFR has been relatively stable varying approximately between 1.6 and 1.9 since the mid-1970s . The allowance consists of two parts: the basic flat rate allowance (341 euros per month in 2016) is given separately for each eligible child, and a means-tested amount (at maximum 183 euros per month in 2016) which depends on the income and size of the family  families receiving child home care allowance, a parent stays at home to care for the child , only about 29% of the users use it for less than 7 months and about 45% of the users for more than a yearHow to organize the care of children in relation to employment is an important decision that families encounter. The theory of the allocation of time by Becker  providesDue to the lower opportunity costs of childbearing, low-income and low-educated women may be more likely not only to have children but also to proceed to subsequent childbearing than women with high education who often have higher income and human capital. According to Becker , women’sInstitutional factors in the form of generous family policies, such as public childcare and home care allowance in particular, are found to be related to increased fertility –2007 because the dependent variable, i.e., second (third) birth, relies on information from the previous year. Thus, inferring a first birth in year Because the study examines the relationship between the use of home care allowance and fertility, and the allowance is mainly used by mothers, the unit of analysis is women. Thus, the population of the study is women aged 19–44 (within fertile ages) between 1991 and 2007, who had a first (and a second) birth during this period. The purpose is to compare the transition to second and third births between mothers who used the home care allowance at some point when the previous child was of eligible age to those who did not use it in order to answer the research question.P(t) in discrete-time is the conditional probability that an event—in this case the annual probability of birth of a second (third) child—will be experienced at a certain time (t) by a certain individual given that it has not been experienced earlier by that individual. The discrete-time logit regression model applied here, takes the following form:α(t) is a set of constants varying by time, β1 is a vector of coefficients for time-constant control variables , and β2 is a vector of coefficients for time-varying control variables . The annual probabilities are combined in a way that allows women to contribute to the risk each year, while removed from the risk pool after childbirth.Discrete-time event-history analysis is applied in estimating the risks of second and third birth for users of the home care allowance in comparison to the non-users. Discrete-time is applied because time is measured in years Allison . The hazBecause patterns of fertility differ by parity, the models for second and third births are calculated separately. Thus, there are two time processes: transition to second birth and transition to third birth. For second (third) birth, the time variable is time since first (second) birth, i.e., time starts in January the year after the first (second) birth for a woman aged 20(21)–44 years, and stops at the event, i.e., second (third) birth. Censoring occurs either at the age of 45, death, emigration, or at the end of the period studied, i.e., year 2007, whichever comes first.2 of the mother at previous birth, marital status, educational level, and calendar year.Four main models were fitted to analyze the transitions to second and third births. Model 1 includes years since the previous birth and the use of home care allowance. It is applied mainly to see if there are differences in the risk of birth between the two groups—mothers not using the allowance and mothers using the allowance while the previous child was under the age of 3—but also to analyze the timing of subsequent birth. Model 2 adds a number of control variables, i.e., age and ageModel 3 also includes an interaction between years since the previous birth and allowance use, and it is applied in order to see if the groups differ in the timing of the next birth. Model 4 is similar to model 2 but additionally includes an interaction between the allowance use and educational level to study the differences in the effects of the allowance by education. Due to the large data size, a considerable part of the estimates becomes significant. For this reason, significance is shown only if the estimates are significant at or below the level of 1%.t) for the previous child during the eligible years. Being a time-varying variable on whether the allowance has ever been used during eligibility, this specification differs from one in which the variable would take the value one only in the years of actual usage. The latter would assume an immediate fertility effect during the eligible years and is thus less plausible.The time variable measures duration, i.e., time since previous birth, as explained in the method section. The main independent variable is a binary dummy indicating whether the mother received the home care