Spontaneous preterm birth is commencement of labor with intact or pre labor rapture of membrane and birth before 37 weeks of gestation. The aim of this study was to identify common factors associated with spontaneous preterm birth in Addis Ababa public hospitals.After random selection of three hospitals from the six Addis Ababa’s Public hospitals having Neonatal intensive care unit, systematic sampling was employed to select study units from admission log book of the neonates. Data were collected using structured checklist. Finally, data entered to EpiData 3.1 and transported to SPSS 22 for analysis. Bivariate and multivariate logistic regression analysis was done for the variables.P = 0.001, AOR = 0.182, 95% CI: ] and maternal HIV infection  significantly associated with spontaneous preterm birth.The mean gestational age of preterm birth was 32.45 (±2.903 SD). Majority (66.1%) of preterm births were spontaneous and 33.9% were induced preterm births. Hypertension during pregnancy [Those mothers who were diagnosed with hypertension during pregnancy less likely gave spontaneous preterm birth than who had no history of hypertension during pregnancy and HIV positive mothers gave spontaneous preterm more likely than HIV negative mothers. Thus, giving emphasis to these factors with appropriate care during pregnancy is important to reduce spontaneous preterm birth. Preterm birth is defined as a delivery which occurs at less than 37 completed weeks of gestation. It is classified as extremely preterm (< 28 weeks), very preterm (28 to < 32 weeks), and moderate to late preterm (32 to < 37 weeks). Likewise preterm birth can be categorized on the basis of birth weight. Neonates weighting less than 2500 g are classified as low birth weight (LBW), < 1500 g are very low birth weight (VLBW) and < 1000 g are extremely low birth weight (ELBW). Preterm birth can also be spontaneous or provider initiated (induced). Spontaneous preterm birth is commencement of labor with intact or pre labor rapture of membrane and birth before 37 weeks of gestation. Spontaneous onset of labor accounts for 65–70% of all preterm births and provider initiated for 30–35%  and maternal HIV infection  remained associated with spontaneous preterm birth and other variables turned insignificant in multivariate analysis. Those mothers who were diagnosed with hypertension during pregnancy less likely gave spontaneous preterm birth than who had no history of hypertension during pregnancy and HIV positive mothers gave spontaneous preterm more likely than HIV negative mothers . Socioeconomic difference with methodology of the study can be reason into account for this variation. But finding in this study is in line with evidence of study from Taiwan for risk of preterm birth. Even though age classification for the association varies, study in Malawi also supports this as younger women are at high risk of giving preterm birth [P = 0.041, AOR = 3.408, CI: 1.048, 11.079). Similarly, HIV disease significantly associated with increased risk of giving preterm birth in Tanzania [Prevalence of preterm birth in NICU admission in this study 16.5%) is higher than that of Gondar university hospital and lower than that of Mettu Karl hospital. The reason for this variation might be methodological differences employed in these previous studies , 5. Majo% is highrm birth , 24. As rm birth , prematuTanzania .Age of mothers younger than 25 years, having at least one medical disorder during pregnancy, maternal HIV infection, hypertension during pregnancy, premature rupture of membrane from which maternal HIV infection and hypertension during pregnancy remained significant in multivariate analysis were factors found to have significant association with spontaneous preterm birth.


Infant birth weight affects neuromotor and biomechanical swallowing performance in infant pig models. Preterm infants are generally born low birth weight and suffer from delayed development and neuromotor deficits. These deficits include critical life skills such as swallowing and breathing. It is unclear whether these neuromotor and biomechanical deficits are a result of low birth weight or preterm birth. In this study we ask: are preterm infants simply low birth weight infants or do preterm infants differ from term infants in weight gain and swallowing behaviors independent of birth weight? We use a validated infant pig model to show that preterm and term infants gain weight differently and that birth weight is not a strong predictor of functional deficits in preterm infant swallowing. We found that preterm infants gained weight at a faster rate than term infants and with nearly three times the variation. Additionally, we found that the number of sucks per swallow, swallow duration, and the delay of the swallows relative to the suck cycles were not impacted by birth weight. These results suggest that any correlation of developmental or swallowing deficits with reduced birth weight are likely linked to underlying physiological immaturity of the preterm infant. Birth weight is an important predictor of neuromotor and physiological performance in early perinatal development of mammals –4. Our kThe second category of infant birth weight studies is more clinical in nature. The questions posed in these studies encompass a wider range of physiologic processes, including long-term growth and feeding behavior , 6. ThesPreterm infants are born at lower weights than their term counterparts and experience lowered growth potentials into adulthood , 9. AlthIn this study, we ask: are preterm infants simply low birth weight infants, or are their rate of growth and neurological development distinct from those of term infants? Using a validated infant pig model , we hypoWhile preterm infant pigs will start out at lower birth weight, they will gain weight at the same rate as the term infant pigs. Alternatively, preterm infants may gain weight at either a lower or higher rate than their term counterparts.Birth weight will explain some variation and differences in physiological swallowing behavior, but birth status (term vs. preterm) will be more of a determining factor. Alternatively, birth weight may be the dominant factor that explains difference in behaviors between terms and preterm infants.We tested these hypotheses by measuring birth weight, daily weight gain, and physiological swallowing measures in term and preterm infant pigs.All animal experiments described in this manuscript were approved by the Northeast Ohio Medical University (NEOMED) Institutional Animal Care and Use Committee protocol #17-04-071. The data were collected between 2017–2019, and used for several published studies , 28–30. Sus scrofa) from 6 Yorkshire/Landrace cross sows  either at term, or at seven days preterm. Preterm neonatal pigs were delivered at 108 days gestation via cesarean section, equivalent to approximately 30 weeks human gestation [This study used a total of 25 piglets  and 17 days postnatal  , 30. At The first hypothesis tested differences in weight gains between term and preterm infants. To address this hypothesis, we analyzed weight data from seven preterm and five term infants from two sows  in two ways , 30. We To test our first hypothesis regarding differences in weight gain, we first used paired t-tests in Excel  as well as generalized linear models with litter as a random effect in R Studio to compare weights of preterm and term infant litters on day one and again on day 17 . Then toTo