Antenatal exposure to Zika virus (ZIKV) is related to severe neurological manifestations. A previous study in Brazil reported an increased incidence of non-severe congenital heart defects in infants with diagnosis of congenital Zika syndrome but without laboratory confirmation of ZIKV infection in the mother or infant. The objective of this study is to report echocardiographic (ECHO) findings in infants with laboratory confirmed antenatal exposure to ZIKV.Cross sectional study of cardiologic assessments of infants born between November 2015 and January 2017 with confirmed vertical exposure to ZIKV in Rio de Janeiro, Brazil.The study enrolled 120 children with a median age of 97 days (1 to 376 days). In utero exposure to ZIKV was confirmed in 97 children  through positive maternal polymerase chain reaction (PCR) results during pregnancy or a positive PCR result at birth; 23 additional children (19.2%) had maternal positive PCR results during pregnancy and postnatally. Forty- eight infants (40%) had cardiac defects noted on ECHO. Thirteen infants (10.8%) had major cardiac defects . None of the defects were severe. The frequency of major defects was higher in infants whose mothers had a rash in the 2nd trimester of pregnancy, or who had altered Central Nervous System (CNS) imaging postnatally or were preterm.in utero ZIKV exposure have a higher prevalence of major cardiac defects, however none were severe enough to require immediate intervention. For this reason, guidelines for performance of postnatal ECHO in this population should follow general newborn screening guidelines, which significantly reduces the burden of performing emergent fetal or neonatal ECHOs in a setting where resources are not available, such as most Brazilian municipalities.Infants with  We performed cardiologic assessment of 120 infants born between November 2015 and January 2017 with confirmed vertical exposure to Zika virus (ZIKV). The diagnosis of ZIKV exposure was confirmed by PCR in maternal blood specimens and/or amniotic fluid during pregnancy and/or infant specimens including PCR of the cerebrospinal fluid (CSF) and/or urine following birth. Our study found a 10.8% incidence of structural heart defects in infants with a history of intrauterine exposure to ZIKV, a rate considerably higher than that observed in the general population. However, no patients were found to have severe structural heart defects. The presence of major defects was increased in infants whose mothers had a history of rash in the 2nd trimester, infants with altered CNS imaging and/or preterm infants. As severe heart defects requiring immediate intervention were not identified, guidelines for performance of postnatal ECHO in this population should follow the same criteria as the ones applicable to newborns in general, particularly since resources for performance of fetal and neonatal echocardiograms are not routinely available in most Brazilian municipalities Zika virus (ZIKV) is an arbovirus of the Flavivirus genus like Dengue virus (DENV) and Yellow Fever virus (YFV) . In respJust as there are no reports, prior to 2015, of severe neurological manifestations related to vertical transmission of any Flavivirus, there are no reports of congenital heart defects in patients with confirmed vertical exposure to these viruses. A study in 2015 in Pernambuco State, Brazil, with 103 patients with diagnosis of congenital Zika syndrome but without laboratory confirmation of ZIKV infection in mothers or infants showed an increased incidence of non-severe congenital heart defects .in utero exposure to the virus. The present study describes the cardiac findings identified in this population.With the increase in the number of studies ordered in mother-infant pairs with suspected or confirmed ZIKV infection in pregnancy, it becomes important to verify which tests are really necessary to promote better use of health resources in Brazil and elsewhere while still enabling optimal care for these patients . During We performed a cross-sectional study of infants born between November 2015 and January 2017 who had confirmed vertical exposure to ZIKV and were followed at our outpatient Pediatric Infectious Disease Clinic at the Fernandes Figueira Institute (IFF-FIOCRUZ). The infants who received echocardiograms were born either at IFF or other institutions with positive ZIKV maternal PCR results during pregnancy or positive PCR results at birth. Our institution is a national research referral center for high risk pregnancies and high risk infants. For this reason, during the Zika epidemic we were the major referral center in Rio de Janeiro for cases of suspected maternal or infant ZIKV infection.All infants had negative serology result for other congenital infectious including toxoplasmosis, rubella, cytomegalovirus, hepatitis B, C and HIV, in addition to no diagnosis of genetic syndromes potentially accompanied by congenital heart defects. None of the children had previous fetal ECHOs. The diagnosis of ZIKV exposure was confirmed by RT-PCR in a blood sample from the mother and/or in the amniotic fluid during pregnancy and/or in infant specimens including PCR of the cerebrospinal fluid (CSF) and/or urine following birth.The following data were abstracted from medical records: maternal history of rash during pregnancy, gestational age at birth, diagnosis of congenital Zika syndrome, results of infants CNS imaging, and PCR results of maternal and infant specimens.Minor ECHO defects were defined as: persistent foramen ovale (PFO), patent ductus arteriosus (PDA) in premature infants up to three months of age or in term infants up to 15 days of age, physiological tricuspid regurgitation, and physiological pulmonary branch stenosis in premature infants. All other ECHO defects were considered major structural defects. Congenital heart defects that required any therapeutic intervention in the first days of life were considered severe structural heart defects .Infant cardiologic evaluation included a complete clinical examination and full 2D and M-mode transthoracic echocardiography with pulsed and continuous Doppler and color Doppler, performed by pediatric cardiologists from the Pediatric Cardiology Department of IFF. The equipment used was the Siemens Acuson X300 Echocardiography system, and the studies were performed without sedation. The cardiologic evaluation was performed between 1 and 376 days of age.Data analysis was descriptive and used absolute and relative frequencies of qualitative variables, like gender, PCR results and major ECHOs defects. Additionally, the 95% confidence interval (95% CI) of relative frequencies was provided. Age in days was described by the median, minimum and maximum. The association between qualitative variables and major ECHO defects (presence or absence) was based on the comparison of absolute and relative frequencies, considering differences of at least 10 percentage points (pp) as indicative of a potential difference between patients with and without major ECHO alterations. In addition, individual data were provided on all patients with major ECHO defects. Due to the study’s descriptive design and the small number of major ECHO defects, we avoid using statistical testing and we added Fisher exact test as only an additional information. The R software version 3.3.3 and the package epiDisplay were used to perform the data analyses.The study was approved by the Institutional Review Board of the Brazilian National Institute of Infectious Diseases (INI-FIOCRUZ). All parents or guardians provided written informed consent. All data analyzed were anonymized.in utero exposure to ZIKV by a positive maternal PCR during pregnancy or a positive PCR result at birth. A total of 23 additional children  had positive maternal PCR results during pregnancy and a positive PCR result at birth. A total of 84 infants in the cohort had microcephaly and 25 had the diagnosis of vertical exposure to ZIKV because microcephaly was diagnosed on the morphologic ultrasound during pregnancy or were born with congenital Zika syndrome.Among 186 children who met inclusion criteria  120 were brought by their parents or guardians to the pediatric clinic for a cardiac consult and performance of an echocardiogram. Sixty-six children were excluded from the study because they did not come for an echo study. The median age among the 120 participants was 97 days (1 to 376 days) with equal distribution of boys and girls. Eigthy nine subjects  were born at term. Ninety-seven infants  had confirmation of ostium secundum type were present in three patients . Physiological tricuspid regurgitation was seen in three patients  and arterial pulmonary hypertension in one infant. No cases of altered ventricular function, pericardial effusion, or coronary anomalies were found. One additional patient presented with left ventricular hypertrophy without dysfunction which was unrelated to the mother’s gestational diabetes. Two infants had more than one defect.Forty-eight infants  had cardiac defects noted on ECHO. A PFO was the most common finding responsible for 72.9%  of ECHO abnormalities. Infants with a PFO had a median age of 29 days, ranging from 2 to 372 days. PDA was found in 6 patients . The median age of infants with PDA was 98 days, ranging from 2 to 288 days. Ventricular septal defects (VSDs) were seen in 4 patients  all of them were small perimembranous VSDs. Atrial septal defects (ASDs) of the small Of 48 infants with ECHO abnormalities, 13 infants had major structural defects noted, representing 10.8% of 120 infants (95% CI = 5.9% to 17.8%). None had severe structural cardiac defects. All infants in the group with major structural defects had positive PCR results in CSF and/or urine at birth as seen in Major heart defects were 14% more frequent in preterm infants than in term babies, 10% higher in infants whose mothers had a history of rash in the 2nd trimester as compared to other time points or no rash, and 11%. higher in infants