allowance (when the previous child was eligible for it) while being at risk of second or third birth, respectively. For the risk of second (third) birth, the variable is zero as long as the mother did not receive the allowance for the first (second) child, and one from the year the allowance was received. If the allowance was not received by the time the previous child turned three (the upper age limit for usage), the variable took the value zero for the entire spell at risk. If the allowance was received, the variable was one starting from the year in which it was used until the end of the spell at risk. Thus, this variable measures whether the mother used the benefit  of the births are not included in the data. In order to reduce potential bias, only a child under the age of 3 in the household is considered as a new child as there is no such information for younger ages in the data.The dependent variable—whether one gets a second or a third child or not—is measured by comparing the number of children in the household across years, thus assuming that the woman does not have children outside the household. This means inferring a birth occurring only if a new child appears in the household in year Table Sociodemographic characteristics such as mother’s age at previous birth, marital status, educational level, and calendar year are adjusted for in the analyses. These control variables represent factors that may influence both fertility and the use of home care allowance. The age of the mother at previous birth is a time-constant covariate measured in years and it is also measured non-linear, by additionally including a quadratic age term. The variable indicating marital status is annually time-varying and is measured as zero for non-married and one for married. Thus, the non-married category comprises single, those living in a non-marital union as well as divorced and widowed. Calendar year is a time-varying covariate measured in years.Education is also a time-varying variable comprising four educational groups: no secondary education, secondary education, lower tertiary education (including post-secondary non-tertiary education and lower level tertiary education) and upper tertiary education . This categorization represents the structure of the Finnish educational system . There is a clear difference between married and unmarried mothers, as the former have approximately 2.3 times as high a risk of having a second birth compared to unmarried mothers. Also, there is a positive gradient of education on the risk of having a second birth: women with upper tertiary education have 46% higher risk of having a second child than women with no secondary education.As Model 2 shows, the age of the mother at first birth is found to increase the risk of having a second child. Instead of increasing linearly, the effect of mother’s age is curvilinear—being first positive (>1), then it levels out and becomes negative (agep < 0.01) compared to Model 2 except for Model 4 for third birth. This means that adding the interaction between years since the previous birth and allowance use as well as the interaction between the educational level and allowance take-up provides a more complete picture.According to the goodness-of-fit test (available by request from the author), Models 3 and 4 give an improved fit  following the first birth than those not using the allowance. Figure Figure The results for third birth are very similar to those for second birth, though mostly smaller in extent. As Model 1 shows, women using the allowance have approximately 1.7 times as high a risk of having a third child as those not using the allowance. Model 2 shows that, unlike for the second birth, mother’s age at previous birth decreases linearly the risk of having a third birth, i.e., the older the mother when having her second child, the lower the risk for her to have a third child. For marital status, the pattern is similar for third birth but the estimate is not as strong as for the second birth. Married mothers are found to have 76% higher risk of having a third birth than unmarried mothers. In regard to educational level and the risk of a third birth, the pattern differs somewhat from the one for the second birth. Yet, also the risk of having a third birth is highest for the most educated women, i.e., those with upper tertiary education.For third birth, the pattern for the interaction between allowance take-up and time since previous birth, as shown in Fig. In summary, the main results for the second and third child are rather similar in that they show the uptake of the child home care allowance to have an effect on the risk of having an additional child. This is in line with the expectations. The results also reveal, as shown in Figs. Cash-for-care benefits have been a debated topic in Finnish politics since the second half of the twentieth century. The child home care allowance has been criticized for strengthening traditional gender roles by encouraging mothers to stay at home, thereby decreasing their labor market attachment. For this reason, and as the allowance is mainly used by