Background: Visualization of the precise course of the visual pathways is relevant to prevent damage that may inflict visual field deficits during neurosurgical resections. In particular the optic radiations (OR) are susceptible to such damage during neurosurgery. Cortical pathways can be mapped in vivo, by using Diffusion Tensor Imaging (DTI). Visualization of these pathways would be potentially helpful to prevent neurosurgical visual morbidity. In this study an anatomical dissection of the visual pathways was compared to DTI fiber tractography (DTI-FT) data of four human brains. The feasibility of a definition of a Safety Zone is investigated.Methods: Four adult brains were dissected using Klingler's fiber dissection method, which allowed preparation of the OR. Measurements before and after dissection were used to establish distances from the cortex to the OR. DTI-scans were also obtained from these brains to determine the same distances.Results: Measurements from specific landmark points on the cortex to the lateral border of the OR were performed in four brains. Analysis through DTI tractography corresponded with the dissection results. Based on the combined results of both dissection and DTI-FT, we defined a quantitative surgical Safety Zone with respect to various anatomical landmarks (in particular the ventricle system).Conclusion: We conclude that there is a good correlation between the visualizations of the optic pathways based on dissection and DTI. Furthermore, we conclude that defining a neurosurgical Safety Zone which could preserve the integrity of the OR during surgery, based on the combination of DTI-FT images and dissection is feasible. The anatomical course of axons within the human brain has been initially studied using post-mortem dissections and histological investigations Forel, . IdentifThe visual pathways have a horizontal and elongated course through the entire brain, which increases the chance of damaging these pathways   .This study focuses on visualization of the course and key points of the OR through both anatomical dissection and DTI-FT. Combining both DTI-FT and anatomical dissection of the OR, the degree of correspondence could be established between the results of these different techniques. This correlation was firstly investigated, after which it was used to validate the accuracy of the DTI-FT method. The visualization of the OR in four human brains using these two techniques provided the basis of defining a surgical The brains that were used in this study were post mortem brains: ♂79 years, ♂82 years, ♂80 years, ♂76 years with no pathology of the central nervous system. In accordance with ethical standards post mortem material was obtained from donors willing to donate their body for purpose of science through the Dissection hall of the University Medical Center Groningen.All brains underwent preparation according to Klingler's fiber dissection method  could start after they were washed with warm water for < 5 min. This process caused for the time difference between DTI acquisition through MRI scans, which needed to be performed before the freezing process, and dissection.The dissection of the brains started at the inferior surface of both the occipital and the temporal lobe. After thawing, the cortex of these lobes could be dissected on the inferior surface. Using this technique, the course of the optic tract and its key structures could be identified. Through this process the optic tract became better visible. This allowed following the fibers of the OR through the visualization of key structures of the optic tract. The fibers of the OR could be identified by visualizing the optic chiasm, the optic tract circumventing the mesencephalon to the colliculi superioris and the lateral geniculate body (LGB). The LGB could be identified through the removal of the parahippocampal gyrus and by following the brachium colliculi superioris, originating from the colliculi superioris. Subsequently, the fibers originating from the LGB (the OR) underwent preparation using the ventricle system as orientation due to their close relationship with the OR   were made, which were of adequate quality to perform tractography on.Three post mortem brains were scanned on a 3.0 Tesla MRI scanner at the Neuroimaging Center in Groningen . To the best of our knowledge, DTI-FT has not yet been performed on 2-weighted scans were acquired using the WIP DTI/s/60dir/APP SENSE protocol with a 90 degree flip angle; matrix size 128 × 128 mm and a field of view of 240 × 140 × 240 mm yielding 70 slices and a voxel dimension of 1.875 × 1.875 × 2 mm. All brains could be processed properly using the Diffusion Toolkit of the Trackvis program . Brains that needed correction with regards to the axes  due to their position within the MRI scanner were performed by using the Diffusion Toolkit. This way, fiber tractography could be performed on the scanned brains.High resolution TDiffusion Toolkit program. They were executed by addressing the tab X-, Y-, Z-axis. By inverting the axes , the orientation of the brain (and its fibers) within the TrackVis program was “anatomically” correct after which fiber tractography could start. The fast continuous tracking algorithm (FACT) was used as the fiber tracking algorithm. A deterministic method of fiber tracking  allows for quick tractography based on ROIs placed in the DTI scan by the observer.In order to adequately perform fiber tractography, the axes in which the post mortem brain was scanned needed to be adjusted. They were not in an anatomical position due to the fact that the post mortem brains were held in a container with saline solution . This was necessary because of the importance of the orientation of the brain in three axes with regards to its fiber directions and color coding of those fibers. The necessary inversions with regards to the axes could be performed with the TrackVis, spherical regions of interest (ROI) were used. The ROIs were placed on known anatomical key structures of the OR which are identifiable on the T2-weighted DTI scans. These structures were: the LGB, the lateral wall of the temporal horn, trigonum, and occipital horn of the ventricle system and the visual cortex.To track the course of the OR in These ROIs were defined for both hemispheres in all brains. In each individual brain, the ROIs were manually placed on the earlier mentioned anatomical key structures in order to track the OR from the LGB to the visual cortex. This deterministic method of fiber tractography resulted in the visualization of the OR. Figures Measurements of the lateral extension of the OR with regards to the ventricle system and the length of the OR could be performed. These results were averaged and their standard deviation was determined the same way as was done with the results from the dissection.The research protocol was approved by the Institutional Review Boards of the University Medical Center Groningen as a scientific research project and was conducted according to the principles expressed in the Declaration of Helsinki. The use of post mortem material in this study was approved by the medical faculty of the University Medical Center Groningen.Table By averaging the results of Table After the dissection it was possible to measure the lateral extension of the OR. This was completed by measuring the distance from the lateral borders of the OR to specific points of the ventricular system . The results of these measurements are shown in Table VI) as cut-off value, an attempt has been made to determine a Safety Zone using the ventricle system as a landmark. This method has been used to ensure the integrity of the OR within the limited population available in this study. These results are shown in Figure By using the results from Table TrackVis program, which allowed for measurements of the length and the lateral extension of the OR. The relationship of the OR with the ventricles became evident, as can be seen in Figures The OR was analyzed using the Safety Zone established based on the dissection data  with regards to tracking cortical pathways could be evaluated.Our main conclusion is that the OR course and dimensions as established on the basis of DTI-FT data and the dissection results are very similar. Therefore, we infer that it is feasible to establish a Safety Zone was established based on a combination of dissection and DTI-FT results, which we believe strengthens its validity. Moreover, the results used to establish it correspond with those of previous studies  could grant benefits for the clinicians in the form of relative quick fiber tractography to isolate the OR in DTI scans.Unfortunately, up until now and to the best of our knowledge there is no validation method for the fibers tracked using the deterministic DTI-FT method, as is being used in this study. In addition, the use of manually placed ROIs in the deterministic method to identify pathways may lead to unwanted bias. Meaning that the ROIs are placed in such a manner, that the pathway resembles the anatomy as is expected from anatomical literature. Identifying key structures in the course of the OR in order to successfully isolate the OR in fiber tractography could potentially grant benefits. Suggested structures which are easily recognized on T2-weighted DTI scans with a deterministic method of fiber tractography by suggesting a predetermined set of key structures of the OR which are recognizable where to place ROIs. These are the LGB, the lateral wall of the temporal horn, trigonum and occipital horn of the ventricle system and the visual cortex.Still, we believe that the DTI-FT method creates potential benefits with regards to presurgical planning and mapping of the OR  in healthy individuals or patientsis recommended. This way, the variability in the course and dimensions of the OR can be determined more accurately. Again, this can help to further improve the Safety Zone. Furthermore, performing preoperative and postoperative DTI-scans complemented with visual field measurements  in a clinical setting could provide useful information on the preservation of the OR and the prevention of postsurgical visual field deficits. Another method to complement the mapping of the OR could be the use of visual evoked potentials (VEPs) during surgery, although the implication of the VEPs is not clear yet , placing ROIs in order to track the OR with DTI-FT and, as an indicator for intra-operative mapping of the OR . Further research is needed—preferably in a clinical setting—to determine the validity of the Safety Zone and the DTI-FT method for visualizing the OR.Based on the combined results, we proposed a neurosurgical 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.