with altered CNS imaging tests. Despite this trend, no statistically significant association was identified. No difference in frequency of cardiac defects was found between infants with and without microcephaly (46.1% in the group with major cardiac defects and 42.9% in the group without cardiac defects). Distribution of findings in infants with normal and abnormal echocardiograms are outlined in Our study found a 10.8% (IC 95% = 5.9% to 17.8%) prevalence of major structural heart defects in infants with a history of intrauterine exposure to ZIKV, a rate considerably higher than that observed in the general population. However, no patients were found to have severe structural heart defects. These results are similar to those of a study from the state of Pernambuco, Brazil, which evaluated infants with congenital Zika syndrome but without laboratory confirmation of intrauterine exposure to ZIKV. That study demonstrated an incidence of 13.5% of major ECHO defects but also found no severe congenital heart defects .The prevalence of major cardiac defects in our study was 10 times higher in ZIKV infants (13 cases in 120 infants) than that observed in the general population. The reported prevalence of congenital heart defects in live born infants in Atlanta and China respectively was 8.1 to 11.1/1,000 , with a Except for two infants with left ventricular hypertrophy and pulmonary arterial hypertension, we found left-to-right shunts in all infants with major cardiac defects, which is similar to that reported in previous epidemiologic studies of congenital heart disease. ,14,15.In our study the finding of PDA in three neonates who were less than 15 days of age was considered physiological, and the presence of a PFO in 29.2% of our subjects should be analyzed within the context of the infants’ age . It is known that in postmortem analyses, the incidence of PFO is 27.3%, but taking age into account, a study showed an incidence of 34.3% in the first three decades of life and a progressive decrease in later decades . HoweverThere was a trend in our study for major heart defects to be more frequently observed in infants with preterm birth, in those whose mothers had second trimester of pregnancy infection and in infants who had altered CNS imaging studies. Our findings however were not statistically significant, but this could be a function of sample size. We believe these factors merit further investigation in future Zika infant cohorts that have larger sample sizes.in utero ZIKV-exposure. None of the infants needed cardiac procedures or surgery in the first days to months of life. We believe postnatal assessments performed routinely in maternity hospitals in Brazil which entail a newborn physical exam and a newborn oxygen saturation test prior to discharge from the hospital would be sufficient for identification of infants with major structural heart defects. Our findings support the recommendation that fetuses or infants with suspected or confirmed ZIKV exposure in utero should receive the same cardiac follow-up recommended for pregnant women and newborns in general.Although our study found a higher prevalence of structural cardiac defects than anticipated, it did not demonstrate any severe structural heart defects in infants with Our study is the first to report echocardiogram findings in infants with laboratory confirmed antenatal exposure to ZIKV. Given the seasonality of ZIKV infection, it is difficult to predict whether it will be possible in the future to report on echocardiographic findings of a larger series of infants with laboratory confirmed diagnosis. It would be important however, to be able to replicate these findings in studies evaluating a larger number of subjects.A higher frequency of major heart defects was noted in ZIKV exposed infants as compared to the general population. None of these defects, however were considered severe. In light of our findings, we believe recommendations for fetal echocardiograms in pregnant women with confirmed ZIKV infection and performance of postnatal ECHOs in their infants, should follow the same criteria as those established for the general population of mothers and infants. This entails a complete physical exam at birth and measure of oxygen saturation prior to discharge. Recommendations for emergent echocardiographic evaluations in the neonatal period for all Zika exposed infants do not appear to be warranted, as a higher prevalence of severe heart defects was not identified. This recommendation is very relevant to scenarios where performance of fetal and pediatric echocardiograms is not feasible, including most Brazilian municipalities which lack the ability to perform these studies. All patients in the study with positive ECHO findings are being monitored prospectively so that the spontaneous closure or possible complications are readily identified.S1 Checklist(DOCX)Click here for additional data file.


Current European Guideline for resuscitation recommends a centrally positioned umbilical venous catheter as the best option for administering necessary drugs. Especially in preterm infants, a frequently used alternative is the peripheral venous catheter.2) and heart rate (HR) were measured using pulse oximetry at the right hand/wrist. In each neonate, either NIRO 200NX  or INVOS 5100C  were used to measure cerebral tissue oxygenation index (cTOI) and cerebral regional oxygen saturation (crSO2), respectively. SpO2, HR, and cTOI/crSO2 during and 1 min before and after successful venous punctures were analyzed.Two randomized controlled studies were conducted at the Division of Neonatology, Medical University of Graz. During neonatal resuscitation, a standardized protocol was filled out by an uninvolved observer including time points after birth of all attempts of venous puncture, time point of successful venous puncture, and total number of needed attempts. Arterial oxygen saturation  1–2] to establish a peripheral venous catheter. In median, intravenous (IV) catheterization was successfully established 5 (IQR 4–9) min after birth. SpOPeripheral IV catheterization during postnatal stabilization of preterm infants is feasible and successful in most of the cases at first attempt. Gaining intravenous (IV) access is often needed within minutes after birth, especially in preterm neonates, for administering medications, fluids, and nutrients during postnatal stabilization . There aThe primary aim of the present study was to investigate how many attempts were needed to establish a peripheral IV catheter during postnatal stabilization. Secondary aims were (a) to determine the time needed to establish the peripheral venous catheter and (b) to investigate any potential side effects of the venous puncture on the vital parameters in preterm neonates.The present study is a retrospective analysis of exploratory parameters of two randomized controlled trials , 5 that via IV catheter  within the first 10 min after birth.Peripheral venous catheterization was the primary vascular access during the study periods. Preterm infants with gestational age <34 weeks were included into the analysis, if there was an intention to treat with medication 2) and heart rate (HR) were measured with the IntelliVue MP30 Monitor  using pulse oximetry at preductal level on the right hand/wrist. In each neonate, either NIRO 200NX  or INVOS 5100C  were used to measure cerebral tissue oxygenation index (cTOI) and cerebral regional oxygen saturation (crSO2), respectively. The sensor was positioned on the forehead in each infant. The sensor on the forehead was secured with cohesive conforming bandage . All variables were stored continuously every second in the multichannel system alpha-trace digital MM  for subsequent analysis.Arterial oxygen saturation , as appropriate. Categorical variables are presented as absolute and relative frequencies. Changes over time were evaluated using analysis of variance for repeated measurements. In cases when assumption of sphericity was violated as estimated by Mauchly’s test of sphericity, Greenhouse–Geisser correction was used.SPSS 23.0.0.2 (IBM Corp. 2015) was used for data analysis. A value of 2 was measured in 48/23 neonates). All 61 preterm neonates received respiratory support via face mask, and 10 neonates needed intubation subsequently during postnatal stabilization.Data of 61 of 70 preterm neonates were analyzed—9 neonates were excluded, because there was no intention to treat. They did not get IV catheterization during neonatal stabilization. Mean gestational age was 31.5 ± 2.2 weeks, and the mean birth weight was 1,527 ± 541 g. In median, it needed one attempt (IQR 1–2) to establish a peripheral venous catheter. In median, IV catheterization was successfully established 5 (IQR 4–9) min after birth, whereby in 38 (62.3%) preterm neonates, the peripheral venous catheter was established with the first attempt. All infants had monitoring of cerebral oxygenation , cTOI (p = 0.001), and crSO2 (p = 0.001) rose significantly. HR increased too, but the rise did not reach significance (p = 0.199).Arterial oxygen saturation, HR, and cTOI/crSOThe present study demonstrates that peripheral venous catheterization during postnatal stabilization of preterm neonates is feasible, and in the majority of patients (62%), only one attempt was necessary. The number of first-time success rate in our study was even higher than the previously reported by Legemaat et al. in NICU population .2 and cerebral regional oxygenation saturation, both rose, but changes were along the percentiles, which represent the physiological increase during the first 10 min after birth (The recent European Guideline  suggestser birth –10. FurtPeripheral IV catheterization during postnatal stabilization of preterm infants is feasible and successful in most of the cases at first attempt. In addition, the IV puncture during postnatal stabilization did not affect the physiological neonatal transition concerning arterial and cerebral oxygenation