women, it has often been labeled a “woman trap” . Thus, the results from this study support the hypothesis that women using the home care allowance have a higher risk of a second and a third birth, and they get a second and third birth sooner after the previous birth than those not using the allowance. The timing clearly matters: for the risk of second birth the difference between those using the allowance and those not using it is greatest in the third year since the first birth and then starts to decrease. This differs from previous findings from Finland which indicate the allowance take-up to be related only to a higher risk of third birth Vikat .However, the previous Finnish study Vikat  studied The findings from Norway  about the partner—that affect childbearing decisions and outcomes. Due to data restrictions, these variables are not included in the analysis. Because the factors mentioned above are not available, this study cannot examine potential causality. Moreover, the effect of the introduction of the home care allowance policy on subsequent childbearing is not studied here because it requires data both before and after the policy was implemented.Also, due to further data restrictions, the measure of allowance take-up used here is crude as it does not capture the length of the allowance use period. Therefore, the duration of allowance use and its effect on subsequent childbearing cannot be studied here. Yet, these are questions that would be interesting for future research, in addition to studying mothers using the allowance for both their first and second child. This may give more insight into how devoted the mothers are in terms of prioritizing family life and if the allowance is used for the spacing of a subsequent birth. Also, looking at the impact of allowance use on fertility by municipality, i.e., whether there are differences over time between municipalities that offer supplements to the allowance and municipalities that do not, would be interesting as it could bring one closer to answering the question of causality.The evidence presented in this paper, i.e., that women using the allowance proceed more often and more quickly to subsequent childbearing than those not using it, is to a large extent in line with the previous findings and supports the claim that the allowance prolongs mothers’ stay out of the labor market. If a mother using the allowance gets another child right before her previous child turns 3 years and then uses the allowance for the newborn child until the child reaches the age of 3, she might stay out of the labor market for 6 years in a row. Such a long absence is very likely to have a negative impact on one’s working skills and social capital, as well as on the overall attractiveness in the labor market. To conclude, regardless of the importance of family time and parental care, in reality, as noted by Sipilä et al. , p. 60 u


This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson’s disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra . In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression. Parkinson’s disease (PD) is a slowly progressing neurodegenerative movement disorder clinically characterized by rigidity, tremor, and bradykinesia that affects about ten million people worldwide . While tEvidence for an involvement of microstructure in PD comes from neuropathological studies that indicate Lewy neurites and Lewy bodies, hallmarks of PD, evolve according to a predictable topographical sequence along major fiber pathways, beginning in the brain stem and eventually advancing to neocortical regions . SeveralWe report longitudinal DTI findings from a large cohort of PD patients (n = 122) relative to findings in healthy aging (n = 50). Our specific aims were: (1) to determine the degree and regional distribution of microstructural integrity decline in PD relative to healthy aging; (2) to test whether this PD-specific microstructural decline correlates with the decline of motor and cognitive functions, as well as the progression of PD biomarkers, such as changes in dopamine deficit and in CSF α-synuclein concentration.123Ioflupane dopamine transporter (DAT) imaging [www.ppmi-info.org) at baseline and after 12 months. The selection of these subjects was driven by the technical capabilities of the PPMI participating centers to obtain DTI in a rigorous and standardized fashion. Subjects were excluded if they withdrew from the study, failed image quality, or were diagnosed with PD but had no evidence of dopaminergic deficit on DAT, the so-called SWEDD group. Finally, 172 subjects  who had two sequential MRI scans on average 12.6 ± 1 months apart were included. A graphical summary of the subject selection is shown in PD patients and healthy control (HC) subjects in this study were enrolled in PPMI. In brief, PPMI is an ongoing observational, international, multicenter study  aimed to identify serological, genetic, spinal fluid and imaging biomarkers of PD progression in a large cohort of newly diagnosed PD patients. The study was launched in June 2010 and has successfully completed its enrollment