test the second hypothesis concerning the effects of birth weight on swallow performance, we conducted three individual covariate analyses using Systat . We first ran an ANCOVA analysis, with a single physiologic variable  as the response and with treatment group as a fixed factor with four levels: preterm day seven, term day seven, preterm day 17, term day 17. Birth weight was listed as a covariate and individual as a random factor. The interaction term tested whether the linear relationship between birth weight and physiologic variable was the same for each of the groups . If therSample sizes used herein were deemed to be sufficient based on power analyses and variation in subtle behaviors observed in previous studies , 38. AddBW = 0.58 ± 0.15 kg, TBW = 1.40 ± 0.16 kg, p < 0.001, tcrit = 2.306). At day four, preterm infants’ weight was equivalent to the terms’ and gained weight at a similar rate through day 17 . Levene’s test revealed that at days one, seven, and 10, the amount of variation between preterm and term was not significantly different (p > 0.05). However, by day 16, the variation in the preterm infants was significantly higher than in the terms . When using corrected age , birth weights were similar however, at day 17  body weight was greater in preterm infants than in term infants.Birth weight was lower in preterm than in term infants . The daily coefficient of variation in the preterm infants was consistently higher than the term infants throughout  and Levene’s test revealed that by day 16, the variation was also greater in preterm infants that in terms .When scaling weight gain by initial birth weight, we saw further amplified differences between preterm and term infants . By the PT = 0.37 ± 0.46 g/ml, WGT = 0.17 ± 0.10 g/ml, p = 0.05, tcrit = 2.1). When scaling the weight gain by their initial birth weight . The weight gained in first 5 days since birth  was higher than in the remaining postnatal days (daily WGPT d6-d17 = 0.19 ± 0.09 kg vs WGT d6-d17 = 0.15 ± 0.10 kg) where the weight gain was similar.When measuring the mean daily weight gained as a function of consumption  did not overlap with those of the term infants, nor did the adjustment of the time scale make the growth rates appears similar to the term infants. Correcting for the degree of prematurity did not appear to put the preterm infants on the same growth trajectory as the term infants. This suggests that infants do not develop in first few weeks of life, during what would have been the end of the gestational period, in the same way had they been carried to full term. Additionally, one limitation that should be noted is that by correcting by degree of prematurity, the results that are seen are simply according to existing ‘day 17’  mass and variation trends. Therefore, by correcting, it makes sense that while preterm infant birth weight aligns with term birth weight, the corrected day 17 weight is much higher as the rate of weight gain has not been corrected or adjusted in any way. However, by eschewing the initial jump in preterm weight gain seen in the first three days, the weight differences between the smallest and largest infants were even more pronounced by age correction. It becomes even more obvious that in preterm infants, individuals that may suffer from obesity or low body weight into weaning may do so to greater degree and in greater numbers relative to the term litter which exhibits less variation relative to the mean.Using corrected ages to account for a shortened time in utero further highlighted differences between preterm and term infants. Preterm infant weights leading up to corrected day 17 Click here for additional data file.S2 TableMeasurements of different swallowing behaviors made on both preterm and term individuals at different days of the postnatal period. Litter/Sow identification is also listed to indicate whether the litter number and term status.(DOCX)Click here for additional data file.


The incidence of neurodegenerative diseases has shown an increasing trend. These conditions typically cause progressive functional disability. Identification of robust biomarkers of neurodegenerative diseases is a key imperative to facilitate early identification of the pathological features and to foster a better understanding of the pathogenetic mechanisms of individual diseases. Diffusion tensor imaging (DTI) is the most widely used diffusion MRI technique for assessment of neurodegenerative diseases. The DTI parameters are promising biomarkers for evaluation of microstructural changes; however, some limitations of DTI restrict its wider clinical use. New diffusion MRI techniques, such as diffusion kurtosis imaging (DKI), bi‐tensor DTI, and neurite orientation density and dispersion imaging (NODDI) have been demonstrated to provide value addition to DTI for evaluation of neurodegenerative diseases. In this review article, we summarize the key technical aspects and provide an overview of the current state of knowledge regarding the role of DKI, bi‐tensor DTI, and NODDI as biomarkers of microstructural changes in representative neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.52 J. MAGN. RESON. IMAGING 2020;52:1620–1636. THE PREVALENCE OF NEURODEGENERATIVE DISORDERS is increasing, in part due to increased lifespan. According to the United Nations report on world population aging (2017),Diffusion magnetic resonance imaging (MRI), which measures the random motion of water molecules in tissues along a specified direction, is a promising approach for noninvasive characterization of tissue microstructure. Currently, diffusion tensor imaging (DTI)Recent developments in diffusion MRI have addressed some of the limitations of DTI. Diffusion kurtosis imaging (DKI),In this review we discuss the key technical aspects and provide an overview of the current state of knowledge regarding the role of these more advanced diffusion MRI approaches. We discuss their potential to provide biomarkers of microstructural changes in neurodegenerative diseases including Alzheimer's disease (AlzD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Since the use of DTI for evaluation of neurodegenerative diseases has been extensively reviewed, we will only briefly touch on the topic of DTI.The principles of DTI and its basic concepts have been extensively reviewed in the literature  is the diffusion‐weighted signal along that direction with a certain b value, and S0 is the nondiffusion‐weighted signal.DKI was proposed as a mathematical extension of DTI. Kurtosis is a dimensionless measure that quantifies the non‐Gaussian distribution of water diffusion in a voxel.The kurtosis parameters such as mean (MK), the average of the diffusion kurtosis along all the diffusion directions; axial kurtosis (AK), the kurtosis along the axial direction; and radial kurtosis (RK), the kurtosis along the radial direction are suitable for evaluating neuronal integrity in white matter (WM) regions with complex arrangements, including in areas with crossing fibers Table .21 MorFree water is defined as the water molecules that do not flow and are not restricted. In the human brain, free water is present as CSF in the ventricles and around the brain parenchyma. Free water may also accumulate in the extracellular space in the brain parenchyma because of brain pathologies such as tumors, trauma, and neuroinflammation.T, MDT, RDT, and ADT) and extracellular free water changes, as measured by the fractional volume of free