This essay plans to explore, expand, and re-tell the human birth narrative. Usually, human birth narratives focus on the origins of a new individual, focusing on the mother and fetus. This essay discusses birth as the origin of a new community. For not only is the eukaryotic body being reproduced, but so also are the bodies of its symbiotic microbes and so is the set of relationships between these organic components. Several parts of the new narrative are surprising: (1) bacterial symbionts might cause some of the characteristics of pregnancy and prepare a symbiotic community for transfer; (2) the first bacterial colonizers of the mammalian organism my enter the fetus prior to the lysing of the amniotic membrane and birth; (3) the same signals that often cause immunological attack against a microbe may serve under these conditions to signal homeostatic stability between symbiont and host; and (4) the mother may actively provide substances that promote the growth and settlement of helpful bacteria. The birth of the holobiont exemplifies principles of co-evolution, co-development, niche construction, and scaffolding. Birth is nothing less than the passage from one set of symbiotic relationships to another. I wish to discuss birth as the origin of a new communityThis essay plans to explore, expand, and re-tell the human birth narrative. Usually, human birth narratives focus on the origins of a new Mammalian birth is one of the great biological stories—the fundamental mammalian symbiosis of mother-and-fetus becoming another fundamental mammalian symbiosis, that of mother-and-child or mother-and-pup. In the classical story, the two partners are obviously the mother and the conceptus . Their interactions constitute the grand idea behind the obstetric subspecialty of Maternal-Fetal Medicine, which justifies its existence through the claim that the mother and fetus constitute a co-organized interacting whole, the “maternal-fetal unit.” Indeed, they are a symbiotic unit, a system, where the treatment of one affects the physiology of the other. The mother influences the fetus, providing it with nutrition, oxygen, antibodies, and hormones for its growth. The fetus reciprocally influences the mother, changing her blood circulation, immune responsiveness, and metabolism, while providing her with hormones to retain pregnancy. The physiology of the mother changes as the pregnancy continues, with both the mother and the fetus producing hormones and other growth factors to influence the other's survival and development.But there is a third major player in this symbiotic mix: the mother's microbes. The pregnant mammal is herself a symbiotic community, a holobiont, composed of numerous species, most of them bacterial  changes dramatically during pregnancy, as the body undergoes hormonal, immunological, and metabolic changes. These include fat gain starting early in pregnancy, and insulin resistance later in pregnancy. These two metabolic conditions, which are often detrimental to men and to non-pregnant women, are thought to be beneficial during pregnancy. At this time, increased adiposity and increased insulin resistance are thought to support fetal growth and to prepare the mother for lactation  during this time between 13 and 33 weeks of pregnancy. Moreover, the microbial community became more streamlined, with the diversity much reduced by the third trimester.Employing 91 women and assuming that stool samples accurately reflect the intestinal microbiota, Koren et al.  used polThe importance of these bacteria to normal pregnancy was demonstrated by transferring the bacteria from the healthy first-trimester and third-trimester women into healthy female germ-free mice. The mice receiving the bacteria from the stools of first-trimester pregnant women remained normal. However, within 2 weeks, the healthy formerly germ-free mice that received the third-trimester bacteria had a pregnancy-like metabolic syndrome, complete with insulin insensitivity, excessive weight gain, and increased markers of inflammation.Lactobacillus species, however, appear to be enriched during pregnancy. Several enriched Lactobacci species digest glycogen, and they produce an acidic environment that prevents pathogenic infection  immune responses against bacteria in the adult are the Toll-like receptors (TLRs). Interestingly, the activity of these receptors appears to be down-regulated in the fetus. The amniotic fluid, in addition to providing suspension and anti-dessication protection to the embryo, also contains large concentrations of Epidermal Growth Factor. This protein prevents the function of the TLRs. So while the early digestive tract is being bathed by amniotic fluid (the mouth and anus are open and exposed to amniotic fluid), the bacteria might be accepted as colonizers  and reduced lymphocyte responses , the activation of PRRs in the newborn induces a homeostatic integration of host and symbiont. It appears that the composition of the early microbiome dictates whether the response of the cells is inflammatory or tolerant  has been sequenced and shown to contain a remarkable region of DNA—a series of genes linked together and dedicated to the intake and digestion of complex sugars found specifically in the earliest secretions of mother's milk. This small (43 kb) unit is not found in related bacteria that are not part of the gut microbiome, and these data indicate a remarkable co-evolution between this symbiotic bacterium and its host, suggesting that the host product (human milk) and the microbial genome enabling the bacteria to use this product have reciprocally formed each other  are wiped out by it (Hooper et al., In this new narrative, we see “birth” as involving the reproduction of the holobiont. In other words, both the mammal and her persistent microbial populations have to be reproduced. Both niche construction and scaffolding are critical. Scaffolds are “material environmental inputs with organizations that are sensitive and responsive to the developmental state of the developmental system being scaffolded” (Griesemer, The mother, through her hormones, anatomy, and milk production, is in large part responsible for the successful handing over of the fetus to a new set of symbionts. Going from the maternal environment to the outside world is not merely leaving a symbiotic support system and gaining “independence.” There is no such thing as “independence.” It's mutual dependency all the way down, and birth is the exchanging of one symbiotic system for another.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


While nutrients involved in one-carbon cycle metabolism are important to fetal growth, associations with specific nutrients remain inconsistent. This study estimates associations between maternal vitamins Bn = 496) with biomarker and birth weight data were enrolled as part of the Newborn Epigenetics STudy. Weight gain data were available for 273 offspring. Among 484 mother-infant pairs, DNA methylation at regulatory sequences of genomically imprinted genes was measured in umbilical cord blood DNA using bisulfite pyrosequencing. We used generalized linear models to estimate associations.Study participants  = 102.08, p = 0.04). The offspring of the mothers in the highest quartile of B12 experienced lower weight gain between birth and 3 years compared to the offspring of the mothers in the lowest . Conversely, maternal PLP was associated with higher weight gain in males; higher maternal PLP concentrations were also associated with offspring DNA methylation levels at the MEG3 DMR (p < 0.01).Multivariate adjusted regression models revealed an inverse association between maternal Hcy concentration and male birth weight  contains supplementary material, which is available to authorized users. Size at birth is a strong predictor of infant growth and survival and has been linked to lifelong health outcomes . Low birWhile maternal nutrition during fetal development has been shown to have long-term health consequences for the offspring , the imp6 and B12. While the literature supports an association between low maternal blood folate concentrations and small size at birth ).Data collection occurred at multiple time points throughout the study period as follows: (1) upon enrollment, participants provided peripheral blood samples  and completed a self-administered questionnaire which queried women on their sociodemographic, reproductive, and lifestyle characteristics in the 6 months prior; (2) upon delivery, birth outcomes were abstracted from medical records and infant cord blood specimens were obtained to assess offspring methylation; and (3) at age 3 years, data on child anthropometry and dietary characteristics were obtained for 273 of the 496 offspring for whom maternal B vitamins were measured. The participants with and without childhood data did not differ with respect to key variables  according to the manufacturer’s instructions. The kit uses the vitamin B12-dependent strain Lactobacillus delbruekii subsp. lactis (ATCC 7830) in a 96-well format. After processing, L. delbruekii growth was measured by turbidimetry at 610 nm using the Molecular Devices, Versa-Max Tunable Plate Reader. Data analysis was performed using the commercially available software Soft-Max version 3.1, Molecular Devices. PLP and PA were measured by high-performance liquid chromatography (HPLC) which requires the removal of plasma protein, conversion of the liberated PLP to 4-pyridoxic acid 5′-phosphate in alkaline medium containing cyanide (derivatization), followed by acidification. The acidified samples were subjected to reversed phase HPLC separation, and detection was carried out with fluorescence with excitation at 320 nm; emission at 416. A Thermo Separation Products System, pump model P200, autosampler model AS300, fluorescence detector model FL300 was used. Plasma Hcy was similarly assessed using HPLC with UV detection at 384 nm. Maternal micronutrient concentrations were right skewed and quartiled.Quantitative analysis of plasma BTrained personnel abstracted parturition data from medical records after delivery. These data included birth weight, gestational age at birth (week), and infant sex. Infant birth weight (grams [g]) showed no evidence of departure from normality and was analyzed as a continuous variable. Age 3 WG (g) was slightly right skewed and calculated using the following formula: ((age 3 weight [g]/age at which weight was obtained [months])*36 months) − birth weight [g] and assessed continuously.The participants self-reported maternal age at delivery, race/ethnicity, marital status, parity, diabetes, and weight and height at last menstrual period (LMP), all of which were subsequently verified with abstracted medical records. Household income, maternal education, cigarette smoking, FA supplementation, and infant feeding practices were self-reported via questionnaire.2. FA supplementation was self-reported at baseline.We considered maternal race/ethnicity, infant sex, maternal pre-pregnancy BMI, and FA supplementation as potential modifiers of the association between maternal micronutrient concentrations and birth weight. Race/ethnic categories were assigned based on women’s self-identification as Black/African American, non-Hispanic White, or Hispanic White. Infant sex was abstracted from medical records. Maternal BMI was calculated from self-reported weight (kg) and height (m) at LMP and expressed as kg/mH19 DMR regulating the IGF2/H19 domain, the MEG3 DMR regulating the DLK1/MEG3 domain, the SGCE/PEG10 DMR positioned between epsilon sarcoglycan and paternally expressed gene 10, and the PLAGL1 DMR [r > 0.99 for all DMRs). Once the optimal conditions were defined, each DMR was analyzed using the same amount of input DNA from each specimen , keeping the thermocycler and pyrosequencer constant. Controls to determine the bisulfite conversion efficiency were included for each DMR with every sample run. For all data included in the analysis, the conversion efficiency exceeded 97 %. Percent methylation for each CpG cytosine was determined using Pyro Q-CpG Software (Qiagen). We interrogated between four and eight CpG sites per DMR: four for H19, eight for MEG3, six for SGCE/PEG10, and six for PLAGL1.Infant genomic DNA (800 ng) was modified by treatment with sodium bisulfite using the Zymo EZ DNA Methylation kit . Bisulfite treatment of denatured DNA converts all unmethylated cytosines to uracils but leaves methylated cytosines unchanged, allowing quantitative definition of cytosine methylation status. Pyrosequencing was performed using Pyromark Q96 MD pyrosequencers (Qiagen) to measure DNA methylation at four imprint regulatory regions known to associate with fetal growth and development in NEST study participants , 18 inclAGL1 DMR . Assays AGL1 DMR . Defined12, PLP, PA, and Hcy using chi-squared tests [p ≤ 0.05). For all models, we considered adjustment for the following covariates: maternal age, race/ethnicity, gestational age at delivery, marital status, parity upon enrollment, household, maternal education, maternal BMI at LMP, maternal smoking, maternal FA supplementation, gestational diabetes, gestational age at blood draw, and infant sex. For childhood WG analyses, we additionally considered adjustment for every breastfeeding, in-home smoking, height, and caloric intake at age 3 years. Final confounders were selected based on directed acyclic graphs [We compared the distribution of demographic and obstetric characteristics across quartiles of Bed tests . Generaled tests  . Cronbach’s alphas were >0.89 for all DMRs considered, suggesting mean methylation levels for each DMR could be used in our models [F tests [p ≤ 0.05). All statistical analyses were conducted in SAS v9.3 .Among 429 term mother-infant pairs where methylation data for at least one of four DMRs was available and nutrient data were measured, we examined associations with maternal micronutrient concentrations. Study participants with DMR data available were similar to those without DMR data with respect to maternal age, micronutrient concentrations, and birth weight (r models . We used[F tests  for para[F tests  to exami[F tests  (a priorThe data set supporting the results of this epidemiologic research will be available with appropriate human subject protection in a separate file.