goal of 400 PD patients and 200 HC subjects. At baseline, PD patients had to be older than age 30, diagnosed with PD within the past 2 years, have a Hoehn and Yahr (H&Y)  stage no123Ioflupane single-photon emission computed tomography (SPECT). The DAT images were centrally reconstructed, attenuation corrected and analyzed with a standardized volume of interest template for extraction of regional count densities (http://www.indd.org/). Putaminal DAT binding ratios were calculated from SPECT imaging as DAT counts in the left and right putamen DAT counts from the occipital lobe as reference (http://www.indd.org/).The subjects were assessed with a wide spectrum of clinical tests at every study visit, including the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)  and the http://www.ppmi-info.org/). CSF β-amyloid (Aβ1–42), tau proteins total (t-Tau) and phosphorylated (p-Tau181) concentrations were analyzed at the University of Pennsylvania as previously described [Cerebrospinal fluid (CSF) collection was performed at each study site as described in the PPMI biologics manual (escribed . CSF α-sescribed . For quaescribed .http://cmrm.med.jhmi.edu) [For quantitative MRI measurements, the anatomical and DTI images were first visually inspected for egregious image artifacts and then processed using an automated processing script designed for longitudinal data analysis. The workflow is illustrated in hmi.edu) . To reduhttp://www.r-project.org/). Linear mixed-effects models were used to estimate rates of DTI, clinical, DAT and CSF biomarker concentration changes by group. Each measurement  of all subjects at all time points were entered as the response variable, time variation and interacted by diagnostic group were entered as fixed effects in the model. Variations across subjects were entered as random effects in the form of a random intercept. Age, gender and medication status were added as covariates. Medication status dichotomized patients into a group that chose to take PD medication during the first year of the study and another group that stayed off PD medication, though all patients were free of PD medication at the time of their MRI baseline scans. Because most PD patients in this study (95%) had unilateral onsets of motor symptoms, a side-by-time interaction term was included in linear mixed-effects models to further test laterality of DTI changes. Side was defined as ipsilateral or contralateral region, according to each patient’s clinically dominant side of Parkinsonian symptoms onset. For all HC subjects and one PD patient with symmetrical symptom onset, left and right DTI values were averaged [q < 0.05 [Statistical tests were carried out using R Project , the midbrain , and the thalamus . Individual trajectories of the annual FA changes in these regions are depicted in PFDR = 0.03) in PD patients involved the contralateral cerebral peduncle, the ipsilateral tapatum of the callosum as well as contralateral superior occipital and ipsilateral middle frontal white matter. PD patients also showed a steeper rD increase over time than HC subjects in the bilateral thalamus , the cerebral peduncle , the midbrain , and the substantia nigra . In addition, less prominent rD changes  in PD involved the body and splenium of the corpus callosum, the contralateral external capsule and ipsilateral superior temporal white matter. PD patients also had a steeper aD increase over one year than HC subjects bilaterally in the thalamus  and to a lesser extent  in the bilateral midbrain, ipsilateral retrolenticular part of internal capsule, contralateral inferior fronto-occipital fasciculus and in ipsilateral superior temporal white matter. Differences in DTI changes between the ipsilateral and contralateral sides in PD patients were not significant.Brain regions with significant group differences in annualized DTI rates are displayed in PFDR = 0.03, r = -0.22 for rD and PFDR = 0.01, r = -0.25 for aD; contralateral: PFDR = 0.001, r = -0.30 for rD and r = -0.32 for aD).Correlations between clinical progression and DTI changes are summarized in PFDR = 0.01, r = 0.25) and a steep rD increase  in the contralateral substantial nigra. Growing dopamine deficiency also correlated with FA reduction  in the contralateral thalamus.Correlation between changes in putaminal DAT binding and changes in regional DTI is shown in PFDR = 0.03, r = -0.34) as well as aD  in the ipsilateral substantia nigra. Similarly, more decrease in CSF total-Tau concentration correlated with a steep FA reduction  as well as a steep rD increase  in the ipsilateral substantia nigra. Scatter plots of the most prominent correlation findings are illustrated in Correlations between changes in CSF bio-marker concentrations and DTI are also listed in The main finding of this study is that PD is associated with higher than normal rates of regional DTI changes that involve primarily the substantia nigra, the thalamus and midbrain regions. This regional pattern of DTI changes is consistent with neuropathological reports of distributed neurodegeneration in PD . In addiThe finding of higher than normal DTI