water (referred as FW) (Table Ctissue) and the other isotropic with diffusion characteristics of free water (Cwater).Abi–tensor is the voxelwise modeled attenuation vector that has an entry for each diffusion orientation and Atissue and Awater are the represented model of attenuation vectors. The scalar f is the fractional volume of the tissue compartment (0 < f < 1), and similarly (1‐f) is the fractional volume of free water. The FW compartment has a fixed diffusivity of 3 × 10‐3 mm2/s (the diffusion coefficient of the FW at body temperature).Bi‐tensor DTI enables the differentiation between alterations in the tissues themselves, as measured by the free water‐corrected DTI indices (referred as FAW) Table .8 ThisThe advantage of this model is that the method requires a single‐shell DTI acquisition and can be easily merged with the existing DTI pipelines.However, the bi‐tensor DTI model does have some limitations. First, the assumption that there is no exchange of water molecules between the compartments. In this context, precaution has to be taken with edema, since it might be correlated with the changes in tissue permeability. An increase in the exchange rate is expected to cause a bias in the estimation of FA, and, therefore, a bias in the FA values of the tissue compartment.A can be written as follows:Ain and Vin are the normalized signal and volume fraction of the intraneurite compartment; Aen is the normalized signal of the extraneurite compartment; and Aiso and Viso are the normalized signal and volume fraction of the CSF compartment, respectively.NODDI is a multishell diffusion technique that enables more specific characterization of the tissue microstructure in the whole brain using a clinically feasible protocol.NODDI enables more specific characterization of the tissue microstructure by estimating the packing density of neurite density and the spatial organization or the geometric complexity of the neurites; these are referred to as the neurite density index (NDI) .‐3 mm2/s. Hence, the assumptions underlying NODDI may represent an oversimplification, which could lead to reduced information about the microstructure, and any deviation from these fixed values can bias the remaining parameters, thereby reducing their specificity. Crossing fibers are not explicitly modeled within the NODDI model; consequently, ODI is sensitive to the presence of crossing fibers. In the case where two bundles of fibers cross with only one degenerating, it will exhibit reduced ODI.The main limitation of NODDI is the absence of any direct diffusivity estimation. NODDI is predetermined and assumes equal parallel intra‐ and extracellular diffusivity  and hyperphosphorylation of tau protein, which leads to the formation of Aβ‐plaques and intracellular neurofibrillary tangles, respectively, leading to neuronal death.MRI volumetry to detect the magnitude and pattern of brain atrophy, notably in the medial temporal lobe including hippocampus, amygdala, and entorhinal area, is now the gold standard for the diagnosis of AlzD.In a multicenter study, significant reduction of FA and a significant increase of MD were demonstrated in core areas of AlzD pathology including corpus callosum, medial and lateral temporal lobes, as well as fornix, cingulate gyrus, precuneus, and prefrontal lobe WM.Falangola et al,Gong et alChen et al181, Aβ42, YKL‐40, sAPPβ, and tTau, in the bilateral temporal and frontal lobes  Fig. .59 LowPD is the second most common progressive neurodegenerative disorder that involves multiple neurotransmitter pathways that are associated with a range of clinical features. The diagnosis of PD is based on the presence of motor deficit including bradykinesia, rigidity, and tremor. The motor features result from a selective loss of dopaminergic neurons in the substantia nigra (SN) pars compacta, and widespread aggregation of α‐synuclein immunoreactive inclusions in the form of Lewy pathology comprising Lewy neurites and Lewy bodies.The parameters of DTI, especially FA and MD, were able to distinguish between PD patients and healthy controls. According to recent meta‐analytic studies,Only two studies have evaluated the SN in PD using DKI and both studies found a significant increase in MK.T values in the posterior SN compared with healthy controls.T beyond the SN, including in the basal ganglia, thalamus, and cerebellum.FW within the SN is considered a promising biomarker to distinguish patients with PD from healthy controls and as a biomarker of disease progression in PD. Both single‐ and multisite studies comprising large cohorts have shown that PD patients have higher FW and unchanged FAIn longitudinal studies, FW in the posterior SN was shown to increase with the progression of PD over 1 yearT and higher MDT, ADT, and RDT  in anterior WM areas as well as higher FW (index of neuroinflammation) in posterior WM areas were observed compared with the controls , and ROI analyses. The changes in bi‐tensor DTI indices were demonstrated in somewhat more specific WM areas compared with the changes of DTI indices, whereas lower FAols Fig. . The autres Fig. . This suPD patients were shown to exhibit decreased NDI in the contralateral SN pars compacta and putamen compared with healthy controls. On receiver operating characteristics curve analysis, NDI also showed the best diagnostic performance compared with DTI measures.In a studyC9orf72) are the most commonly known genetic causes of ALS. The diagnosis of ALS is based on a history of painless progressive weakness associated with signs of upper and lower motor dysfunction.ALS is a neurodegenerative disease primarily characterized by progressive atrophy and weakness of the limbs, as well as the bulbar and respiratory muscles due to the impairment of lower and upper motor neurons.According to some systemic reviews and meta‐analytic studies,In the ROI analysis of the motor cortex  of ALS patients with mild‐to‐moderate impairment, MK, AK, and RK were found to be reduced compared with that in healthy controls; however, no significant between‐group differences were observed with respect to the DTI parameters.In a voxel‐based analytic study, ALS patients showed lower MK and RK in the following WM areas as compared with that in controls: bilateral precentral gyrus, bilateral corona radiata, bilateral middle corpus callosum, left occipital lobe, and right superior parietal lobule. In the GM, ALS patients showed decreased MK and RK in the bilateral precentral gyrus, bilateral paracentral lobule, and left anterior cingulate gyrus Fig. .87 RedTo the best to our knowledge, no studies have investigated the use of bi‐tensor DTI in ALS.Whole‐brain voxelwise analysis in patients with ALS manifestation using NODDI demonstrated significantly reduced NDI throughout the intracranial corticospinal tracts up to the subcortical WM of the precentral gyri and across the corpus callosum, with increased ODI in the anterior limb of right internal capsule and increased ISO adjacent to the right lateral ventricle relative to healthy controls Fig. .89 FurC9orf72 mutation.C9orf72 mutation carriers demonstrated WM alterations in 10 tracts, involving frontotemporal‐related and corticospinal tracts with NDI and only five tracts with DTI  metrics. Effect size results confirmed that NDI was more sensitive than DTI metrics, whereas the effect size of the two tracts was significantly higher for NDI than for DTI metrics.ROI analysis showed that NODDI also had greater sensitivity compared