and HR.This study was carried out in accordance with the recommendations of Regional Committee on Biomedical Research Ethics with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Regional Committee on Biomedical Research Ethics.Conception and design: BU, NB-S, and GP. Collection and assembly of data: NB-S, BS, LM, GP, and BU. Analysis and interpretation of the data; critical revision of the article for important intellectual content; final approval of the article: NB-S, BS, LM, GP, BU, and AA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Executive functions are frequently a weakness in children born preterm. We examined associations of executive functions and general cognitive abilities with brain structure in preterm born adolescents who were born with appropriate weight for gestational age and who have no radiological signs of preterm brain injury on neuroimaging.The Stockholm Neonatal Project (SNP) is a longitudinal, population-based study of children born preterm (<36 weeks of gestation) with very low birth weight (<1501g) between 1988–1993. At age 18 years  134 preterm born and 94 full term participants underwent psychological assessment . Of these, 71 preterm and 63 full term participants underwent Magnetic Resonance Imaging (MRI) at mean 15.2 years (range 12–18 years), including 3D T1-weighted images for volumetric analyses and Diffusion Tensor Imaging (DTI) for assessment of white matter microstructure. Group comparisons of regional grey and white matter volumes and fractional anisotropy  and, within each group, correlation analyses of cognitive measures with MRI metrics were carried out.Significant differences in grey and white matter regional volumes and widespread differences in FA were seen between the two groups. No significant correlations were found between cognitive measures and brain volumes in any group after correction for multiple comparisons. However, there were significant correlations between FA in projection fibres and long association fibres, linking frontal, temporal, parietal, and occipital lobes, and measures of executive function and general cognitive abilities in the preterm born adolescents, but not in the term born adolescents.In persons born preterm, in the absence of perinatal brain injury on visual inspection of MRI, widespread alterations in regional brain tissue volumes and microstructure are present in adolescence/young adulthood. Importantly, these alterations in WM tracts are correlated with measures of executive function and general cognitive abilities. Our findings suggest that disturbance of neural pathways, rather than changes in regional brain volumes, are involved in the impaired cognitive functions. It is well known that preterm birth is associated with adverse developmental and cognitive outcomes  even in Impaired executive functions in adolescents and young adults born preterm are also reported by others –11, and In the present study, we wanted to investigate relationships between brain white matter microstructure and cognitive functions, particularly executive functions, in the cohort of preterm adolescents for which we have recently reported cognitive outcome at adolescent age . The speThe preterm participants of this study are part of the cohort that forms the Stockholm Neonatal Project (SNP), a longitudinal, population-based study of children born preterm with very low birth weight  between 1988–93, at Karolinska Hospital or Löwenströmska Hospital in Stockholm, Sweden. The gestational age range of the SNP cohort is 23–36 weeks (mean 28.1). This cohort has been followed prospectively since birth. The SNP cohort was psychologically assessed at 10 months , 20. At The longitudinal study was originally approved by the Ethics committee at Karolinska Hospital, and cognitive assessments at age 18 years, MRI, as well as continued use of the original data base was approved by the Regional Ethics Board of Stockholm (2007/46-31/3 and 2009/1229-32). All participants gave their written consent prior to the data collection.The assessment involved an extensive battery of cognitive tests, described in detail elsewhere . In the 3; axial Turbo Spin Echo T2-w images , and coronal Fluid Attenuated Inversion Recovery (FLAIR) images , and a 2D twice-refocused Spin Echo Diffusion dataset .Data were acquired on a 1.5 T MR-system  at Karolinska University Hospital in Stockholm, Sweden. The majority of the data were acquired between April 2005 and February 2006 (n = 119). The remaining data were acquired between October 2009 and December 2009 (n = 15). In between these two data collection periods, the scanner underwent a software upgrade. An analysis including the scanner as a confounding variable was performed and showed that this did not have an effect. The protocol included the following sequences: a high resolution 3D T1-weighted (w) Spoiled Gradient Echo (3D SPGR) image with TR = 24ms, TE = 6 ms, flip angle 30°, voxel size 0.98x0.98x1.5 mmImages were visually inspected for quality . Eleven 3D T1-w datasets  and 15 DTI datasets (11 preterm and 4 term born controls) of the original 134 datasets were excluded because of poor quality. The T1-w and T2-w images were assessed for radiological signs of preterm brain injury , and eight datasets from the original number of good quality datasets from the preterm group were excluded . None of the term born control datasets had radiological abnormalities. After exclusion of datasets from participants who were SGA at birth, those who had radiological signs of preterm brain injury on visual inspection of MRI, and the data sets with poor quality, the final dataset consisted of 52 preterm participants and 63 full term controls for voxel-based morphometry analyses, and 52 preterm participants and 59 term controls for the DTI analyses.The 3D T1-w datasets were pre-processed and analysed in SPM8 using the VBM8 toolbox . After cThe Diffusion MR data sets were corrected individually for Eddy current artifacts and realigned. The mean of the four reference images was used to estimate the extent of susceptibility-induced distortion. The two data sets were then combined into a single undistorted series, from which the diffusion tensor and fractional anisotropy (FA) maps were calculated.The processing and statistical analysis of the FA images followed the Tract-Based Spatial Statistics pipeline (TBSS ) made avVoxel-wise comparisons of GM showed smaller volumes in the preterm group compared to the term group in the frontal lobe ; the parietal and occipital lobe , and the temporal lobe . The preterm group had larger GM volumes in the temporal lobe (right and left fusiform gyrus), the limbic lobe, the anterior cingulate, the right insula, and right anterior amygdala. White matter volumes were smaller in the preterm group within the temporal lobe , but larger in the right insula.In the preterm group there were no positive or negative correlations between any of the executive function measures and GM or WM volumes at corrected  level. In the term born group, there were no significant positive or negative correlations between any of these measures and GM at corrected level. For WM, there was a significant positive correlation  with the score for attention and speed in the left frontal lobe .In neither the preterm group nor the term group were there any positive or negative correlations between VIQ or PIQ measures and GM or WM seen after correction for multiple comparisons .The preterm group had lower FA than the term born group in the inferior longitudinal fasciculus bilaterally, the external capsule bilaterally , the right anterior limb of the internal capsule, the left fornix, and the left occipital WM. There was no significant difference for the opposite contrast in any of the analyses.Results from the correlation analyses are shown in In the preterm group significant positive correlations between working memory scores and FA were present in the uncinate fasciculus bilaterally; the forceps minor, the retrolenticular part of the posterior limb of the internal capsule on the left; on the level of the anterior limb of the internal capsule bilaterally in the anterior thalamic radiation and the inferior fronto-occipital fasciculus, and the inferior longitudinal fasciculus bilaterally; on the level of the superior corona radiata the cortico-spinal tract and the superior-longitudinal fasciculus  on the left; the anterior thalamic radiation bilaterally.For the cognitive flexibility scores, significant positive correlations with FA were seen in the uncinate fasciculus bilaterally, the inferior fronto-occipital fasciculus bilaterally, the superior longitudinal fasciculus bilaterally; on the level of the internal capsule the right cortico-spinal tract, and the retrolenticular part on the left; the anterior thalamic radiation bilaterally; the right external capsule; on the level of the superior corona radiata the cortico-spinal tract, and the anterior thalamic radiation bilaterally.There were no significant positive correlations between FA and attention and speed scores at corrected level, although there were some trends in the right anterior thalamic radiation, the right inferior fronto-occipital fasciculus and the right superior longitudinal fasciculus (p < 0.06). There were no significant negative correlations between FA and any of the executive function scores at corrected level.In the term born group, no significant positive or negative correlations between any of the executive functions measures and FA were seen after correction for multiple comparisons.In the term born group, there were no positive or negative correlations between FA and IQ measures after correction for multiple comparisons.The main finding of this study is that there were strong correlations between microstructure of multiple WM tracts and several cognitive functions in the preterm adolescents, whereas this was not seen in the term born controls after correction for multiple comparisons. Importantly, these