rates, especially FA and rD, in the substantia nigra, thalamus and midbrain is consistent with neuropathological reports ,24 that It is also interesting to note that abnormal DTI changes occurred in regions of deep association tracts such as the splenium and tapatum of the corpus callosum, the external capsule, cerebral peduncle, retrolenticular internal capsule, inferior frontooccipital fasciculus, and white matter regions underlying the middle frontal, superior occipital and superior temporal neocortices. According to Braak’s staging of PD, Lewy body pathology progresses to mesocortex and neocortices at later disease stages IV to VI. Whether the abnormal DTI changes in cortico-cortical pathways are predictive for advanced PD progression warrants further studies.This study found a strong positive correlation between increased changes in thalamic diffusivities (rD and aD) and progressive cognitive decline in PD patients. The thalamus is known for its role in cognitive behavior, including learning and memory, inhibitory control, decision-making, and the control of visual orienting response –30. A loThe finding of relationships between high DTI changes in the substantia nigra and increasing putaminal DAT deficiency in PD is novel. This finding links declining nigral integrity to striatal dopamine transporter deficiency, potentially via the nigrostriatal dopaminergic pathway. The finding is also in line with previous cross-sectional DTI results from PPMI subjects  and withThe positive correlation between increased nigral diffusivity (rD and aD) over time and diminished CSF α-synuclein concentration in a subsample of PD patients is also worth to discuss. Low α-synuclein in CSF has been proposed as a biomarker candidate for PD as the protein accumulates in Lewy bodies and Lewy neurites of the brain parenchyma ,17,33–35An interpretation of the DTI alterations in terms of their underlying microstructural origins is notoriously difficult, because DTI is sensitive to a broad spectrum of microscopic alterations in brain tissue, and the model-based concept of DTI has theoretical limitations that can mislead when the model is violated, such as in case of crossing-fiber bundles. In general, however, an increase in rD has been associated with demyelination whereas an increase in aD is thought to primarily indicate cell degradation and loss. Either of these changes theoretically leads to reduced FA. Although for most of the brain regions, decreased FA and increased diffusivity (rD and aD) occurred consistently together, in some regions FA changes dominated rD or aD changes and vice versa. We cautiously interpret these differences as index of the variability in microstructural alterations in PD. In addition, because of fundamental limitations in DTI, the degree to which the changes in gray matter areas reflect degeneration of passing fibers or of local gray matter remains unclear. This distinction can only be made with more technically advanced MRI methods, such as Q-space  or diffuThe study has several merits: First, this DTI study replicates two previous reports of progressive microstructural changes in the substantia nigra in PD on a larger sample across multiple MRI centers. The finding emphasizes that diffusion MRI of the substantia nigra is an important marker in assessing PD progression. Second, the study indicates that progressive microstructural degeneration beyond the substantia nigra, encompassing mainly the thalamus and the midbrain, occurs in early stages of PD. Third, the novel finding that microstructural degeneration in the substantia nigra is correlated with increasing dopaminergic deficits as well as abnormal CSF biomarker concentrations in PD implies that DTI can be useful for monitoring the course of the disease and also for assessing efficacy of treatment interventions. Lastly, the study demonstrates the practicability of multi-center diffusion imaging in PD.Several limitations of our study should be mentioned. The clinical diagnosis of PD was not confirmed by autopsy. Aside from diagnostic uncertainty, it is possible that some patients diagnosed with PD also had other comorbid neurological conditions that may have skewed the outcome of this study. Another limitation is that some patients went on PD medication during the first year of the study, which may have increased the variability in symptomatology across patients and thus reduced sensitivity to detect correlations between DTI and clinical changes. A statistical limitation is that contrary to a FDR corrected statistical threshold of p = 0.025, a Bonferroni correction for multiple comparison yielded no significant results. We can conclude with high confidence (97.5%) that DTI shows an effect of microstructural progression in PD, although we cannot say that any single significant result is accurate. Lastly, results of correlations between changes in CSF-biomarkers and DTI may be biased because there was no control of the subset of PD patients with longitudinal CSF biomarker data.S1 FileComplete list of PPMI authors and study investigators.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.