Birth order has been proposed as a cardiovascular risk factor, because the lower birth weight and greater infant weight gain typical of firstborns could programme metabolism detrimentally.We examined the associations of birth order (firstborn or laterborn) with birth weight-for-gestational age, length/height and body mass index (BMI) z-scores during infancy, childhood, and puberty using generalized estimating equations, with age at pubertal onset using interval-censored regression and with age-, sex- and height-standardized blood pressure, height and BMI z-scores at 13 years using linear regression in a population-representative Chinese birth cohort: “Children of 1997” .Compared with laterborns, firstborns had lower birth weight-for-gestational age  -0.23, -0.14), lower infant BMI , greater childhood height  and BMI , but not greater pubertal BMI , adjusted for sex, parental age, birthplace, education and income. Firstborns had earlier onset of pubic hair , but not breast or genitalia, development. Firstborns had greater BMI , but not height , at 13 years, but similar blood pressure.Differences by birth order continue into early adolescence with firstborns being heavier with earlier pubic hair development, which could indicate long-term cardiovascular risk. Differences between groups in cardiovascular disease (CVD) rates at the same level of well-established adult risk factors suggest etiologic gaps, which could be exploited to develop more focused and effective interventions. The WorlIn this situation, examining the effects of other naturally occurring drivers of birth weight and subsequent growth, such as birth order, may help elucidate the role of birth weight and infant growth. Firstborns are different from laterborns in having lower birth weight,–6 possibMost previous studies of parity and CVD risk mainly examined size at a single time point and only one study examined pubertal development. Collating snapshots of growth at different ages from various settings and birth years may not fully reveal growth and development across life-course by birth order, particularly in the presence of sociocultural influences. Hong Kong provides a contrasting, economically developed, non-Western setting to clarify how firstborns differ from laterborns. In Hong Kong, families usually have one to two children with firstborns tending to have younger more educated parents, whereas n = 8,327) that covered 88.0% of all births in Hong Kong from April 1, 1997 to May 31, 1997, described in detail elsewhere.[n = 7,999, 96% successful matching); and annual weight and height and bi-annual pubertal status (grade 1 (age 6–7 years) onwards) and blood pressure (grade 5 (age 10–11 years) onwards) from the Student Health Service, Department of Health, which provides free annual check-ups for all school students . At the Student Health Service, height without shoes was measured by stadiometer to the nearest 0.1 centimetre and weight without shoes and outer clothing was measured by digital scale to the nearest 0.1 kilogram. BMI was calculated as weight in kilograms divided by height in meters squared. Blood pressure was measured by nurses on the right arm in a seated position after more than 10 minutes of rest with an age and size appropriate cuff size using an automated oscillometric device. Initial systolic or diastolic blood pressure more than the 90th percentile for sex, age and height was double checked by physicians with a sphygmomanometer after 15 minutes of rest and this second measurement was recorded. Pubertal status was visually assessed by physicians for breast (girls) or genitalia (boys) and pubic hair (both sexes) development according to the criteria of Marshall and Tanner.Hong Kong’s “Children of 1997” birth cohort is a population representative Chinese birth cohort n = 8,7 that coInformation on birth order was obtained from self-administered questionnaires completed mainly by mothers at recruitment  at the Maternal and Child Health Centers. Birth order was categorized as “firstborns” or “laterborns”, because relatively few families had more than two children (11.0%).z-scores (standard deviation scores) at different growth phases, age at pubertal onset, and blood pressure, height and BMI z-scores in early adolescence as previously defined.[The outcomes were birth weight-for-gestational age z-score, length/height and BMI  defined.–35 Since defined. Gestatio defined. Each coh defined. and the  defined. Age at p defined. Finally,We used multivariable linear regression to assess the adjusted associations of birth order with birth weight-for-gestational age z-score, blood pressure, height and BMI z-scores at ~13 years and multivariable generalized estimating equations with an exchangeable working correlation structure to assess the adjusted associations with height or BMI z-scores during infancy, childhood and puberty, from which mean differences in birth weight-for-gestational age, blood pressure, length/height or BMI z-scores with 95% confidence intervals (CI) are presented. We used multivariable interval-censored regression, with a lConfounders included were sex, mother’s and father’s age at birth, mother’s and father’s birthplace, highest parental education and household income per head, as categorized in Since our participants are children, informed consent was obtained from the parents, next of kin, caretakers or guardians (informants) on behalf of the participants by completing the questionnaire at enrollment as approved by The University of Hong Kong Medical Faculty Ethics Committee. Ethical approval for further studies was obtained from the University of Hong Kong-Hospital Authority Hong Kong West Cluster Joint Institutional Review Board and/or the Ethics Committee of the Department of Health, Government of the Hong Kong Special Administrative Region as appropriate.Of the original 8,327 cohort members, as of December, 2013, 26 had permanently withdrawn. Among the 8,260 adolescents with at least one measurement of birth weight-for-gestational age, length/height, BMI, blood pressure and pubertal onset, 47.5% were firstborns. In this economically-developed non-Western setting, firstborns had lower birth weight-for-gestational age, lower infant BMI, greater childhood height and BMI, but not greater BMI during puberty than laterborns. By 13 years, firstborns had higher BMI than, but similar height as, laterborns. As a result firstborns had a different trajectory of BMI and height that laterborns with lower BMI in infancy but higher BMI into puberty, they also had somewhat greater childhood and pubertal height which was transient. Firstborns also had earlier age at onset of pubic hair, but not breast or genitalia, development than laterborns. At ~13 years firstborns had similar age-, sex- and height-standardized blood pressure to laterborns.Several limitations of this study exist. First, we do not have birth length or head circumference as a proxy of fetal growth. Second, pubertal stage was assessed by different physicians. However, a standard guideline for staging and an orchiometer were available and, with our large sample, statistical power is unlikely to have been compromised. Third, using a single blood pressure measurement may slightly overestimate average blood pressure, but systThe finding that firstborns have distinctive growth patterns at different phases across the early life course from laterborns is broadly consistent with previous studies focusing on size at particular ages. Firstborns were lighter at birth adjusted for gestational age.–6 They hOur findings of earlier onset of pubic hair, but not breast or genitalia, development among firstborns are similar to the only previous study (from Brazil) that examined pubertal onset, althoughThe lack of association of birth order with age-, sex- and height-standardized blood pressure in early adolescence are less consistent with a positive association in Brazilian adolescents and BritAlternatively, parents may pay more attention to firstborns and feed or raise them differently from laterborns. Many firstborns may be only children, whilst laterborns are not. A difference in intelligent quotient between first-borns and laterborns appears to be socially rather than biologically driven, because second-borns whose older sibling dies in infancy have similar intelligent quotient as firstborns. In this 2). Based on 1 kilogram higher birth weight is associated with 16% lower risk of ischemic heart disease[Firstborns were heavier into early adolescence. They also had earlier pubic hair, but not breast or genitalia, development, perhaps due to biological factors that underlie growth and pubic hair development and are more common in firstborns. Whether these differences extend into adulthood and affect cardiovascular risk remains to be elucidated in a range of settings with different confounding structures. Our study highlights the importance of replicating observations in different settings that allows thorough investigation of the underlying biological mechanism to presage any consequences in populations with increasing proportion of firstborns. Equally important, our findings showed very modest differences in birth weight  or BMI z-scores between firstborns and laterborns until adolescence Click here for additional data file.