correlations were seen in a sample from which those preterm participants who were born SGA and/or had radiological signs of preterm brain injury were excluded. The well-defined and characterised cohort with stable cognitive abilities between the 5.5 year and 18 year assessments, the rigorous inclusion and exclusion criteria, and the application of rigorous statistical correction for multiple comparisons in the neuroimaging analyses, are particular strengths of this study. Overall, our findings provide additional strong evidence that the observed differences in cognitive functioning between persons born preterm and those born at term are a consequence of widespread altered brain connectivity, still present many years after preterm birth. Furthermore, our findings also support the notion that preterm birth per se induces altered brain development, with long lasting anatomical and behavioural consequences.Interestingly, the areas for which correlations between cognitive measures and WM structure were seen were also areas in which group differences in WM structure between the preterm and term born participants were detected. It is tempting to infer a causal relationship, i.e., that disturbance of the neural pathways in these specific areas are the primary cause of the impaired cognitive functions. However, our data can only show associations, and there might be other primary causes, e.g. neuronal death in cortical areas resulting in secondary changes of the axons. Against that, however, speaks that we could only find minor changes in GM, and that those did not show correlations with cognitive measures. While several GM areas differed in volume between the preterm and the term born group, there were no significant correlations between GM volumes and cognitive measures once corrected for multiple comparisons. White matter volumes were also different between the two groups, but in contrast to the GM volumes, there was a significant correlation between left frontal lobe  volume and the score for attention and speed in the term born group.When examining correlations of FA measures with cognitive measures, in the preterm group significant positive correlations of both IQ measures and, in particular, two of the three executive function measures (namely working memory scores and cognitive flexibility scores) were seen, while no such correlations were seen in the term born group. Intact WM microstructure appears particularly crucial in relation to functional outcome after preterm birth, while normal variation in term born children does not seem to interfere. Fractional anisotropy is a measure that is often used to infer on WM microstructure and is influenced by a variety of factors , which iNeuroimaging and lesion studies have shown that executive functions are not solely located in the frontal lobe. It has been proposed that the prefrontal cortex serves as a modulator, subserved by posterior cortical regions, dependent on distributed neural networks including fronto-parietal and fronto-striatal pathways . SimilaIn conclusion, this study provides strong evidence that in persons born preterm, in the absence of radiological signs of preterm brain injury, widespread alterations in regional brain tissue volumes and white matter microstructure are still present in adolescence/young adulthood. Importantly, the observed microstructural alterations in projection fibres and the long association fibres linking frontal, temporal, and parietal lobes and also temporal and occipital lobes, are correlated with measures of general cognitive abilities and executive function measures. Based on this, our findings suggest that early growth disturbance of the neural pathways, rather than changes in regional brain volumes, are the primary cause of poorer cognitive functions in preterm born persons.S1 Table(DOCX)Click here for additional data file.S1 File(ZIP)Click here for additional data file.


To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix  in the mid‐trimester.This was an updated systematic review and meta‐analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid‐trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS , the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated.vs 43.1%; RR, 0.69 ; moderate‐quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death ), respiratory distress syndrome ), composite neonatal morbidity and mortality ), use of mechanical ventilation ) and birth weight < 1500 g ) . There were no significant differences in neurodevelopmental outcomes at 4–5 years of age between the vaginal progesterone and placebo groups.IPD were available for 303 women  and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta‐analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid‐trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.  Twin births have become more prevalent in developed countries over the last decadesPreterm birth is the most important factor determining neonatal morbidity and mortality among twins. The risk of preterm birth < 37 and < 32 weeks' gestation is eight‐ to ninefold higher in twin than in singleton gestationsA short cervix, traditionally defined as a transvaginal sonographic cervical length (CL) ≤ 25 mm in the mid‐trimester of pregnancy, is an important risk factor for spontaneous preterm birth and has emerged as one of the strongest and most consistent predictors of preterm birth in asymptomatic women with singletonA meta‐analysis of individual patient data (IPD) published in 2012 reported on the efficacy of vaginal progesterone in preventing preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a CL ≤ 25 mm in the mid‐trimesterThe objective of this study was to update the previous IPD meta‐analysis on the efficacy of vaginal progesterone in asymptomatic women with a twin gestation and a sonographic CL ≤ 25 mm in the mid‐trimester for the prevention of preterm birth and neonatal morbidity and mortality.The study was conducted according to a prospectively prepared protocol and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses statementprogesterone’, ‘preterm birth’, ‘randomized controlled trial’ and ‘twin gestation’. Google Scholar, proceedings of congresses on obstetrics, maternal‐fetal medicine and ultrasound in obstetrics, reference lists of identified studies, previously published systematic reviews and review articles were also searched. Experts in the field were contacted to identify further studies. No language restrictions were applied.We searched MEDLINE, EMBASE, POPLINE, CINAHL and LILACS , the Cochrane Central Register of Controlled Trials and Research Registers of ongoing trials using a combination of keywords and text words related to ‘RCTs in which asymptomatic women with a twin gestation and a sonographic short cervix (CL ≤ 25 mm) in the mid‐trimester were allocated randomly to receive vaginal progesterone or placebo/no treatment for the prevention of preterm birth and/or adverse perinatal outcomes were eligible for inclusion in the review. Trials were included if the primary aim of the study was to prevent preterm birth in women with a twin gestation and a short cervix, or to prevent preterm birth in women with an unselected twin gestation but for whom outcomes were available in those with a prerandomization CL ≤ 25 mm. We excluded quasirandomized trials, trials that evaluated vaginal progesterone in women with preterm labor, arrested preterm labor (as maintenance tocolysis), preterm rupture of membranes or second‐trimester bleeding, trials that assessed vaginal progesterone in the first trimester only to prevent miscarriage and studies that did not report clinical outcomes. Studies published only as abstracts were excluded if additional information on methodological issues and results could not be obtained.All of the potentially relevant studies were retrieved and reviewed independently by two authors to determine inclusion. Disagreements were resolved by discussion amongst the reviewers.The corresponding author of each eligible trial was contacted and asked to provide anonymized data (without identifiers) about baseline characteristics and outcomes for every randomly assigned patient, as well as data on study characteristics and details of interventions and co‐interventions. All initial communications with authors were based on a template explaining the study and the data required. Data provided by the investigators were merged into a master database specifically constructed for the review. Data were checked for missing information, errors and inconsistencies by cross‐referencing with the publications of the original trials. Quality and integrity of the randomization processes were assessed by reviewing the chronological randomization sequence and pattern of assignment, as well as the balance of baseline characteristics across treatment groups. Inconsistencies or missing data were discussed with the authors and corrections were made when deemed necessary.Informed consent was provided by the patients upon enrollment in each of the original trials. In the present study, the data were not used for any purposes other than those of the original trial and no new data were collected. Therefore, informed consent specifically for this project was not considered necessary. This study was exempted from review by the Human Investigation Committee Administration Office of Wayne State University.The primary outcome measure was preterm birth < 33 weeks' gestation. Secondary outcome measures included: preterm birth < 37, < 36, < 35, < 34, < 32, < 30 and < 28 weeks' gestation; spontaneous preterm birth < 33 and < 34 weeks' gestation; respiratory distress syndrome (RDS); necrotizing enterocolitis; intraventricular hemorrhage; proven neonatal sepsis; retinopathy of prematurity; fetal death; neonatal death; perinatal death; a composite outcome of neonatal morbidity and mortality ; birth weight < 1500 g and < 2500 g; admission to the neonatal intensive care unit; use of mechanical ventilation; and long‐term