with DTI in the WM and GM volumetry of presymptomatic carriers of the HD is an autosomal dominant, progressive neurodegenerative disorder that typically presents in young middle age. The condition is characterized by motor, cognitive, and psychiatric disturbances.A recent meta‐analysisTo date, DKI has not been applied in patients with HD. However, in some studies using ROI analysis, kurtosis indices have been shown to change with the pathological alterations in aged transgenic HD rats. Blockx et alSteventon et alIn a study of premanifest HD (pre‐HD) using NODDI, a widespread reduction in axonal density (indexed by NDI), which overlapped with increased MD, was observed in the WM tracts, including the corpus callosum and the surrounding basal ganglia; reduced NDI in the corpus callosum showed a positive correlation with a marker of severity Fig. . The resEarly diagnosis of neurodegeneration is important for the future development of neuroprotective therapies for neurodegenerative diseases. This review indicated that DKI, bi‐tensor DTI, and NODDI may serve as potential sensitive biomarkers for assessment of microstructural changes in neurodegenerative diseases and as biomarkers of disease progression. Additionally, DKI, bi‐tensor DTI, and NODDI showed remarkable advantages over DTI with respect to detection of GM changes in neurodegenerative diseases.Importantly, the FW map obtained with bi‐tensor DTI and NODDI may be used as a biomarker of neuroinflammation.A growing body of evidence suggests the involvement of myelin as a crucial neuropathological feature of neurodegenerative diseases.Even though multiple sclerosis has been recently considered a neurodegenerative disease, it was not covered in the current article.


Preterm birth (occurring before 37 completed weeks of gestation) affects 15 million infants annually, 7.5% of which die due to related complications. The detection and early diagnosis are therefore paramount in order to prevent the development of prematurity and its consequences. So far, focus has been laid on the association between reduced intrauterine fetal growth during late gestation and prematurity. The aim of the current study was to investigate the association between accelerated fetal growth in early pregnancy and the risk of preterm birth.This prospective cohort study included 69,617 singleton pregnancies without congenital malformations and with available biometric measurements during the first and second trimester. Estimation of fetal growth was based on measurements of biparietal diameter (BPD) at first and second trimester scan. We investigated the association between accelerated fetal growth and preterm birth prior to 37 weeks of gestation. The outcome was further stratified into very preterm birth (before 32 weeks of gestation) or moderate preterm birth (between 32 and 37 weeks of gestation) and medically induced or spontaneous preterm birth and was further explored.The odds of prematurity were increased among fetuses with accelerated BPD growth (> 90th centile) estimated between first and second ultrasound scan, even after adjustment for possible confounders . The findings remained significant what regards moderate preterm births but not very preterm births. Regarding medically induced preterm birth, the odds were found to be elevated in the group of fetuses with accelerated growth in early pregnancy . On the contrary, fetuses with delayed fetal growth exhibited lower odds for both overall and spontaneous preterm birth.Fetuses with accelerated BPD growth in early pregnancy, detected by ultrasound examination during the second trimester, exhibited increased odds of being born preterm. The findings of the current study suggest that fetal growth in early pregnancy should be taken into account when assessing the risk for preterm birth.The online version contains supplementary material available at 10.1186/s12884-020-03458-x. Preterm delivery, i.e., birth prior to 37 gestational weeks, complicates 4–13% of deliveries worldwide and is the predominant cause of neonatal morbidity and mortality, having an impact on approximately 15 million infants annually  or stillbirths (n = 197) were excluded, resulting in a final study population of 69,617 singleton pregnancies.Singleton pregnancies  from the population area of the study with available data on biometric measurements in the first and early second trimester between January 1st, 2008 and October 22nd, 2014 were included in the study sample. Pregnancies with congenital malformations (2). Expected gestational age at second trimester scan was calculated by adding number of days between the two examinations to the observed gestational age at first trimester scan. The difference between observed and expected gestational age at second trimester scan, was expressed in z scores , measured by ultrasound scan during the first half of pregnancy. The Swedish Association for Obstetrics and Gynecology (SFOG) dictates that fetal BPD should be measured from the outer edge of the proximal parietal bone to the inner edge of the distal parietal bone at the level of thalami and septum pellucidum and performed by specially trained midwives according to a standardized protocol . FirstlyThe outcome measure was overall prematurity (i.e. birth at < 37 + 0 weeks). Furthermore, we analyzed the odds for very preterm birth (birth at < 32 + 0 weeks) and moderate preterm birth (birth between 32 + 0 and 36 + 67 + 0 weeks). Preterm births with clinician-initiated obstetric interventions, as opposed to spontaneous preterm births, were defined as medically induced preterm births and included prelabor C-sections and induced labors.2), primiparity (yes/no), smoking at early pregnancy (yes/no), use of in vitro fertilization (IVF) for the current pregnancy (yes/no), pre-gestational diabetes mellitus (yes/no), chronic hypertension (yes/no) and male fetal gender (yes/no). Pre-pregnancy diabetes mellitus was defined by the ICD-10 diagnosis codes O240, O241, while chronic hypertension was defined as treatment with antihypertensive medication at first antenatal visit and/or ICD-10 diagnosis code indicating chronic hypertension  developed at any time point before the 20th gestational week. ICD codes were provided by the responsible doctor at discharge from the hospital after delivery, while information regarding blood pressure measurements, proteinuria, and medication was provided by midwives at antenatal care or at the hospital before delivery. Information on fetal gender was collected from delivery charts. Maternal country of birth was divided into Sweden, other Nordic countries , and non-Nordic countries. Information on paternal characteristics was not available in the database.Pregnancy characteristics collected from the woman’s medical records regarded maternal age at first antenatal visit (15–35 years or 36–55 years), maternal height (130–154 cm or 155–200 cm), BMI at early pregnancy  or delayed growth (<10th percentile) were calculated based on discrepancy in fetal growth at early second trimester scan, using fetuses with appropriate growth (10th to 90th percentile) as the reference group. The odds of preterm birth were estimated by binary logistic regression analysis and expressed as crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age (< or ≥ 35 years), maternal height (< or ≥ 155 cm), BMI (< or ≥ 30 kg/m2), non-Nordic origin (yes/no), primiparity (yes/no), smoking (yes/no), IVF (yes/no), pre-gestational diabetes mellitus (yes/no), chronic hypertension (yes/no) and male fetal gender. The selection of potential confounders recorded at the first antenatal visit, was based on directed acyclic graphs (DAGs)  was used for the statistical analyses and a two-sided ) Figure . Lastly,The study was approved by the Regional Ethical Review Authority in Stockholm, Sweden (Dnr 2014/2179–31/1). The need for written or oral informed consent for participation in the study was waived since all collected data were depersonalized prior to the analysis.There was no patient or public involvement in the design, conduct, reporting or dissemination plans of our research study.The characteristics of the study population according to gestational age at birth are presented in Table Based on the information on biometric measurements, 7091 (10.1%) of fetuses had BPD growth more than the 90th percentile at the second trimester ultrasonic scans. In 55,571 (79.8%) of fetuses, the growth was between 10th and 90th percentile, while 10.1% of fetuses had a BPD growth smaller than expected (< 10th percentile). Mothers whose fetus had exhibited accelerated fetal growth at second trimester were more often younger and multiparous compared to those whose fetus had appropriate fetal growth. Male fetuses at second trimester were more often larger in size than female fetuses Table .Table 2Compared to fetuses with appropriate growth at early second trimester ultrasound, fetuses with accelerated growth had a 40% increased risk for prematurity, both what regards moderate as well as very preterm birth. The association between fetal growth and overall and moderate preterm birth remained unchanged despite adjusting for maternal characteristics, pre-pregnancy diabetes, chronic hypertension and fetal gender Table . HoweverMedically induced labor was observed in 40.6% of preterm births with the odds of prematurity being increased among fetuses with accelerated growth compared to fetuses with appropriate growth at second trimester scan. Even after adjustment for relevant confounders, the odds remained elevated . Among them, 234 fetuses were born preterm (31 were born very preterm and 203 moderate preterm). Fetuses that experienced delayed growth in early pregnancy, had a decreased risk for preterm birth , an effect seen mostly among spontaneously preterm born infants . These findings underline the importance of accelerated fetal growth in early pregnancy and the potential association to complications later in pregnancy.p = 0.074) [In accordance with our study, Pedersen et al. demonstrated an increased risk for prematurity among fetuses with accelerated growth; OR 3.27  for very preterm births 22–33 weeks and OR 2.30  for moderate preterm births [= 0.074) , 7. In t= 0.074) . On the = 0.074) . Another= 0.074) –16, it iThe incidence of preterm birth estimated in our study is in accordance with the reported national rates in Sweden and other Nordic countries , 17, 18.Although the exact pathophysiological mechanism behind our findings still remains unknown, a number of possible hypotheses associated to the onset of labor have been proposed. One of the theories to explain the timing of birth refers to prelabor mechanical distention and stretching of the myometrium . The oveOne of the major strengths of our study is the accurate estimation of gestational age based on ultrasonographic measurements at the first trimester of pregnancy and not on the self-reported last menstrual period of the participating women which can often be unreliable. Furthermore, we attempted to explore growth velocity based on the measurements of only one biometric characteristic , since it was the only biophysical parameter that was readily available both at first and second trimester scan. The latter, in addition to the possibility of calculating gestational age solely based on BPD measurements also justifies why the formula by Selbing was employed, enabling us at the same time to avoid uncertainty introduced by utilizing different calculation methods. Another major strength lies on the large sample size with detailed information collected prospectively, which limits the risk for recall bias. The large cohort size in the study, made it possible to stratify the analysis in spontaneous and medically induced groups, as well as in moderately preterm and very preterm groups and therefore explore rare outcomes. Furthermore, Sweden has a long tradition of valid registries entailing routinely collected, comprehensive and accurate data especially in the perinatal field. In addition, the publicly funded healthcare system of the country enables equal access to prenatal healthcare and early identification and possibly preventive intervention against preterm birth. That makes Sweden an appropriate model country to explore the research question. Lastly, since all ultrasound units in Sweden follow the same professional standards, we can only assume that the performance variation of the ultrasound examiners is restricted .The present study is however not void of limitations. First and foremost, we lack information on the paternal characteristics, which along with the maternal might influence fetal growth. We also lack information on potential risk factors associated to the outcome (i.e. preterm birth) such as prior preterm birth, cervical length, uterine fibroid or malformations and genitourinary infections. However, all of these covariates are not anticipated, according to the literature, to be unevenly distributed between the groups of interest, i.e. the reference group of fetuses with appropriate growth and the comparison group of fetuses with accelerated growth. Furthermore, as we were obliged to restrict our population to pregnancies where CUB was performed and a fraction of the population did not perform first trimester sonographic scans, a potential selection bias related to advanced maternal age cannot entirely be ruled out. We have therefore tried to account for it by adjusting for advanced maternal age in the logistic regression analysis. However, despite the fact that the CUB scan is optional in Sweden, many women choose nevertheless to undergo ultrasound examination both in the first and second trimester making our results applicable in the clinical setting. There is of course the risk that fetal growth velocity was already affected at the time of the dating of the pregnancy , on which the calculation of gestational age was based. By including in the performed risk analyses detailed information on maternal, pregnancy and fetal characteristics, known to affect both first-trimester growth and the risk of preterm birth –31 that Accelerated fetal growth during early gestation is associated with an increased risk of preterm birth overall, as well as with medically induced and spontaneous preterm birth. There is currently no recommendation on the management of pregnancies with accelerated fetal growth early in pregnancy. Identification of pregnancies at risk could allow proper interventions such as counselling on maternal nutrition and physical activity or even introduction of more appropriate surveillance considering the risk for prematurity. Further research on the topic is therefore warranted.Additional file 1: Figure S1. Directed acyclic graph (DAG) showing the relation between covariates included in the analyses and exposure  and outcome (preterm birth).Additional file 2: Supplementary Table. Growth in early pregnancy and multivariable risk of overall preterm birth and its subcategories .