Aim. To report on the use of indocyanine green (ICG) during surgical removal of pediatric orbital lacrimal duct cysts. Method. We conducted a retrospective review of our cases of surgical excision of orbital lacrimal duct cysts using intraoperative injection of indocyanine green (ICG), which was used following inadvertent cyst rupture and volume loss. The dye allowed complete cyst visualization and complete excision despite volume loss or cyst rupture. Results. The study included 6 children . Mean follow-up period was 9.3 months. All cysts were located in the inferonasal quadrant of the orbit (4 in the right side). In all cases, ICG was injected into the cyst at the time of surgery following unintentional cyst rupture. After the dye injection, it was easy to identify the borders of the cyst, permitting complete cyst removal, without any intra- or postoperative complications. Pathological examination revealed that all cysts were of lacrimal duct origin. Conclusion. Intraoperative injection of ICG into orbital cysts in children can aid surgeons in identifying cyst borders following inadvertent rupture, allowing complete removal. Dermoid cysts, mucocele, and congenital ocular anomalies are the most common orbital cystic lesions in children . HoweverIn order to prevent local recurrence, it is necessary to remove the entire cyst at the time of surgery without leaving any residual cyst tissue. On occasions, this may be challenging since cyst boundaries are not easily apparent, especially posteriorly. Inadvertent puncture of the cyst capsule may further limit complete excision.Indocyanine green  is a coloring dye that has numerous uses in ophthalmology with established intraocular, topical, and intravenous safety . ReportsThe purpose of the study is to report on our experience in using ICG during removal of pediatric orbital cysts, raising the awareness of surgeons for the possibility of its use during such surgery.We reviewed all cases of pediatric orbital lacrimal cysts that were operated using intralesional ICG injection at the time of surgery. Data collection included demographics, clinical history, localization of the lesion, imaging findings, surgical technique, and complications. Pathological analysis, surgical outcome, and duration of follow-up were also recorded. The study was approved by the IRB committee of our medical center and its compliance was in agreement with rules and regulations.All procedures were performed under general anesthesia. Surgical approach was via a skin incision or through the conjunctiva in the fornix. After the cystic lesion was identified, if leakage was recognized along with loss of cyst volume, ICG dye was injected into the lesion with a 25-gauge needle. Cyst borders were readily apparent even though there was immediate loss of volume subsequent to the injection. Following delineation of the cyst capsule with the green dye, complete excision was performed. The skin or conjunctiva was closed using 7/0 vicryl sutures and the surgical site was bandaged with a topical antibiotic ointment. All children were seen one week after surgery and final assessment of surgical outcome was made at least 6 months afterwards.Six children (3 boys) were included in this study. All children had orbital imaging preoperatively; two children had computerized tomography (CT), one had magnetic resonance imaging (MRI), and 3 children had orbital ultrasound. All lesions were unilateral , always located in the inferomedial orbital quadrant. Four cysts were diagnosed soon after birth due to the presence of medial subcutaneous swelling seen at the area of the lacrimal system, accompanied by cystic sensation upon palpation; however all surgeries were performed after the age of 3 years  when there was evidence of progressive enlargement causing globe compression or cosmetic disfigurement unacceptable to the parents. None of the children were operated on for relief of nasolacrimal duct obstruction.Surgical excision was performed through the skin in two cases and through the conjunctiva in the remaining four cases. No complications occurred at the time of local ICG injection. ICG was injected when intraoperative loss of cyst volume was noted. None of the cysts were connected to the nasolacrimal duct, and all showed patency of the lacrimal system on syringing after cyst removal, with no evidence of any leakage to the surgical site. Therefore, no silicone tube intubation was required.A successful outcome was achieved in all cases. In all cases the pathology report confirmed complete excision of a cystic lesion lined with epithelium of lacrimal duct origin. None of the children had cyst recurrence during follow-up (mean follow-up 9 months) or any evidence of nasolacrimal duct obstruction.One of the patients had a right inferomedial cystic lesion noted soon after birth. The patient was followed up regularly and when the lesion was growing considerably, an orbital CT was performed demonstrating a 2 cm hyperdense homogeneous mass in the inferomedial aspect of the right orbit, with mild compression of the right eye . The patA second patient was examined in the clinic for evaluation of a left inferomedial orbital cyst that was recognized since the age of 3 months. The patient had a Doppler ultrasound examination which identified a cystic lesion with a clear liquid content. During follow-up there was evidence of progressive enlargement of the lesion. Orbital MRI performed shortly before surgery demonstrated a 0.7 × 1.5 cm oval mass with clear fluid contents located in the left inferomedial orbit, causing mild globe compression . This leThe patient was treated with topical chloramphenicol 5% ointment over the surgical wound. Pathological analysis identified a cyst lined with epithelium of lacrimal duct origin. During the 6-month follow-up period no surgical complications or cyst recurrence were noted.By using intralesional ICG injection, we were able to completely remove lacrimal duct orbital cysts in children, even though unintentional volume loss occurred earlier, without any complications or recurrence. This dye is frequently used in ophthalmology, including during orbital surgery, with an established safety profile in humans .Kobayashi et al. used ICG during removal of an acquired conjunctival cyst . They noTo the best of our knowledge, our study is the first to report on the use of ICG for demonstration of orbital cysts during pediatric orbital surgery, although its use has been reported earlier in an adult . Using tIn conclusion, we believe that ICG has a role in pediatric orbital lacrimal cyst surgery, helping with improved visualization of the cyst capsule and allowing complete cyst removal, especially with unintentional rupture of the cyst and volume loss that occurred earlier.


Severe thrombocytopenia (21-50x109/L) occurred in 25 neonates (8%) in the SGA and 2 neonates (1%) in the AGA group . Platelet counts <20x109/L were not recorded. Within the SGA group, lower gestational age at birth (p = <0.01) and erythroblastosis (p<0.01) were independently associated with a decrease in platelet count. Platelet count was positively correlated with birth weight centiles. In conclusion, early-onset thrombocytopenia is present in over 50% of SGA neonates and occurs 2.7 times as often as in AGA neonates. Thrombocytopenia is seldom severe and is independently associated with lower gestational age at birth and erythroblastosis.Thrombocytopenia is a common finding in small for gestational age (SGA) neonates and is thought to result from a unique pathophysiologic mechanism related to chronic intrauterine hypoxia. Our objective was to estimate the incidence and severity of early-onset thrombocytopenia in SGA neonates, and to identify risk factors for thrombocytopenia. We performed a retrospective cohort study of all consecutive SGA neonates admitted to our ward and a control group of appropriate for gestational age (AGA) neonates matched for gestational age at birth. Main outcome measures were incidence and severity of thrombocytopenia, hematological and clinical risk factors for thrombocytopenia, and bleeding. A total of 330 SGA and 330 AGA neonates were included, with a mean gestational age at birth of 32.9 ± 4 weeks. Thrombocytopenia (<150x10 The relationship between birth centiles and platelet count is depicted in Erythroblastosis was detected in 43% (140/325) of SGA neonates versus 10% (34/328) of AGA neonates  and leucocytopenia was detected in 21% (69/329) of SGA neonates versus 6% (21/330) of AGA neonates . The relationship between NRBC count and platelet count is depicted in 9/L. Three (27%) neonates had moderate thrombocytopenia, 3 (27%) had mild thrombocytopenia and 5 (45%) had normal platelet counts. Other possible factors that could be related to the hemorrhages included birth weight <1000 grams (n = 4), gestational age less than 28 weeks (n = 6) and respiratory distress syndrome (n = 7). Pulmonary hemorrhage occurred only in 2 neonates, both in the SGA group, one neonate had severe thrombocytopenia and the other had moderate thrombocytopenia. No cases of severe gastrointestinal hemorrhage were reported.Cranial ultrasound examination within the first three days of life was performed in 86% (287/330) and 80% (263/330) of SGA and AGA neonates. In the subgroup of neonates with a gestational age of <35 weeks, cranial ultrasound within the first 3 days of life was performed in 98% (203/208) and 98% (204/208) of SGA and AGA neonates, respectively. Because of the high incidence of missing ultrasounds in (near-)term infants, cerebral ultrasound outcomes are only presented for the subgroup of infants with a gestational age <35 weeks. IVH was detected in one (SGA) neonate with a gestational age >35 weeks. In one SGA neonate, the postnatal age at which the IVH occurred could not be determined. The incidence of severe IVH in the SGA and AGA groups with a gestational age <35 weeks was 1% (2/203) and 4% (9/204), respectively. This difference was not significant (Fisher’s exact test p = 0.062), but the study was not powered to assess this outcome. Of the 11 neonates with severe IVH, none had platelet counts below 50x102: 0.32)(9/L) was 74  compared to 10  in neonates without thrombocytopenia. The coefficients in 9/L) by which a platelet count is increased (for positive coefficients) or decreased (for negative coefficients) for every unit change in risk factor, provided that the other risk factors remain constant. For example: platelet count increases with 6.7x109/L with every week increase of gestational age at birth, and platelet count decreases with 43.3x109/L in the presence of erythroblastosis. If the confidence interval overlaps zero, the change in platelet count is not significant. Multivariable analyses were repeated for the AGA group, in order to detect differences in risk profiles between both groups (SGA and AGA). The results were very similar, with erythroblastosis and gestational age being independent predictors of platelet count.In the subgroup of SGA neonates, four risk factors were significantly associated with platelet count in univariate analysis: low gestational age at birth, maternal hypertension, low birth weight and erythroblastosis.. Because2: 0.32). The medThis study confirms that early-onset thrombocytopenia is a common problem in SGA neonates, occurring in half of our SGA cohort. Our findings show that the incidence of thrombocytopenia is 2.7 times higher in SGA neonates compared to a group of AGA neonates matched for gestational age at birth, which is in agreement several other studies.,7,14,20 et al found significantly lower platelet counts in severe (p<5) compared to moderate (p5-10) SGA.[et al describe a correlation between fetal abdominal circumference and fetal platelet count.[As shown in erate p5- SGA.[10,-10) SGA. Van den et count. Because et count. Associatet count. Our resuTwo risk factors were independently associated with platelet count in our multivariate model. The first, erythroblastosis, was also assessed by birth weight centile, but showed a threshold pattern, with relatively constant erythroblast counts in AGA neonates, and a significant increase in erythroblast count for all SGA groups. Several other studies have also found a relationship between low platelet counts and erythroblastosis, or between SGA and erythroblasosis.,15,23–25The second risk factor that was associated with platelet count in our study was gestational age, which is also in accordance with previous studies.,7,14 TheOur results should be interpreted with care due to several limitations including the retrospective nature of the study and the related possibility of bias. Firstly, no distinction was made with regard to the causes of inappropriate birth weight in SGA neonates. Although SGA is mostly due to intrauterine growth restriction, some neonates may be constitutionally small. Constitutionally small infants do reach their growth potential, but are constitutionally smaller than average, in contrast to SGA neonates, who do not reach their full growth potential. ConstituIn conclusion, we found that SGA neonates are at increased risk of early onset thrombocytopenia compared to AGA neonates, but that the thrombocytopenia is usually mild to moderate. A direct correlation exists between the severity of SGA and neonatal platelet count. Erythroblastosis at birth and low gestational age identify neonates at higher risk, for which monitoring of the platelet count during the first week is necessary, in order to detect severe thrombocytopenia. Further research is necessary to assess the relationship between SGA and severe bleeding.S1 File(SAV)Click here for additional data file.