neurodevelopmental outcomes .Cochrane Handbook for Systematic Reviews of InterventionsThe risk of bias in each included trial was assessed independently by two authors using the criteria outlined in the I2. We pooled results from individual studies using a fixed‐effect model if substantial statistical heterogeneity was not present (< 50%). If I2 values were ≥ 50%, a random‐effects model was used to pool data across studies. For adverse perinatal outcomes, we estimated pooled RRs using analytical methods that assumed independence between neonates. However, to avoid incorrect conclusions due to the non‐independence of newborns from twin gestations, we also used a generalized linear model with generalized estimating equations to estimate parameters while controlling for cluster correlationsWe included all randomized women and their fetuses/infants and performed all analyses on an intention‐to‐treat basis. For outcomes dealing with gestational age at delivery, the unit of analysis was the pregnancy, whereas for perinatal outcomes, the unit of analysis was the fetus/neonate. IPD were combined in a two‐stage approach in which outcomes were analyzed in the original trial and then summary statistics were generated using standard summary data meta‐analysis techniques to give an overall measure of effect (pooled RR with 95% CI)P‐value ≥ 0.05 was considered to indicate that the effect of treatment did not differ significantly among subgroups. We planned to carry out sensitivity analyses to explore the effect of trial quality assessed by allocation concealment and random sequence generation (considering selection bias) and blinding (considering performance and detection biases), with studies rated as ‘high risk of bias’ or ‘unclear risk of bias’ for these domains being excluded from the analyses in order to assess whether this made any difference to the overall result. Subgroup and sensitivity analyses were only performed for the primary outcome of preterm birth < 33 weeks' gestation and for the secondary outcome of neonatal death. We also planned to explore potential sources of heterogeneity and to assess publication and related biases if at least 10 studies were included in a meta‐analysis, but these analyses were not undertaken due to the limited number of trials included in the review.Subgroup analyses were performed to evaluate the effect of vaginal progesterone according to CL , daily dose of vaginal progesterone  and obstetric history (no previous spontaneous preterm birth < 37 weeks' gestation and at least one previous spontaneous preterm birth < 37 weeks' gestation). A test for interaction between the treatment and subgroups was performed to examine whether treatment effects differed among subgroupsGRADE HandbookWe used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the We performed all statistical analyses using Review Manager  and SAS version 9.2  software.in‐vitro fertilization or intracytoplasmic sperm injectionFigure The individual characteristics of the studies included in the meta‐analysis are shown in Table et al.Three studies used vaginal progesterone 200 mg/day capsule, one useet al.The risk of bias in each included study is summarized in Figure vs 43.1%; RR, 0.69 ; P = 0.01; I2 = 0%; six studies, 303 women; moderate‐quality evidence) compared with those allocated to placebo/no treatment ; moderate‐quality evidence), perinatal death ; moderate‐quality evidence), RDS ; moderate‐quality evidence), composite neonatal morbidity and mortality ; moderate‐quality evidence), birth weight < 1500 g ; moderate‐quality evidence) and use of mechanical ventilation ; moderate‐quality evidence) . Nonetheless, vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation and neonatal death in women with a CL between 10 and 20 mm  and 0.20 , respectively) and women who were administered 400 mg of daily vaginal progesterone  and 0.42 , respectively). Moreover, vaginal progesterone significantly decreased the risk of neonatal death in women with a CL between 21 and 25 mm ) and women with no previous spontaneous preterm birth ).Subgroup analyses of the effect of vaginal progesterone on preterm birth < 33 weeks' gestation and neonatal death, according to CL, daily dose of vaginal progesterone and obstetric history, are shown in Table When the sensitivity analysis was restricted to the five trials with adequate blinding of patients, clinical staff and outcome assessorsn = 225) or placebo (n = 212), at a mean age of 57 monthsP = 0.03), although there was no statistically significant difference in the risk of low ASQ score (< 10th percentile) between the study groups ). A subgroup analysis showed that dichorionic twins who were exposed prenatally to vaginal progesterone had a significantly lower risk of having a low total ASQ score than those who were exposed to placebo ).No study has reported the effects of vaginal progesterone on long‐term neurodevelopmental outcomes in twin gestations with a short cervix. Thus far, two trials have reported the effects of prenatal exposure to vaginal progesterone on long‐term neurodevelopmental outcomes in unselected twin gestationsThe main finding in this updated IPD meta‐analysis is that the administration of vaginal progesterone to asymptomatic women with a twin gestation and a mid‐trimester sonographic short cervix significantly reduces the risk of preterm birth < 33 weeks' gestation (primary outcome) by 31% and neonatal death by 47%. In addition, patients who received vaginal progesterone had a significantly decreased risk of preterm birth < 35, < 34, < 32 and < 30 weeks, spontaneous preterm birth < 33 and < 34 weeks, perinatal death, composite neonatal morbidity and mortality, RDS, birth weight < 1500 g and use of mechanical ventilation. Moreover, evidence from two trials that assessed vaginal progesterone in unselected twin gestations showed that there were no significant differences in the risk of neurodevelopmental disability at 4–5 years of age between children exposed prenatally to vaginal progesterone and those exposed to placebo.Evidence for most critical outcomes assessed with GRADE methodology was considered to be of moderate quality (Table S1). We downgraded the evidence from high quality to moderate quality because most of the pooled effect was provided by one study with moderate risk of bias. A judgment of moderate quality means that we have some confidence that our results approach the true impact of vaginal progesterone on preterm birth and adverse neonatal outcomes in twin gestations with a short cervix; at the same time, we acknowledge that future trials may change these results.We evaluated several clinically important subgroups based on CL, daily dose of vaginal progesterone and history of spontaneous preterm birth. Overall, subgroup analyses indicated that the beneficial effects of vaginal progesterone did not differ significantly across patient groups, as the interaction tests for subgroup differences were non‐significant. Patients with a CL between 10 and 20 mm or those who received vaginal progesterone 400 mg/day seemed to have a greater‐than‐average reduction in the risk of preterm birth < 33 weeks' gestation and neonatal death. However, analyses of categories such as CL < 10 mm, daily dose of vaginal progesterone of 100 or 200 mg and history of spontaneous preterm birth were based on small numbers of women, reflecting the pattern of recruitment to the original trials, in which most women had a CL between 10 and 25 mm, used vaginal progesterone 400 mg/day and did not have a history of spontaneous preterm birth. As a result, our analysis was limited in its power to estimate effects within those groups of patients. Thus, although prespecified and clinically interesting, these subgroup analyses should be interpreted with caution.in‐utero exposure to vaginal progesterone, administered in twin gestations for the prevention of preterm birth, has no detrimental effects on long‐term neurodevelopmental outcomes. A total of 761 surviving children who participated in two placebo‐controlled trials of vaginal progesterone to prevent preterm birth in unselected twin gestationsCurrent evidence suggests that et al.et al.With regard to the effects of the prenatal exposure to vaginal progesterone on childhood health outcomes in twins, the follow‐up study by McNamara et al.et al.In our previous IPD meta‐analysisI2 = 0%), whereas the majority of meta‐analyses regarding adverse perinatal outcomes had low heterogeneity or no heterogeneity; and (iv) the sensitivity analyses restricted to trials at low risk of bias that were consistent with (and thus supportive of) the overall findings.The main strengths of our meta‐analysis include: (i) the use of patient‐level data, which offer several advantages over study‐level analysis, including the ability to use more appropriate statistical methods not always feasible using study‐level analysis, define outcome measures consistently across studies, investigate subgroups in which treatment may be either more or less effective, address questions that have not been satisfactorily resolved by individual trials, minimize publication and reporting biases and adjust for prognostic variables that may have confounded the original treatment comparisons; (ii) the baseline balance in prognostic factors between the two study groups, which reduces the possibility of causing bias in the intervention effect estimates; (iii) the absence of substantial heterogeneity in most of the meta‐analyses performed; indeed, all meta‐analyses on the effect of vaginal progesterone on preterm birth had no observed heterogeneity  or no treatment (NCT02329535) in ∼750 women with a twin gestation and a sonographic short cervix will help to determine whether vaginal progesterone can be recommended to these patients with the aim of preventing preterm birth and improving perinatal outcomes.Table S1 Summary of findings of the quality of evidence for each outcome measureClick here for additional data file.