The subgroup analysis revealed that probiotic intake by women with GDM decreased newborn birth weight, whereas probiotic intake by obese pregnant women increased newborn birth weight. Thus, no evidence indicates that probiotic intake by pregnant women with GDM or overweight can control newborn birth weight.High birth weight indicates the future risk of obesity and increased fat mass in childhood. Maternal gestational diabetes mellitus (GDM) or overweight are powerful predictors of high birth weight. Studies on probiotic supplementation during pregnancy have reported its benefits in modulating gut microbiota composition and improving glucose and lipid metabolism in pregnant women. Therefore, probiotic intervention during pregnancy was proposed to interrupt the transmission of obesity from mothers to newborns. Thus, we performed a meta-analysis to investigate the effect of probiotic intervention in pregnant women with GDM or overweight on newborn birth weight. We searched PubMed, EMBASE, Cochrane Library, and Web of Science databases up to 18 December 2019. Randomized controlled trials (RCTs) comparing pregnant women with GDM or overweight who received probiotic intervention during pregnancy with those receiving placebo were eligible for the analysis. Newborn birth weights were pooled to calculate the mean difference with a 95% confidence interval (CI). Two reviewers assessed the trial quality and extracted data independently. Seven RCTs involving 1093 participants were included in the analysis. Compared with the placebo, probiotics had little effect on newborn birth weight of pregnant women with GDM or overweight (mean difference = −10.27, 95% CI = −90.17 to 69.63,  Childhood obesity is currently one of the most severe public health concerns, and it attracts extensive attention worldwide. It is associated with a broad spectrum of adverse health outcomes. In 2016, the World Health Organization estimated that 41 million newborns and young children were overweight or obese, which is still increasing. High birth weight is associated with a two-fold higher risk of obesity in both sexes and type 2 diabetes, particularly in young male adults ,4,5,6. MTo prevent transgenerational obesity, several randomized controlled trials (RCTs) focusing on lifestyle modifications and weight control during pregnancy have been conducted ,17,18,19Bacteroides fragilis species and a decrease in the genus Bifidobacterium were associated with increased BMI in later childhood , [(probiotics OR synbiotics) AND (pregnancy OR overweight)] plus the Medical Subject Headings and related terms. The definitions of overweight  and obesity  are according to the World Health Organization. Furthermore, the reference lists of eligible studies were searched manually. The search was not restricted by language. The study protocol was registered to the PROSPERO database (registration number CRD42019138887).2 or diagnosed as having GDM; (2) RCTs comparing probiotic or synbiotic agents with a placebo in which probiotics were taken during the pregnancy period; (3) participant age > 18 years; (4) gestational age < 34 weeks; and (5) outcomes of newborn birth weight provided.All the selected studies met the following eligibility criteria: (1) Pregnant women with body mass index (BMI) ≥ 25 kg/m2 or without GDM diagnosis; (2) were experimental trials on animals or nonhumans; (3) were non-RCT studies; (4) analyzed probiotics in conjunction with other GDM therapies in the same intervention group; (5) were abstracts, case reports, expert opinions, reviews, letters, or editorials; and (6) lacked sufficient data or did not meet the inclusion criteria.Studies were excluded if they met any of the following criteria: (1) included pregnant women with BMI < 25 kg/mTwo reviewers independently determined eligible studies. The following basic characteristics were extracted and tabulated: study (authors/year), study design, the sample size of the intervention group compared with the control, intervention period , and outcome as newborn birth weight. Regarding the two reviewers having different opinions, we will seek another author as the third person who will provide a different angle for the review.The included studies were evaluated for bias using the Cochrane risk-of-bias (RoB 2.0) tool. Each included study was evaluated for the following biases: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. The reviewers’ judgment was categorized as “low risk,” “high risk,” or “unclear risk” of bias. The discrepancies were resolved after consultation and discussion with a third investigator.p values for pooled results were two-tailed, and p < 0.05 was regarded as statistically significant.For statistical analyses, we used the Comprehensive Meta-Analysis software . Newborn birth weight with 95% confidence intervals (CIs) of pregnant women who were overweight or had GDM in the included study was summarized. A random-effects model was used in the meta-analysis. Heterogeneity across studies was evaluated using Cochran’s Q test and I2 test. Subgroup analysis was performed to investigate the potential sources of heterogeneity among pregnant women with overweight/obesity compared with GDM. The Egger’s linear regression test and Begg’s funnel plot were used to determine potential publication bias. The A total of 189 citations were identified during the initial database search based on the predefined inclusion and exclusion criteria. Then, 182 articles were excluded for various reasons, leaving seven eligible articles involving 1093 participants, including 540 participants in the intervention group who took probiotics or synbiotics and 553 participants in the control group took a placebo. The PRISMA flowchart  describeLactobacillus salivarius [Lactobacillus acidophilus [Lactobacillus casei [Bifidobacterium bifidum [Lactobacillus salivarius [Lactobacillus rhamnosus [Bifidobacterium animalis subsp. lactis [2, which meets the definition of overweight; one study [2 during enrollment. All participants were randomly assigned to receive daily probiotics, synbiotics, or the placebo, and the daily probiotic consumption varied from 109 colony-forming units (CFU)/g to 6.5 × 109 CFU/g per day. We focused on the postinterventional outcome of newborn birth weight.The meta-analysis included 7 RCTs published between 2014 and 2019, and their characteristics are listed in livarius , Lactobadophilus ,44,46, Lus casei ,43, and  bifidum ,43,45. O bifidum ,48 withihamnosus , and Bif. lactis . The int. lactis . Of the . lactis ,43,46 inne study  was >25 All the included studies had a low risk of bias; the risk-of-bias analysis indicated generally good methodological quality . Meta-rep = 0.80; p = 0.1). Furthermore, the subgroup analyses of the GDM and overweight groups were performed. The results for newborn birth weight in the four trials of GDM groups showed a decreasing tendency of birth weight . In contrast, three trials on overweight women revealed an increasing tendency of birth weight . However, no clear significant difference compared with the placebo