Background: Low birth weight (LBW or birth weight <2500 g) is one of the most serious health problems in today's world.Objective: The purpose of this study was to evaluate growth parameters of neonatal intensive care unit (NICU) admitted LBW preterm neonates at corrected ages of 6 and 12 months.Materials and Methods: In a prospective cohort (follow up) study, all LBW preterm neonates whom were admitted to Shahid Sadoughi Hospital NICU in 2008, followed up for one year and their weight, height and head circumference evaluated at ages of 6 and 12 months.Results: Twenty four boys and 26 girls with mean gestational age of 31.3±2.7 weeks and mean birth weight of 1480.3±422.8gr were evaluated. The most frequency of underweight and short stature was seen at the age of six months. Exclusive breast feeding infants had the lowest frequency of underweight at the age of six. Frequency of underweight at the age of six months and NICU stay days were more in neonates with birth weight of less than 1000 gr.Conclusion: It is necessary to emphasize on the importance of growth assessment of LBW children and proper education of their mothers about nutrition of their children for early and timely diagnosis and management of growth retardation and prevention of subsequent problems. LBW neonates are sub grouped according to the first weight determination after birth: moderately low birth weight (MLBW): between 1500 and 2499 gr, very low birth weight (VLBW): less than 1500 gr and extremely low birth weight (ELBW): less than 1000 gr  statistics, the rate of LBW is 17% in the whole world  .Over the past two decades, LBW rate has increased primarily because of an increase in preterm births . LBW andUp to the age of 15 years, LBW children showed a higher risk of death and in LBW children, rate of hospitalization was higher for the first 14 years of life . By incrIn growth monitoring of preterm infants by standard growth charts, gestational age should be corrected for weight through 24 months of age. It is through 40 months of age for stature and 18 months of age for head circumference . Little is known about the growth of LBW infants in Iran. The purpose of this study was to evaluate growth parameters  of NICU admitted LBW preterm neonates at corrected ages of six and 12 months in Yazd, I.R.Iran. The sample size based on Z formula and a confidence interval of 95% with 80% power to detect a significant difference between the two groups with a level of 0.05 was calculated to be 50 children. Gestational age less than 37 weeks was considered as preterm neonate. In a prospective cohort (follow up) study, all consecutive preterm LBW neonates whom were admitted to Shahid Sadoughi Hospital NICU in 2008, followed up and their growth parameters  in corrected ages of 6 and 12 months were evaluated. Corrected age was calculated by subtracting gestational age from 37 weeks and the result was subtracted from chronological age: .Multiple pregnancies, severe asphyxia, children with major congenital malformations, small for gestational age (SGA), chromosomal abnormalities, genetic syndromes and neonates who had serious complications such as intraventricular hemorrhage, patent ductus arteriosus, hydrocephaly, bronchopulmonary dysplasia and necrotizing enterocolitis during NICU admission period were excluded. All babies were weighted by children digital weighing scale with sensitivity of 10 gram without diapers. The weighting scale was calibrated at regular intervals. The supine crown heel length was measured on the infantometer with the help of an assistant to the nearest millimeter in the recumbent position.The weighing scale and infantometer were Germany made Seca. Head circumference was measured using a flexible non-stretchable tape measure which runs from the supraorbital ridge to the occiput in the path as the maximum occipitofrontal circumference. To obviate errors due to interobsever variations, all measurement were made in Pediatric Clinic of Shahid Sadoughi Hospital by one pediatric resident involved in this research. For assessment of growth parameters, the WHO growth charts were used .Weight below the third percentile on a standard growth curve weight, as reached 40 postmenstrual weeks, was considered underweight. Height of less than two standard deviation from height age was considered short stature  and headThe same children were evaluated at six months, followed up to 12 months and their growth parameters were evaluated again at 12 months. This study was approved by the Ethic Committee of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Statistical analysisThe data were analyzed using SPSS  version 15 statistical software. Chi-square test or Fisher exact test were used for data analysis of qualitative variables and mean values were compared using independent T-test. Differences were considered significant at p-values of less than 0.05.Parents of five infants did not return for follow up and therefore their infants were excluded from the study. Twenty four boys (48%) and 26 girls (52%) with mean gestational age of 31.3±2.7 weeks (range=26-37 weeks) and mean birth weight of 1480.3±422.8 gr (range= 700-2300 gr) were evaluated. Comparison of mean weight, height and head circumference at birth and gestational age based on sex is presented in Frequency of underweight, short stature and microcephaly at ages of six and 12 is shown in Comparison of frequency of underweight, short stature and microcephaly at ages of six and 12 months based on sex is presented in Results of this study showed that growth parameters of LBW children partially improved at the age of one year as frequency of underweight and short stature decreased and no child had microcephaly in one year. In an Indian study, children with birth weight of less than 1.25 kg and less than 30 gestation weeks had delayed and poor catch up growth and they had considerable lag that persisted up to 1 year of age .In a Chinese study, growth parameters of 132 LBW neonates and 49 normal birth weight term infants were followed up and compared. LBW children had lower weight, length, and head circumference from birth for up to three years . A prospEvaluation of growth in LBW infants should be more emphasized since growth failure in such infants might be associated with many complications including increasing the number of hospitalization, learning disabilities, growth retardation in childhood and reductions in adult lung function and capacity , 17.In the present study, infants who had exclusive breast feeding for six months had lower frequency of underweight at the age of six months and it is in compliance with other studies which suggested a beneficial effect of breastfeeding on childhood growth rates of LBW newborns and efforts must be continued to breast feed all low birth weight neonates in the NICU and even after discharge -20.In this study, growth parameters of LBW infants partially improved in year one and it might be due to emphasize to continue breast milk feeding, education of supplementary feeding and evaluation of physical growth of these high risk babies by researchers and personnel of health centers. “In a study in Norway, 118 VLBW infants had significant catch-up growth in weight and length during the first year. But, their head circumference showed a normal growth pattern after two months” .In a study in São Paulo of Brazil, growth patterns of 60 neonates weighing less than or equal to 2000 gr during the first year were followed up. It showed that in spite of their corrected age, such infants growth curves were below the reference curve standards .Limitations of the present study were; small sample size, lack of a control group and short follow up period. Therefore, it is suggested that further studies be conducted with a larger sample size and a control group  for comparison. In conclusion, physical growth assessment is necessary in low birth weight infants and accurate recording of growth parameters of LBW infants by personnel of health centers, regular and frequent visiting of such children, education of their parents about growth process, and follow up and encouragement to exclusive breastfeeding should be emphasized for early and timely diagnosis, investigation and management of growth disorders in LBW children.Factors influencing catch up growth should be recognized and adequate measures to improve growth parameters (like attention to feeding practices) and overall outcome of such children should be taken. Therefore, it is significant to curb the rate of LBW neonate and to offer scientific guidance on care and early training to promote development and growth of infant.