Low birth weight (LBW) is defined as a birth weight of less than 2500 g (up to and including 2499 g), as per the World Health Organization (WHO) The term low birth weight refers to an absolute weight of <2500 g regardless of gestational age. Small for gestational age (SGA) refers to newborns whose birth weight is less than the 10th percentile for gestational age. This report will focus specifically on birth weight <2500 g. Further details related to case definitions for PTB Globally, it is estimated that 15–20% of all births, or >20 million newborns annually, are low birth weight infants. Low- and middle-income countries account for a disproportionate burden of LBW; over 95% of the world’s LBW infants are born in LMICs. There are marked global and regional variations in LBW rates. An estimated 6% of infants are born LBW in East Asia and the Pacific, 13% in Sub-Saharan Africa, and up to 28% in South Asia One of the major challenges in monitoring the incidence of LBW is that more than half of infants in the LMICs are not weighed 1.1.1Low birth weight is a valuable public health indicator of maternal health, nutrition, healthcare delivery, and poverty. Neonates with low birth weight have a >20 times greater risk of dying than neonates with birth weight of >2500 g In addition, economic studies in low-income settings have demonstrated that reducing the burden of low birth weight would have important cost savings both to the health system and to households 1.1.2The underlying causes of both PTB and IUGR are multifactorial, and the biological pathways and preventive strategies for these two conditions are quite different In general, the causes of IUGR can be due to maternal, fetal, and placental factors. Although the etiologies are different, they often have the final common pathway of insufficient uterine-placental perfusion and fetal nutrition.IUGR can be asymmetrical IUGR , symmetrical IUGR  or mixed IUGR. Asymmetrical IUGR is the most common (70–80%) form of IUGR, resulting from an insult  later in pregnancy, which results in affected babies having normal length and head circumference (brain sparing), but reduced weight. Symmetrical IUGR on the other hand arises from an insult  occurring earlier in pregnancy leading to a reduction in all anthropometric parameters in fetus/newborn Insufficient perfusion, through abnormal placentation, aberrant placental vascularization, maternal hypertensive disorders, and tobacco use, all result in IUGR. Multiple gestation  is associated with increased risk of both IUGR and PTB Preterm birth may be spontaneous or medically-indicated, such as induction or cesarean section for maternal complications such as pre-eclampsia. Infectious and inflammatory processes are associated with increased risk for PTB, including chorioamnionitis, bacterial vaginosis, bacteriuria, and systemic or remote site infection such as sepsis and periodontal disease.1.1.3Transplacental antibody transfer is an active process mediated by Fc receptors in the placental syncytiotrophoblast Clostridium tetani, Streptococcus pneumonia, and varicella-zoster virus in some studies Maternal antibody levels, receptor density and functionality, avidity, antigen nature, and gestational age determine the efficiency of placental antibody transfer 1.1.4Maternal infections, including influenza, have been associated with increased risk of low birth weight newborns The field of immunization of pregnant women has highlighted the importance of knowing background rates of adverse pregnancy events, including LBW, PTB, SGA, IUGR, stillbirths, and neonatal death, which can vary markedly between and within regions. The greatest impact of disease prevention from maternal immunization is expected to be observed in LMIC, where the burden of disease is greatest and access to health care services is most limited. For this reason, particular attention is being given to advancing maternal immunization trials in LMICs. Unfortunately, reliable, accurate, and timely reports of vital statistics and demographic data are often limited in these settings.Data Safety Monitoring Boards are established to review clinical trial data, including regular assessment or review of adverse event rates in trial participants. Without accurate information on background rates of low birthweight and other adverse pregnancy outcomes, it will be impossible to detect an increase in adverse events following immunization. Development of standardized methods to collect and report LBW and other essential outcomes will be essential to advancing maternal immunization programs worldwide.Birth weight is usually included under demographics of trial participant infants, and the differences in birth weights between participants enrolled in active and placebo or control arms of interventional trials in pregnancy are usually assessed.The LBW Working Group recommends use of traditional case definitions of LBW as defined by the World Health Organization. This report therefore focuses on delineating data quality related to methods used to estimate birth weight in LMICs, and summarizes some surrogate measurements that are under investigation to assess birth weight and estimate population-level background LBW rates.1.2http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Low birth weight Working Group was formed in 2016 and included 16 members of varied backgrounds including clinical, academic, public health and industry. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html.Following the process described in the overview paper To guide the decision-making for the guidelines, a literature search was performed using Medline/PubMed, Embase, ClinicalKey (ebooks), ScienceDirect (eBooks), eBrary (eBooks) and the Cochrane Libraries, including the terms: ‘pregnancy, vaccines and low birth weight’, and restricted to English language publications since 2005. The search resulted in the identification of 41 references. All abstracts were screened for possible reports of Low birth weight following immunization. Thirty-two articles with potentially relevant material were reviewed in more detail, in order to identify studies using case definitions or, in their absence, providing clinical descriptions of the case material. This review resulted in a detailed summary of 19 articles, including information on the study type, the vaccine, the diagnostic criteria or case definition put forth, the time interval since time of immunization, and any other symptoms. Multiple general medical, pediatric and infectious disease book chapters were also searched.The definition of low birth weight used was consistent across all literature reviewed.A second literature search using the search terms ‘birth weight and tools’ was performed using Pubmed, to identify other measurements used as proxies for birth weight. The search, unrestricted for language and year of publication, identified in 235 results. Titles were screened and 10 articles were identified for further review.1.31.3.1‘Low birth weight’ (LBW) has been defined as first weight recorded within hours of birth of <2500 g. Very low birth weight (VLBW) is accepted as <1500 g and extremely low birth weight (ELBW) is <1000 g Within the definition context, however, the three diagnostic levels must not be misunderstood as reflecting different grades of clinical severity. They instead reflect diagnostic certainty.The levels of certainty have been formulated such that the Level 1 definition is highly specific for the condition. Two additional diagnostic levels have been included in the definition, offering a stepwise loss of precision and accuracy from Level One down to Level Three, while retaining an approach to expand utilization of available data. In this way it is hoped that information on low birth weight can be captured more broadly at the population level.1.3.2The birth weight is described as the first weight measured, however, in settings with low rates of facility-based deliveries, a newborn may not be assessed by a health care worker until several days old. Birth weight should be assessed within hours of birth, prior to significant weight loss The LBW working group decided to restrict ‘birth weight’ to a weight measured in the first 48 h of life. In the absence of a weight measured within the first 48 h of life, a weight measured during the first week of life, could be classified as an ‘early neonatal weight’ but not ‘birth weight’.In a clinical trial scenario, measurement of weight within first 48 h of life should be achievable, as the clinical trial would procure adequate equipment, employ and train staff to assess birth weight in a timely manner, and enroll participants who reside in areas which are relatively easily accessed by trial or health care staff.Many newborns globally are not weighed within hours of birth, mainly due to difficulty in accessing health care personnel, facilities, and essential equipment. Specific time frames for onset of symptoms following immunization are not included for the following main reasons:We postulate that a definition designed to be a suitable tool for testing causal relationships requires ascertainment of the outcome (e.g. low birth weight) independent from the exposure (e.g. immunizations). Therefore, to avoid selection bias, a restrictive time interval from immunization to birth of a LBW newborn should not be an integral part of such a definition. Instead, where feasible, details of this interval should be assessed and reported as described in the data collection guidelines.Further, measurement of birth weight often occurs outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the assessment of a birth weight, particularly in less developed or rural settings. In order to avoid selecting against such cases, the Brighton Collaboration case definition avoids setting arbitrary time frames. The time between delivery and measurement of birth weight should be recorded and accounted for in the analysis.1.4As mentioned in the overview paper 1.5Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.2Level 1 of diagnostic certaintyLevel 2 of diagnostic certaintyLevel 3 of diagnostic certaintyLevel 4 of diagnostic certaintyThe newborn weight assessment is presumed to be assessed accurately as per health care center’s standard operating procedures. In many instances, trialists need to rely on the attending medical staff at health care facility for birth weight assessment. Strengthening training and oversight of birth weight measurement would be expected to strengthen data both in clinical trials and post-marketing surveillance.2.1Up to 60 million infants are born at home annually The lack of data available has encouraged the development of a mathematical model to calculate the expected number of adverse events, including neonatal and maternal deaths, SGA, preterm birth and major congenital malformations Several anthropometric measurements, including chest circumference, foot length and mid-upper arm circumference, have been assessed as proxies for birth weight In addition to these measurements, other tools are utilized in some communities to assess birth weight, including difference between adult weight with and without newborn in arms see .Fig. 1To3Working Group for Low birth weight to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about low birth weight. However, implementation of all guidelines might not be possible in all settings. The availability and quality of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, epidemiological study, post-marketing surveillance, or an individual report. Also, as explained in more detail in the overview paper It was the consensus of the Brighton Collaboration 3.1These guidelines represent a desirable standard for the collection of data on availability following immunization to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. The guidelines are not intended to guide the primary reporting of low birth weight to a surveillance system or study monitor. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines.Guidelines numbers below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 3.1.1(1)Date of report.(2)Name and contact information of person reporting(3)Name and contact information of the investigator responsible for the subject, as applicable.(4)Relation to the patient .For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.23.1.2.1(5)Case/study participant identifiers for mother and newborn  or code . Each newborn should have a unique identifier, ideally linked to mother’s identifier (e.g. participant code could be same for mother and baby(ies), with an added prefix/suffix to identify mother/baby).(6)Maternal date of birth, or if not available, maternal age.(7)•For collection of birth weight, ideally record timeline of weight measurement (e.g. time of delivery to time of weight), type of scale used (e.g. surface-mounted spring) and place where birth weight was measured .For each infant: Date and time of delivery, single or multiple, live birth vs. fetal death (fresh or macerated), estimated gestational age, method of determination of gestational age  and birth weight.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.2.2(8)Maternal past medical history, including hospitalizations, gravidity and parity, underlying diseases/disorders; complications of pregnancy, labor, or delivery; pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma.(9)Any medication history (other than treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect. .(10)Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI)), in particular occurrence of low birth weight after a previous maternal immunization.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.3(11)Date and time of maternal immunization(s).(12)Description of vaccine(s) , vaccine diluent (composition and lot number) and number of dose if part of a series of immunizations against the same disease).(13)The anatomical sites (including left or right side) of all immunizations .(14)Route and method of administration , other injection devices).(15)Needle length and gauge.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.4(16)For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded.(17)Severity of Low birth weight , and if there was medical confirmation of the LBW .(18)Date/time of observation,6(19)Concurrent signs, symptoms, and diseases, including prematurity.(20)•Values and units of routinely measured parameters (grams for birth weight);•Method of measurement ;•Weight should be recorded with minimal or ideally no clothing;Measurement/testing.(21)Objective clinical evidence supporting classification of the event as “serious”.7(22)Exposures other than the immunization 24 h before and after immunization  considered potentially relevant to the reported event.8Specifically document:3.1.5(23)The duration of surveillance for low birth weight should be from 0 to 48 h of life. Any weight measured after 48 h of age should not be considered a ‘birth weight’.9(24)Methods of data collection should be consistent within and between study groups, if applicable.10(25)Investigators of patients with low birth weight should provide guidance to reporters to optimize the quality and completeness of information provided.3.2(26)Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis.The following guidelines represent a desirable standard for analysis of data on low birth weight to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting.Event classification in 5 categoriesEvent meets case definition(1)Level 1: Criteria as specified in the Low birth weight case definition(2)Level 2: Criteria as specified in the Low birth weight case definition(3)Level 3: Criteria as specified in the Low birth weight case definitionEvent does not meet case definitionAdditional categories for analysis(4)Reported Low birth weight with insufficient evidence to meet the case definition.7(5)Birth weight not assessed, therefore data unavailable.(27)The interval between immunization and reported Low birth weight could be defined as the date/time of immunization to the date/time of assessment(28)If birth weight is assessed by more than one method, the value recorded which fulfills the highest level of certainty should be used as the basis for analysis.(29)The distribution of birth weight data could be analyzed in predefined increments . Increments specified above should be used. When only a small number of cases are presented, the respective values can be presented individually.(30)Data on Low birth weight obtained from participants whose mothers received a vaccine should be compared with those obtained from an appropriately selected and documented control group to assess background rates of LBW in non-exposed populations, and should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials.3.3(31)All reported events of Low birth weight should be presented according to the categories listed in guideline 31.(32)Data on Low birth weight events should be presented in accordance with data collection guidelines 1–25 and data analysis guidelines 26–30.(33)Data should be presented as rates with a numerator and denominator (n/N) (and not only in percentages), with confidence intervals around the point estimates.These guidelines represent a desirable standard for the presentation and publication of data on Low birth weight following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology  (34)The incidence of cases in the study population should be presented and clearly identified as such in the text.(35)If the distribution of birth weight data is skewed, median and range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided.(36)•The study design;•The method, frequency and duration of monitoring for Low birth weight;•The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation;•The type of surveillance (e.g. passive or active surveillance);•The characteristics of the surveillance system ;•The search strategy in surveillance databases;•Comparison group(s), if used for analysis;•The instrument of data collection ;•Whether the day of immunization was considered “day one” or “day zero” in the analysis;•Whether the date of onset•Use of this case definition for Low birth weight, in the abstract or methods section of a publication.11Any publication of data on Low birth weight should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify:Although immunization safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described .The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant’s organization . Specifically, the findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.


We aimed to describe newborn body composition and identify which anthropometric ratio  best predicts fat mass (FM) and fat-free mass (FFM).n=247). Standards for the best-predicting anthropometric ratio were calculated utilizing the same population used for the INTERGROWTH-21st Newborn Size Standards .Air-displacement plethysmography (PEA POD) was used to estimate FM, FFM, and body fat percentage (BF%). Associations between FFM, FM, and BF% and weight/length, BMI, and PI were evaluated in 1,019 newborns using multivariate regression analysis. Charts for FM, FFM, and BF% were generated using a prescriptive subsample (+0−36+6 weeks’ gestation) and with impaired intrauterine growth. Weight/length by gestational age (GA) was a better predictor of FFM and FM  than BMI or PI, independent of sex, GA, and timing of measurement. Results were almost identical when only preterm newborns were studied. We present sex-specific centiles for weight/length ratio for GA.FFM and FM increased consistently during late pregnancy. Differential FM, BF%, and FFM patterns were observed for those born preterm (34Weight/length best predicts newborn FFM and FM. There are differential FM, FFM, and BF% patterns by sex, GA, and size at birth. A wide range of exposures in pregnancy can influence fetal and early postnatal growth and development. Traditionally, weight at birth has been used to quantify those intrauterine effects; however, it is increasingly acknowledged that the measure by itself, without consideration of gestational age (GA), is an inadequate predictor of health outcomes.We have already demonstrated that preterm birth , newbornLarge neonatal body composition data sets are not generally available for technical reasons; thus, mostly anthropometric indices have been used as a proxy—e.g., combinations of weight, length, skinfold thickness, and various body circumferences. Indices such as weight/length, or those in which weight is normalized with the power of length, may be practical alternatives.The availability of air displacement plethysmography  has improved our understanding of newborn body composition and the implications of feeding regimens especially for preterm and growth-restricted newborns .st Project, in which mothers and their babies were monitored prospectively from early pregnancy to 2 years of age. The project has generated international standards for use during pregnancy  of the INTERGROWTH-21regnancy , as wellregnancy , 6, and regnancy , recentlregnancy . Our aimst Project has been described elsewhere , were eligible, provided they were alive on hospital discharge. This population constituted the NBCS  and included newborns with different intrauterine growth trajectories and anthropometric characteristics at birth to enable the relationship with body composition to be examined across a wide range of newborn nutritional states. This total NBCS population was used for the following: (i) to describe FM and FFM patterns at birth across the range of GAs; (ii) to evaluate which anthropometric index best predicted FM and FFM at birth; and (iii) to select a subpopulation, with the same prescriptive criteria used to generate the INTERGROWTH-21st Standards (n=247).The present analysis