group was observed. The heterogeneity across studies in the current meta-analysis was not significant .A pooled analysis was performed on a total of 7 studies, but limited differences were found between probiotic and control groups for newborn birth weight  for 6 weeks on newborn birth weight in pregnant women with GDM. However, Kijmanawat et al. [L. acidophilus and B. bifidum) had no favorable effects on newborn birth weight when given for 4 weeks to pregnant women with diet-controlled GDM. Studies have suggested that no positive outcomes result from the daily use of probiotic supplements with two strains of bacteria  by pregnant women with BMI > 25 kg/m2 from <20 weeks’ gestation until birth [L. salivarius) by pregnant women with BMI > 30 kg/m2 for 4 weeks from <20 weeks’ gestation to give birth [L. salivarius) had no favorable effects on newborn birth weight when given to women with GDM for 4–6 weeks. Okesene-Gafa et al. [L. rhamnosus and B. animalis subspecies lactis) by pregnant women with BMI > 30 kg/m2 from 12–17 weeks’ gestation until birth increased newborn birth weight. This lack of a favorable effect may be attributable to these supplementations with only one or two probiotic strains and the duration of treatment for less than 6 weeks.The study participants included in our meta-analysis mostly enrolled in the studies in the second trimester, and the probiotics for intervention are genus t varies . Karamalt varies  and Badet varies  demonstrt et al.  showed til birth ,48 or wive birth ,48. In ave birth  showed ta et al.  conductePrevious studies tend to use multistrain probiotics because a greater number of strains means more opportunities for success, a broader efficacy range, and the possibility of an additive effect or even a synergistic effect ,57. As dA study has shown that maternal obesity is a stronger predictor of a large-for-gestational-age infant than maternal hyperglycemia . A largeThis study had a few limitations. First, the duration of probiotic intake in the GDM group ranged from 4 to 6 weeks, which could be a possible heterogeneity source. Our findings suggest that further long-term RCTs conducted over at least 6 weeks are needed. Second, variation in the probiotics used may have increased heterogeneity among the studies. Standardized probiotic strains must be used, and participants must be appropriately stratified to identify the most efficacious strains and the extent of birth weight alternation due to probiotic supplementation. Third, the additional data on pregnancy and birth outcomes are insufficient for analyzing other possible factors influencing probiotics intake.Further data related to pregnancy and birth outcomes should be included for additional analysis, including characteristics of mothers, such as pre-pregnancy and pregnancy body weight, BMI, age, smoking habits, insulin sensitivity test results, and delivery type, as well as the gestational age at birth and presence of neonatal jaundice or hyperglycemia. Moreover, children must follow up in the long term to capture their health profile. Finally, the relatively limited number of included studies also resulted in some bias.Probiotic supplements did not considerably affect newborn birth weight in pregnant women with GDM or overweight. This meta-analysis provides essential guidance for ongoing research on probiotic supplementation protocols in pregnant women, with a more personalized probiotic intervention and exploration of the critical period of the intervention.


In addition, cumulative incidence over time of childhood malignancies, leukemia, and kidney tumors were significantly higher in LGA children . In a Cox regression model controlling for other perinatal confounders, LGA at birth remained independently associated with an increased risk for childhood malignancy . Conclusion: LGA at birth is associated with increased long-term risk for childhood malignancy and specifically leukemia and kidney tumors. This possible link may help to improve current knowledge regarding potential exposures that are associated with childhood cancer development. Objective: The aim of this study was to evaluate the association between large for gestational age (LGA) at birth and future risk of childhood neoplasm. Study design: a population-based cohort to compare the long-term risk (up to the age of 18 years) of childhood neoplasms  in children that were born LGA vs. those that were appropriate for gestational age (AGA), between the years 1991–2014. Childhood neoplasms diagnosis were defined according to international classification of disease 9 (ICD-9) codes recorded medical files. Kaplan–Meier survival curves were used in order to compare cumulative incidence of oncological morbidity over the study period. The Cox proportional hazards model was used to control for confounders. Results: 231,344 infants met the inclusion criteria; out of those 10,369 were diagnosed LGA at birth. Children that were LGA at birth had a higher incidence of leukemia (OR 2.25, 95%CI 1.08–4.65,  The theory of fetal “programing” during pregnancy deals with the possibility that some intrauterine exposures cause changes in fetal development that may have implementations on future risk for specific diseases during childhood . SeveralIn general, the birth weight of children in Israel has been shown to be slightly lower that of children born in European and North American countries but higher than that of black Americans and Japanese . Large fWith regard to the association between LGA and the future risk for childhood malignancies, data in the literature is not abundant and sometimes contradicting. Results from previous studies generally support this association with published data that show an increased risk for childhood cancer and specifically malignancies, such as leukemia and central nervous system tumors in children who were born LGA ,12,13,14A population-based retrospective cohort study that included all the deliveries (between the years 1991–2014) at the Soroka University Medical Center (SUMC), the only tertiary center in southern Israel. Data analysis in the study is based on a non-selective population. The study was approved by the institutional review board .Long-term incidence (up to the age of 18) of childhood neoplasms was compared between children who were born with the diagnosis of LGA  [The collection of data was performed using two databases, one was the SUMC (“Demog-ICD9”) computerized hospitalization database and the second was a computerized perinatal database from the obstetrics and gynecology department. The data was cross-linked and merged for the purpose of data analysis. The hospitalization database comprises all demographic information as well as medical diagnosis (coded to ICD-9 codes) that were made during hospitalizations at SUMC. ICD-9 coding information in our institution provides coding according to the topography as well as the behavior of a neoplasm; however, it does not provide information regarding the morphology of malignancies. Perinatal data is recorded following each