After several decades of research, we now have evidence that at least six interventions are suitable for immediate use in contemporary clinical practice within high-resource settings and can be expected to safely reduce the rate of preterm birth. These interventions involve strategies to prevent non-medically indicated late preterm birth; use of maternal progesterone supplementation; surgical closure of the cervix with cerclage; prevention of exposure of pregnant women to cigarette smoke; judicious use of fertility treatments; and dedicated preterm birth prevention clinics. Quantification of the extent of success is difficult to predict and will be dependent on other clinical, cultural, societal, and economic factors operating in each environment. Further success can be anticipated in the coming years as other research discoveries are translated into clinical practice, including new approaches to treating intra-uterine infection, improvements in maternal nutrition, and lifestyle modifications to ameliorate maternal stress. The widespread use of human papillomavirus vaccination in girls and young women will decrease the need for surgical interventions on the cervix and can be expected to further reduce the risk of early birth. Together, this array of clinical interventions, each based on a substantial body of evidence, is likely to reduce rates of preterm birth and prevent death and disability in large numbers of children. The process begins with an acceptance that early birth is not an inevitable and natural feature of human reproduction. Preventative strategies are now available and need to be applied. The best outcomes may come from developing integrated strategies designed specifically for each health-care environment. Each year, 15 million babies are born preterm  and possIn most countries, the rate of preterm birth has risen in recent decades and worldwide now represents the largest cause of neonatal death  and the Prevention of early birth, however, presents several great challenges. The condition merely describes an event that occurs before its due time, and is not a diagnosis in itself. There are many pathways leading to preterm birth and the prevention of each requires different types of scientific inquiry and clinical strategies, which together encompass a wide array of measurement systems and clinical interventions across many health-care disciplines .With such a great challenge, what evidence do we have that prevention of preterm birth is possible and feasible?Changing rates of preterm birth in populations in transition provide some evidence that environmental and lifestyle factors may be involved, and these may be amenable to intervention.In China, the rate of preterm birth is not known with certainty as there is no national obstetric data reporting system, but the estimated rate is thought to be relatively low by international standards. Hospital-based reports suggest rates ranging from 3 to 6% –8. A geoMexican women after migration to USA also experience an increase in risk of preterm birth. Long-term immigrants who had lived in USA for more than 5 years were shown to have a 1.9-fold greater risk of delivering preterm, and a 1.5 greater risk of giving birth to a low-birth weight infant when compared with more recent arrivals . The fac“Green shoots” are now appearing in the field of preterm birth prevention. At least in high-resource settings, some strategies are suitable for immediate use in clinical practice, have a high likelihood of success, and in many regions have already been adopted in part or in whole. Other strategies have potential and feasibility, but evidence for their effectiveness is still uncertain. Finally, there are initiatives in place aimed at other clinical end-points but which may incidentally prevent some cases of early birth.The levels of evidence employed in this review and that enable description of potential effectiveness in high-resource settings are shown in Table There are six strategies currently available with various levels of evidence of effectiveness that are suitable for translation into clinical practice in high-resource settings and have a high chance of successfully preventing a proportion of preterm births.The most feasible approach to rapidly lowering the overall rate of preterm birth is to address non-medically indicated late preterm birth. Late preterm birth is defined as birth between 34 weeks 0 days and 36 weeks 6 days and these infants account for 70% of all preterm births . In USA,Late preterm birth is a potential danger to the child. Infants born in the late preterm period are physiologically and metabolically immature. Their brain mass is approximately 70% of that of a term infant and the ongoing process of myelination is reduced accordingly . In the Recently, the effect of birth in the early term period has received increasing attention . Early tA significant proportion of all late preterm and early term births result from obstetric or medical complications of pregnancy, while others may be precipitated out of concern for maternal or fetal well being. As a result, assessment of outcomes after birth is confounded by the relative contributions of prematurity and any abnormalities in the pregnancy that contributed to the early gestational age at birth. The role of such biological determinants has been investigated and found to be amplified at earlier gestational ages, but quantification of the true relative contributions of gestational age and biological determinants remain challenging and will require further investigation .Strategies addressing the increase in late preterm and early term births will be enhanced by an understanding of the demographic characteristics of those most at-risk. In a review of the factors contributing to the rise in preterm birth rates at 36 and 37 weeks gestation in USA between 1992 and 2002, non-Hispanic white births were found to be the greatest contributor , while stillbirths rates were unchanged.The findings of this intervention cohort study provide strong evidence that the rate of late preterm and early term birth may be lowered and result in a 15% reduction in admissions to neonatal intensive care. Such an approach does not appear to increase the rate of stillbirth. Education alone did not significantly improve outcomes, but the process of education was aimed solely at the health-care providers, and it is yet to be seen if a combined approach of providing education to both the women themselves and the health-care personnel may result in a more favorable outcome.The price for obstetricians and their hospitals of delaying birth, however, is an increase in the number of births out-of-hours. In a secondary analysis of the Danish randomized controlled trial of planned Cesarean birth at 38 or 39 weeks gestation , preterm birth <37 weeks , perinatal death , need for assisted ventilation , necrotizing enterocolitis , and admission to neonatal intensive care  .When givThere is also strong evidence that progesterone treatment may prevent preterm birth in women shown to have a short cervix on ultrasound imaging in mid-pregnancy. Meta-analysis of individual patient data of five trials has shown that vaginal progesterone given to pregnant women in the mid-trimester with a short cervix ( ≤25 mm) is associated with a significant reduction in the rate of preterm birth <28 weeks , <33 weeks  and <35 weeks , in addition to significant reductions in risk of newborn complications including respiratory distress syndrome, need for mechanical ventilation, admission to neonatal intensive care, and composite morbidity and mortality .If progesterone is so effective in preventing preterm birth in women with a short cervix in mid-pregnancy, should all pregnant women be screened for cervical length at this time? The question is of great importance and remains controversial. In one of the major and most important trials in this field, Hassan and colleagues allocated at random asymptomatic women with a singleton pregnancy and short cervix (10–20 mm) between 19 weeks 0 days and 23 weeks 6 days to receive either vaginal progesterone gel or placebo daily . PretermThere is no doubt that any clinical strategy that would prevent the preterm birth of so many infants would be of considerable benefit to our patients and their families. The cost-effectiveness, however, would be dependent on the health-care environment and availability of appropriate resources and funds. In a decision analysis model comparing no routine cervical length screening with a single routine ultrasound trans-vaginal cervical length measurement at 18–24 weeks gestation, with the women with a short cervix then offered vaginal progesterone treatment, the policy appeared to be cost effective . In US dAt this time, the American College of Obstetricians and Gynecologists has not recommended routine cervical length screening for all pregnancies, probably as a result of the large numbers requiring to be screened, and a perceived need for further studies to be conducted across a variety of health-care settings , 50. PraProgesterone has also been evaluated as a potential treatment in other conditions that may lead to preterm birth. Studies conducted to-date have shown that progesterone treatment is not effective in preventing preterm birth in multiple pregnancies, preterm labor, or preterm pre-labor rupture of membranes , 47.Cervical cerclage is the surgical placement of a suture or tape around the cervix in an attempt to prevent dilatation and subsequent preterm birth. The procedure was first described by Shirodkar in 1955 and involved dissection of the bladder superiorly to enable placement of the suture as close to the internal os as possible . A simplThe decision to insert a cervical cerclage in mid-pregnancy is based on one of the three scenarios. First, a history of preterm births, classically recurrent and painless second trimester losses. Second, shortening of the cervix on ultrasound imaging. Third, short or dilated cervix on physical examination .The mechanistic basis by which cerclage is effective is simplistically described as physical closure of the cervix, but the concept of cervical “incompetence” remains as much an enigma today as it was when described by Shirodkar in 1955 . As a reMeta-analysis of the RCTs that have compared cervical cerclage against no treatment has shown a significant reduction in preterm births of 20%  and with a reduction in perinatal deaths although this difference did not quite reach statistical significance  . HoweverOnly one trial has attempted to directly compare ultrasound-indicated cervical cerclage with a progesterone . The proNo trial has compared vaginal progesterone versus cerclage for ultrasound-detected cervical shortening in mid-pregnancy . An indiAt this time, the evidence guiding clinical practice in making a decision to insert a cervical cerclage versus administration of progesterone is incomplete. Decisions need to be based on informed consent and include patient and clinician preference, as well as the local availability of surgical resources and expertise.Cervical pessaries have been proposed as an alternative method of preventing preterm birth . A rangeTobacco smoking in pregnancy causes preterm birth in addition to a dose-dependent reduction in birthweight , 56, 57.The nicotine in cigarette smoke is addictive and produces the positive feelings inherent in addictive behaviors. Strategies aiming to prevent smoking in pregnancy, however, are complicated by the many factors that contribute to the decision-making processes in women who elect to smoke while pregnant. In high-income countries, rates of smoking in pregnancy have declined in recent years but the reduction has not been in all groups , 60. SmoNevertheless, the risk of preterm birth attributable to smoking has been estimated as more than 25% and reducing smoking rates in pregnant women must be of highest priority . PsychosPharmacological interventions may be of less value. Nicotine replacement therapy is the only pharmacotherapy for smoking cessation in pregnancy that has been adequately tested. A review of the six published trials was unable to confirm benefit . FurtherIn contrast, smoke-free legislation appears to be of great benefit . A revieThe advent of fertility assistance has contributed to a significant increase in the rate of preterm birth. Central to this contribution has been an increase in the incidence of multiple pregnancies. In USA, the incidence of multiple births has doubled from 1.8% of all births in 1972 to 3.5% in 2011 , and thiin vitro fertilization (IVF) cycles in many countries are relatively easy to analyze; however, the data capture on less invasive treatments, such as ovulation induction and intra-uterine insemination cycles (often combined with ovarian stimulation) are less readily available. These treatments often involve ovarian stimulation and clinicians and patients may elect to proceed to fertility treatment when several follicles are potentially available for ovulation. In such circumstances, multiple pregnancies may result. In 2000, the incidence of twin gestations resulting from non-IVF fertility treatment was estimated to be 20% (Data on o be 20% .http://www.HFEA.gov.uk). Meanwhile, in USA, the percentage of single embryo transfers was 21%, resulting in IVF being responsible for one in five multiple births in that country in 2011  in women who attended a dedicated clinic and with lower rates of composite major neonatal morbidity (5.7 versus 16.3%) . The intDespite the relatively large number of preterm birth prevention clinics now operating in various parts of the world, a review of their effectiveness could identify only three trials that qualified for inclusion in the analysis, and with only one study providing outcome data on most end-points . When daIn addition to the enhanced provision of expert care and application of effective interventions for at-risk women, an important function of dedicated preterm birth prevention clinics may also be to alleviate maternal anxiety. Stress has been thought for many years to be a possible cause of some cases of early birth, and research is needed on the potential benefits or otherwise of attendance at such clinics .Intra-uterine infection and inflammation play a well-recognized role in the etiology of spontaneous preterm labor, particularly in deliveries less than 32 weeks gestation  or thoseUreaplasma and Mycoplasma species  has been associated with an increased risk of preterm birth, while obesity has been shown to be protective . ObesityIt has been known for many years that there are associations between preterm birth and low serum levels of many micronutrients. Proving a causative role and using supplementation to reduce preterm birth rates has, however, so far remained elusive.In a large cohort study, a strong association was observed between use of pre-conception folate supplementation for one year or more and reduction in risk of preterm birth before 32 weeks gestation, but not at later gestational ages . Howevern – 3 (omega-3) long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) in the last half of pregnancy resulted in fewer preterm births before 34 weeks gestation, longer gestations and shorter hospital stay for preterm infants  predispose women to preterm birth in subsequent pregnancies, including early preterm birth . Such trIn recent decades, advances in newborn care have resulted in improved outcomes for large numbers of children who have been born too early but this progress has not been matched by similar advances in our ability to prevent preterm birth. Times have changed. We now have increasing evidence that a variety of interventions have potential to significantly and safely prevent a meaningful proportion of preterm births. Translation of recent discoveries into clinical practice will have different requirements for high and low-resource settings, and for different population groups. For each setting, the best chance of success will come from an integrated implementation strategy that harnesses both the health-care personnel and the pregnant women for whom they provide care. The interventions are in many cases multi-disciplinary and require the participation of personnel from multiple fields including those who make local and national policies. This process begins with awareness across the medical and general communities that preterm birth is one of modern health care’s greatest challenges, but that prevention in many cases is now possible.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.