was performed in two steps with their corresponding populations: in the first step, all singleton babies, born between 7 June 2011 and 7 April 2016, to women enrolled in the INTERGROWTH-21tandards , 5, to pst population used to construct the Newborn Size Standards .In the second step, we constructed international standards for the best-predictive newborn anthropometric index  with the same INTERGROWTH-21tandards  and Verytandards  , 7 mm (length), or 5 mm (head circumference), then both observers independently took that measurement again and, if necessary, a third time. The monitoring and quality-control methods used across the sites are described in detail elsewhere . In the Body composition was estimated within 96 h of birth  using the PEA POD; 97% were measured less than 72 h. The PEA POD is designed for use in infants up to 6 months of age or weighing up to 8 kg. It is unclear how valid estimates are at very low birth weights, but they are reliable for stable preterm babies .The PEA POD estimates body composition by whole-body densitometry using a two-compartment model. Body volume is measured by air displacement plethysmography and body weight is measured using an electronic scale. A computer program calculated body composition from these data using the “Fomon” model . Once boThe PEA POD was routinely calibrated and used in a temperature-controlled room. The baby was evaluated undressed in the test chamber for 2 min, and, if necessary, duplicates of irremovable items  were measured before the examination.Measures were summarized according to sex, age at examination, preterm or term birth, and fetal growth by GA using means and proportions. Body composition measures approximated to a normal distribution, although the distribution of FM was slightly skewed.Multiple linear regression analyses between weight/length ratio, BMI, and PI as the independent, explanatory variables and FM, FFM, and BF% as the dependent (outcome) variables in separate models, adjusting by sex, GA at birth (weeks), and postnatal age (hours) at body composition estimation, were carried out. The statistical methods selected to construct standards have been discussed previously , 10.Q statistic , the latter using the GAMLSS framework (https://cran.r-project.org/web/packages/gamlss/index.html). Tables containing centile values and z-scores, and printable charts will be available free on the INTERGROWTH-21st Project website (https://intergrowth21.tghn.org).We used STATA version 12.1  or R statistical software version 3.2.4 (http://medscinet.com), online electronic data management system (http://www.medscinet.net/intergrowth/protocol.aspx?lang=1).Data were entered directly into the specially developed (st Project was approved by the Oxfordshire Research Ethics Committee “C” (reference: 08/H0606/139), the research ethics committees of the individual participating institutions, as well as the corresponding regional health authorities where the project was implemented. A list of all study contributors is given in the The INTERGROWTH-21n=1,019); (ii) evaluated which anthropometric index best predicted FM and FFM at birth ; and (iii) selected a subpopulation, with the same prescriptive criteria used to generate the INTERGROWTH-21st Standards (n=247).Results are presented following the two steps described in the Methods section. In the first step, we (i) described body composition at birth across the range of GAs .In the second step, we constructed international standards for the best predictive newborn anthropometric index identified in (ii) above, with the same INTERGROWTH-21tandards  and Verytandards   were used to describe body composition patterns and their association with perinatal conditions and anthropometric indices. The demographic and baseline characteristics of the initial 1,923 mothers, the 1,019 mothers whose babies were included in NBCS and the 461 mothers who did not wish to participate, were remarkably similar (data not shown).st Project  met the low-risk inclusion criteria , 5 requiP<0.001); however, there was no significant difference in absolute FM between the sexes (P=0.26).P<0.001) but higher mean FM/FFM ratio (P=0.001). These results suggest that the increase in fetal weight late in pregnancy is mostly due to an increase in FFM in both sexes and that FFM is slightly higher in boys, whereas BF% is slightly higher in girls across GAs.There was a linear increase in FFM, 155 g/week (95% CI 140–171 g) for girls and 169 g/week (95% CI 152–186 g) for boys, with less variability than that for fat indicators at all GAs. Overall, average FFM increased from close to a mean of 2 kg at 34 weeks’ gestation to a mean of over 3 kg at 40 weeks’ gestation for boys and girls. FFM patterns were the inverse of those for FM, i.e., boys on average had more FFM than girls at all GAs after 34 weeks’ gestation. Testing the regression lines at the mean GA, girls had a lower mean FFM  newborns had significantly lower FM, FFM, BF%, and FM/FFM ratio than their term counterparts . The prest charts , large for gestational age , newborn wasting (BMI<3rd centile), and stunting (length-for-GA<3rd centile), as well as late preterm birth according to the INTERGROWTH-21t charts .z-scores (z-scores . There aR2 and regression coefficient). This analysis allowed identification of the anthropometric ratio that best predicted body composition indicators.R2 values. The simple weight/length ratio measured at birth was superior at predicting FFM than either BMI or PI (R2=0.92 vs. 0.81 and 0.62); the same pattern was also observed for FM (R2=0.71 vs. 0.64 and 0.43) and BF% (R2=0.54 vs. 0.50 and 0.35). Comparing unadjusted analyses with the adjusted data in Multivariable linear regression analyses, adjusted by GA at birth (weeks), sex, and age at PEA POD measurement, demonstrated that the weight/length ratio by GA was the best predictor for FM and FFM as evaluated by adjusted We also present in n=247) of newborns, selected from the total NBCS population according to the same inclusion criteria used for constructing the INTERGROWTH-21st standards  and statistical methodology as the INTERGROWTH-21st Newborn Size Standards  and references (<33 weeks’ gestation) for newborn weight/length ratio . Supplemst Newborn Size Standards  FFM deposition has a dominant role in fetal weight changes during late pregnancy; (ii) FM and FFM patterns at birth are slightly different in boys and girls across GAs; (iii) preterm newborns have less FM, FFM, and BF% than term newborns; (iv) compared with AGA newborns, the lower birth weight of newborns SGA is related to a reduction of 27% in FM and 73% in FFM; (v) the heavier birth weight of newborns LGA consists, on average, of 36% FM and 64% FFM; (vi) the simple weight/length ratio at birth by GA is a better predictor than BMI of body composition parameters because of its stronger relationship with both BF and FFM. Accordingly, we provide international standards by GA and sex to judge the proportionality of newborn size, complementing the INTERGROWTH-21We have compared body composition estimates at <12, 12–24, and >24 h after birth adjusting for GA at birth. We have confirmed a pattern of weight reduction during the first 4 postnatal days of 9% (95% CI 6.6–11.2%), mostly related to loss of FFM (likely due to water loss or hydration status), independent of GA and sex, with minor or no changes in BF%  21). He. He21). et al. . Specif43; ref. . BF% wit43; ref. . It is, 43; ref. , 26, 27.43; ref. , 25.st standards that were based on data from eight sites worldwide. It was not possible, therefore, to assess heterogeneity across sites. In addition, studying a low- to medium-risk population meant that very few early preterm births occurred despite the large sample size. Interestingly, even among low-risk newborns, the BF% values range between 3 and 20% at term, compatible with healthy neonates.The body composition ‘normative’ data presented here should be used cautiously because they were derived from the Oxford site, unlike other INTERGROWTH-21It is also important that our results should not be used to recommend postnatal feeding practices because infants were assessed before much or any postnatal feeding, and the results are derived from cross-sectional measures at birth; hence, they only demonstrate how tissues were deposited during intrauterine life. Postnatal body composition standards, produced with a similarly robust methodology, population selection, and standardized human milk-based feeding practices do not exist at present; however, a recent meta-analysis of individual cases from four studies using dual-energy X-ray absorptiometry to evaluate postnatal body composition represents a positive step toward a tool for clinical practice .After 34 weeks’ gestation, we observed overall a progressive increase in FFM by GA, a greater absolute increase than that for FM and BF%, although proportionally the FM slope (average change per week) represents 10% of the mean FM, whereas the FFM slope is 6% of the total FFM . We alsoin utero across the birth weight range in the “controlled” environment provided by relatively healthy and adequately nourished pregnant women. The data suggest that the FM and FFM dynamics are dissimilar for SGA and LGA. FFM is clearly the leading component in the process of lower or higher birth weights; conversely, expressed as BF% of term infants, the largest difference is related to FM (We described the patterns of tissue deposition ed to FM . Howevered to FM , which cThe high variability observed in the fat indicators’ data has to be interpreted, bearing in mind that, at birth, most fat is subcutaneous and very little is intra-abdominal. Furthermore, the main difference between growth-restricted and AGA newborns is in subcutaneous fat; intra-abdominal amounts are similar . MoreoveThese considerations are important because the increased risks associated with adult adiposity are related to visceral, not subcutaneous, fat. It is difficult to know what role subcutaneous fat in newborns, which varies considerably in amount, has in the etiological pathway to high adult body fat and long-term health. Clearly, however, the effect on these same long-term outcomes of changes in the very small proportion of newborn intra-abdominal fat, as well as the associations with neonatal morbidities, needs to be studied, while considering that the stress associated with neonatal morbidities may itself drive the deposition of intra-abdominal fat .2, is in the denominator, the association between the denominator and numerator is considerably reduced (We also demonstrated that the newborn weight/length ratio by GA and sex best reflects primarily FFM, plus FM and BF%. This accords with data from newborns and children showing that BMI is not a good indicator of body fat, but rather reflects overall body tissue . The rea reduced . The wea reduced  and the  reduced . Hence,  reduced .