Neonatal mortality accounts for an estimated 2.8 million deaths worldwide, which constitutes 44 % of under-5-mortality and 60 % of infant mortality. Neonatal mortality predictors vary by country with the availability and quality of health care. Therefore, aim of this study was to estimate survival time and identify predictors of neonatal mortality in Tigray region, northern Ethiopia.A prospective cohort study design was carried out among a cohort of neonates delivered in seven hospitals of Tigray from April to July, 2014 and followed up for a total of 28 days. Data were collected by interviewing mothers using structured questionnaires and assessments of the neonate and mothers by midwives. Kaplan-Meier, Log rank test and Cox-proportional hazard regressions were used. STATA V-11 program was used for data entry, cleaning and analysis.From 1152 neonates, 68 died , 73.52 % of the neonates died within 7 days, 60 were lost to follow-up and the percentage of survival at 28 days was 93.96 % . Predictors of neonatal mortality were: normal birth weight , not initiating exclusive breastfeeding , neonatal complications , maternal complications  and proximity .Neonatal mortality is unacceptably very high. Managing complications and low birth weight, initiating exclusive breast feeding, improving quality of services and ensuring a continuum of care are recommended to increase survival of neonates. Neonatal mortality (NM) accounts for an estimated 2.8 million deaths worldwide , which cHigh maternal and neonatal mortality and still birth often occur because of inadequate care during pregnancy and childbirth. Hence, these deaths are considered as sensitive indicators of the quality of the healthcare system in the area . One-thiFurthermore, causes of NM vary by country and region with the availability and quality of health care, therefore, understanding NM in relation to these factors is crucial , 19, 20.A prospective cohort study was conducted among a cohort of neonates delivered between April 2014 and July 2014 in randomly selected seven hospitals of Tigray region, which is one of the nine administrative Federal regions of Ethiopia. Tigray region has an estimated total population of 4,565,000, . The Ethiopian health care has a decentralized four-tier system of primary, district, zonal and specialized hospitals. The primary care includes rural health posts, nested into health centers serving 25,000 populations. District hospitals form the tiers expected to serve 250,000 catchment populations. Zonal and specialized hospital serves 500,000 and 5,000,000 populations respectively. In Tigray region, one of the 11 administrative states in Ethiopia, has a total of 15 public hospitals; 6 zonal, 1 specialized hospitals, and the remaining 8 in the district and primary health care category. All hospitals provide maternal and newborn services including delivery services free of charge. Seven hospitals were randomly selected from the 15 hospitals of the region by lottery method . All motMothers with their Neonates, who gave live birth in the study hospitals or admitted within six hours, from April -July, 2014 were included in the study. Mothers who were unable to speak and mothers with psychiatric illnesses were excluded from the study.The sample size was 1162 neonates, which were determined by using STATA statistical package, Version 11.0. Based on the assumptions of 2.19 hazard-ratio  associatTigrigna. Two midwives, with a qualification of university degree and can speak the local language from each hospital were recruited for data collection. The data collectors had been collecting information by interviewing all mothers who delivered a live birth at the selected hospitals within the first 6-h after delivery. Besides, the clinical information was extracted by assessment of the neonate and mother. Mothers and live births were followed for 28 days, using three alternatives. The data collector visited the neonate daily, while he/she was in the hospital. After the mother was discharged; the data collector met the mother every 7-days either using a phone call or by creating liaison with a health extension worker and inquired about the neonatal condition and survival. Mothers who were not at home during the scheduled visit were revisited. When death occurred, the date and cause of death was recorded and probable cause of death was assigned after agreement between midwives and physicians based on national guidelines [Data were collected prospectively using pre-tested structured questionnaires and using a checklist for data that were collected from assessments of the neonate and mother. The questionnaire was derived from related literatures and WHO standard verbal autopsy questionnaires . The queidelines  and the idelines . The datThe inclusion of variables was partly guided by the Mosley and Chen conceptual framework  previousThe variables assessed in this category were: monthly reported income categorized into, low (<500 ETB), medium (500–1500 ETB) and rich (>2000ETB), and residence classified into ‘rrban’/‘rural’. Age at first marriage was measured in continuous scale yet for the sake of analysis later it was categorized into below age of 18 (teenagers), ‘18 years and above’. Similarly, educational status was first categorized in to ‘unable to read and write’,’able to read and write but no formal education’, ‘1–4 grade’, ‘5–8 grade’, ‘9–12 grade’, ‘college and above’ but later during analysis considering the few number of observations in the ‘able to read & write’ category, we merged it into (unable to read & write with able to read & write), and finally categorized into : ‘’, ‘primary education (1–8 grade)’, ‘secondary (9–12 grade)’ and ‘tertiary (college and above grades)’.Likewise, marital status was first categorized into married (living together), single, widowed, divorced and separated but later during analysis due to few observations, we merged the categories other than the ‘married’ category in to ‘others’. Occupation was classified based on the mothers report into ‘house wife/farmer’, ‘own business’ ‘government employee’ and ‘student’.This category includes: Gestational age, which was measured by using last menstrual period and/or ultrasound. Gestational age was categorized into preterm (<259 days), term (259–293 days) and post term birth (> = 294 days) but during analysis due to the few observations of post term births coded with term birth. Birth weight was defined according to the WHO classification as low birth weight (<2500 gm); normal birth weight (> = 2500 and <4000 gm); and macrosomia (> = 4000 gm)  but lateth percentile for age, ‘Small for gestational age’ birth weights below the 10th percentile. ‘Appropriate for gestational age’ defined as birth weight between the 90–10th percentile [Body mass index (BMI), measured by a standard height, weight measuring instrument found in the study hospitals and was categorized into underweight (BMI less than 18.5), normal (BMI 18.5–24.9), Overweight (BMI ≥25.0). Weight for gestational age was categorized according to WHO definitions into: ‘Large for gestational age’ was defined as a birth weight greater than the 90rcentile . The cutrcentile  and adapIn our study, fertility (no of children) defined as the actual production of live offspring excluding stillbirths, fetal deaths and abortions. It was classified into primiparae (only the current birth), 2–4 and multiparty (> = 5). But parity was defined as the number of full term children previously borne by a woman, excluding miscarriages or abortions in early pregnancy, but in contrast to fertility it includes stillbirths. It was categorized into ‘none’ ‘one’ ‘two’ and ‘> = three’.We defined gravidity as the number of pregnancies (completed or incomplete) experienced by a woman in contrast to fertility and gravidity it includes all pregnancies. We categorized it into ‘no pregnancy’, ‘one pregnancy’, ‘two pregnancy’ and ‘> = three pregnancy’.Antenatal follow up was assessed by categorizing in to ‘Yes’, if the mother ever had at least one antenatal follow up, ‘No’ if the mother never had antenatal follow up.Diagnosed medical disease was assessed using, ‘Yes’ if the mother had a medically known/diagnosed disease such as HIV/AIDS, Hypertension, Diabetes mellitus, epilepsy and ‘others’. ‘No’, if the mother did not have medically diagnosed disease.History abortion defined as mother history of abortion either induced, spontaneous or self initiated abortion before the current birth. It was categorized into ‘Yes’/‘No’.Induced abortion was defined as an abortion induced medically by a health professional, but self induced abortion was defined as abortion initiated by the women without medical and legal indication. Spontaneous abortion was defined as an abortion, which is neither medically induced nor self initiated, but the fetus spontaneously aborted itself. Similarly, history of still birth was categorized into ‘Yes’ and ‘No’.Place of birth (inborn or out born) was defined ‘Inborn’ if the neonate was delivered inside the study hospitals, ‘out born’ if the neonate was delivered in either health facility or home outside the study hospital. We categorized into ‘Yes’ if inborn or ‘No’ if out born.Place of death was defined as the place where the neonate died after included in the study, which was categorized into ‘hospital’ if the neonate died inside the hospital where he/she delivered, ‘Home’ if he/she died after discharged from the given hospital, ‘other health facility’ if the neonate died in other health facility other than the given hospital.Birth type was initially categorized into ‘single’, ‘twin’, ‘triple and above’. Yet for the purpose of analysis twin and triple birth were merged into ‘Multiple births’. Mothers who gave twin and triple birth were counted separately for each birth for the sake of analysis.Distance was recorded in continuous scale, but later categorized in to <5 km far from the nearest health facility, 5–10 km and > =10 km far from the nearest health facility.Mode of delivery is classified into ‘spontaneous vaginal delivery’, ‘operative  vaginal delivery’ and ‘cesarean section’. Instrumental delivery was defined as the application of either forceps or a vacuum device to assist the mother in effecting vaginal delivery of a fetus.The variables considered in this category were: Hypothermia in which it was classified according to WHO recommendations into ‘Yes’ if body temperature below the normal range (36.5 °C–37.5 °C), ‘No’ if it is within the normal range and above .Temperature control for the hypothermic neonates categorized into: ‘Yes’ if the hypothermic neonate temperature returns to normal after appropriate interventions was undertaken and ‘No’ if the hypothermic neonate temperature is not returned to normal range after the intervention. We did not consider this variable in the Cox-regression model due to large missing values.Exclusive breast feeding (EBF) (Yes/No): was defined as feeding with only breast milk and nothing else, with the exception of vitamin supplements and prescribed medicines.Maternal complication categorized into ‘yes’ or ‘No’, which is considered present if the mother had an obstetric hemorrhage, puerperal sepsis and pyrexia, prolonged labor, eclampsia and preeclampsia, mal-presentation and mal-position, premature rupture of membrane (PROM), cord prolapse, obstructed labor, cephalopelvic disproportion (CPD), emergency cesarean section, and retained placenta.Neonatal complication is considered presented if the neonate had asphyxia, prematurity, infection, hypothermia, jaundice and other rare complications during birth.Early neonatal mortality rate (ENM) was defined as the probability of dying before 7 completed days of life. Late neonatal mortality rate (LNM) as the probability of dying between 7 completed days and before 28 completed days; and overall NM was defined as death of a newborn within 28 days of his/her birth. NMR was defined as the number of deaths of neonates per 1000 live births. NM was categorized into ‘Yes’ if the neonate died ‘No’ if the neonate censored.Censored births were the neonates who were alive at the end of follow up, withdrawal and lost-to-follow-up. Time-to-death was defined as death of a neonate at specific time (day) within the 28 days follow-up time.The outcome of the follow up was categorized into ‘death’ if he/she died during follow up, ‘lost to follow up’ if the mother phone was not working, moves to another area from the original place of residence and not met by health extension worker. ‘Withdrawal’ if the mother refuses the follow up due to inconvenience and ‘alive’ if the neonate survival is assured by the data collector at the last follow- up time.Death of neonate was the event of interest and the coding were “1” for death and “0” for censored. Time-to-death was calculated by subtracting the date of death from birth.Data was entered, cleaned, recoded and analyzed using STATA version-11.1. For description, frequencies, percentages, and rates, Kaplan Meier curves were used to estimate survival time. Log-rank test was used to look statistical differences among/between the categories of variables. To identify potential predictors of NM, Cox-proportional hazard regression model was fitted by successive stepwise backward elimination. Statistical significance was declared at p-value <0.05. Confounding and effect modification was checked by looking at regression coefficient change if greater than or equal to 15 % and multi-collinearity was checked using variance inflation factor and value of <10 was used as a cutoff point, indicating no colinearity.Proportional hazard assumption was tested by using covariate specific Proportional hazard assumption test. Residuals were checked using goodness-of-fit test by Cox Snell residuals.Ethical clearance was obtained from Mekelle University, College of Health Sciences Ethical review board. Permission letters were also sought from Tigray Regional Health Bureau. Written Informed consent from the mother was obtained after clear explanation of the purpose of the study. Confidentiality and anonymity was maintained.n = 1162), however, ten (0.96 %) observations were excluded from the analysis due to incompleteness  mothers, 1071 (92.97 %) were married, 368 (31.94 %) of the live births were from teenage mothers (below the age of 18 years), nearly one third 361 (31.34 %) of the mothers had completed secondary school and 373 (36.73 %) of the mothers had a reported monthly income >1500 ETB  of the mothers had previous history of abortion and 91 (7.9 %) of the mothers had a history of stillbirth. The mean and standard deviation of the current age of mothers was 26.65 (sd = ± 5.4).).Regarding medically diagnosed diseases, 100 (8.7 %) had medically known disease. Of these, hypertension had highest prevalence 26 (26 %). But some mothers had two medically diagnosed diseases at the same time, for instance, both hypertension and HIV, for this reason the ‘disease others’ category instead of comprising 68 mothers, it became 73 mothers. It was due to 5 mothers that had double burden of disease simultaneously  and 273 (sd = ±14. 3) respectively. Of the total, 1012 (87.8 %) neonates received EBF and 180 (15.6 %) were large for gestational age neonates. In our study, only few 67 (5.8 %) neonates were outside the study hospitals (out bearing). Among all respondents, 836 (76.3 %) of the mothers were living in <5 km distance to the nearest health facility  neonates died which makes the NMR 62.5 per 1000 live births. At the end of follow up, 1024 (88.9 %) were alive, 53 (4.6 %) lost to follow up and 7 (0.6 %) were withdrawal  , place of residence , number of children , history of stillbirth , history of abortion , birth type , maternal complication , EBF , neonatal complication , weight for GA , hypothermic birth, 1 and 5 min Apgar score, length of neonate, birth defect, distance to nearest health facility, delivery assistance and place of delivery  had 55 % lesser hazard of neonatal death compared to neonates born with a birth weight of less than 2500 gm (low birth weight) . Neonates who were not initiated EBF had 7.5 times higher hazard of death than neonates who were initiated EBF . Neonates born from mothers who did not have complications were 63 % less likely to die than neonates born from mother’s who had complications . Neonates born from mothers residing in ≥10 km far from their nearest health facility had 2.5 times higher to die than neonates born from mothers residing within ≤5 km distance . Neonates who had no complication after birth had 99.86 % lesser hazard of death than who had the complication   was observed, which is striking because the deaths happened in hospitals where highly skilled birth attendants and formal health care system are present. This rate is higher than several studies conducted in Ethiopia and Africa , 31–34 aThe incidence of ENM was higher than the LNM and the overall incidence is almost two times higher than the study findings of Butajira, Ethiopia . This diOur study has revealed that most neonatal deaths occurred in the first 24 h and in the first week of life, which is consistent with different studies conducted before , 37, 38.The current study finding revealed that neonates with a low birth weight experienced higher mortality. This finding is similar to a study conducted in different parts of developing countries , 38, 39.Our findings showed that neonates born from mothers who have complications during birth had a higher chance of death. This is similar to previous studies reported on maternal complications related to high risks of NM , 34, 42.In accordance with our findings, in general, studies show that male-presentation, prolonged labor, hemorrhage, infection, PROM and obstructed labor were associated with NM , 36, 39.Distance to the nearest health facility was also among the independent predictors of NM. Similarly, several studies also reported that neonates who live in remote and hard to reach areas from health facilities are at increased rate of death than those who live in nearby to the health facilities , 37, 39.The current study findings revealed that initiating EBF has a protective effect on hazards of NM. This is also reported by some studies, as EBF is essential to reduce newborn deaths . Other sNeonatal complications are also one of the independent predictors for NM. In this study, the main causes of neonatal complications were: meconium aspiration, prematurity, low birth weight and prolonged labor, which lead to Apgar score less than 7 and birth asphyxia. The causes of complications result in neonatal asphyxia, hypothermia, sepsis and other complications, although there are no significant differences among them. Similarly, reports indicate that complications of prematurity are currently among the leading causes of NM , 2, 14. The strength of this study is that it had included all predictors of NM and data collection was also complete and reliable. The study area covers the entire region of Tigray; it is generalizable to all hospitals of the region and Ethiopia. Limitations of this study are that the effect of seasonal variation on NM was not considered and the study was conducted only in public health institutions. Moreover, home deliveries and neonates who arrived at study hospitals after 6 h of birth were not considered as part of the study, as we failed to track the deaths that occurred at home and this may underestimate the NM rate because home deliveries are at risk of complications and deaths. We encountered 5.2 % lost to follow up and withdrawals because mothers were unable to answer phone calls, meet with health extension workers and/or are not available during physical visits. Most of the mothers were moved from the original place of residence and their phone was not working during the follow up time. These mothers may encounter neonatal deaths that could underestimate our neonatal mortality rate.In this study, unacceptably high burden and incidences of NM  was observed, which is unexpected as the births were attended by highly skilled health workers. Moreover, proximate factors  were the important predictors.Therefore, a comprehensive effort should be undertaken to improve health service provided in the region, especially on the competency of health workers and quality of health services, including availability of necessary equipment and setup to manage neonatal and maternal complications. In addition, maternal health before delivery, including quality of antenatal care utilization, low birth weight, initiating exclusive breast feeding, continuum care of the neonate after discharge and access should be considered to improve survival time of neonates.AIDS, acquired immuno deficiency syndrome; BMI, body mass index; CPD, cephalo pelvic disproportion; EBF, exclusive breast feeding; ENM, early neonatal mortality; ETB, Ethiopian birr; HIV, human immunodeficiency virus; LNM, late neonatal mortality; NM, neonatal mortality; NMR, neonatal mortality rate; PROM, premature rupture of membrane; U5M, under-five-mortality; WHO, World Health Organization