delivery by an obstetrician and is reviewed and recorded to the database by experienced medical secretaries routinely. This process of collecting data is assuring maximal completeness and accuracy of the information collected.In order to perform the statistical analysis, we used the SPSS package 23rd ed. . Chi-square was used to compare general associations between categorical data. Differences in continuous variables were assessed using the Student t-test. Kaplan–Meier curves for survival were used in order to compare the incidence of neoplasms throughout the study period. Log-rank test was used to assess differences between children that were born LGA to those that were AGA at birth.p-value of < 0.05 was considered statistically significant.In order to establish independent association and control for other confounding variables we used the Cox proportional hazards model analysis. The potential confounders that were evaluated included maternal age at delivery, gestational age at delivery, gestational diabetes mellitus, and pre-pregnancy obesity. All analyses were two-sided, and a 231,344 infants met the inclusion criteria during the study period; out of those 10,369 were diagnosed as LGA at birth. In our cohort, the 95th percentile for the whole cohort  for boys and girls were 4.05 kg and 3.9 kg, respectively. These values are comparable to the crude values according to the WHO (boys 4.2 kg and girls 4.0 kg). p value = 0.140). However, the incidence of total neoplasm related hospitalizations as well as malignancy related hospitalizations were significantly higher in the LGA group .p = 0.09) and all-cancer morbidities .There were no differences between the fetal gender in all neoplasm morbidities .With regard to possible differences in age of diagnosis, we have compared data regarding median age at diagnosis (between LGA and AGA) for benign, malignant, and total neoplasm rate. Median age at diagnosis did not differ between the groups for any of the categories  as well as childhood malignancies  compared to those that were born AGA. p value of 0.021 and 0.028, respectively).In order to evaluate cumulative incidence of childhood neoplasms during the study period we used Kaplan–Meier survival curves total incidence as well as malignant and benign . Childrep = 0.039).The Cox proportional hazards model for assessing the risk of childhood malignancies in children that were born with a diagnosis of LGA while controlling for confounders is presented in In the current study we found that a diagnosis of LGA at birth is significantly related to increased incidence of total malignant neoplasms during childhood, specifically leukemia and kidney cancer. The results of our study are adding to previously published studies from more than seven geographical areas in the world showing similar relations and a linear relation between increasing birth weight and childhood cancer ,11. Malip = 0.025). When considering the results of the current study together with previously published studies, there seems to be a link between a history of LGA at birth and future risk for childhood leukemia. Current information may lead to further studies evaluating this association.Several previous case control studies have tried to evaluate the association between birth weight and future risk for leukemia ,14,22,23p = 0.028). Taking together the results of the current study and previously published studies, despite the relatively small number of studies and their limitations, we can conclude that a positive association probably exists between LGA and kidney tumors.Two previous studies have evaluated the association between birth weight and future risk for kidney tumors. In a study by O’Neill et al. authors reported data that was gathered from registries from both the United States (US) and the United Kingdom (UK) . In thisControversy exists regarding the association between birth weight and brain tumors. Several previous studies have showed higher incidence of brain tumors in children who had a history of LGA at birth ,13. HoweThe strengths of the current study lie in the low probability for incorrect outcome measurements as well as recall bias since it is based on results that were collected from a computerized database of a single regional medical center. Virtually all the deliveries that are taking place in our region are managed in our hospital, and this same center is also providing comprehensive pediatric care for children in our region. This has enabled us to assess the association of perinatal characteristics, such as LGA, and a relatively long-term outcome such as childhood malignancy while controlling many confounding parameters. There are also limitations for the current study; our major limitation comes from the fact that childhood malignancy incidence is relatively low and the absolute case number for each specific malignancy is small. Nevertheless, we were able to show significant differences in specific cancer types as well as in the total childhood malignancy incidence. Moreover, conclusions regarding specific types of cancer should be carefully made and based on the sum of results from the different studies that were published. In our hospitalization database, coding of malignancy diagnosis is based on ICD-9 coding that relates to the topography as well as the behavior of a neoplasm. Unfortunately, the data do not provide information regarding histologic sub-types (ICD-O-3 coding). Finally, our database does not include data regarding other possible exposures such as environmental exposures that can perhaps be associated with childhood cancer risk. Nonetheless, in this study, the population came from the same region and it is reasonable to assume that these exposures were similar between children with and without a history of LGA at birth.In conclusion, in the current study we found a significant association between a history of LGA at birth and the future risk for childhood malignancy, specifically leukemia and kidney tumors. Cancer is one of the leading causes of death during childhood and our knowledge of the underlining causes and risk factors is very limited. Additional studies are needed in order to improve current knowledge regarding potential exposures that are associated with childhood cancer development.


Tranexamic acid (TXA) is an antifibrinolytic pharmacologic agent with demonstrated effectiveness for reducing the incidence of death from blood loss following trauma and major surgery. In intrapartum care, TXA is being used in in conjunction with uterotonic agents to treat postpartum hemorrhage (PPH). Based on the findings of the WOMAN trial that found TXA reduced maternal death due to PPH, the World Health Organization recommends that TXA be part of the standard comprehensive PPH treatment package, and US professional organizations recognize its use as adjunctive treatment for PPH. Evidence suggests that TXA used prophylactically in the setting of cesarean birth may decrease blood loss and the incidence of PPH. There is limited evidence for prophylactic use of TXA in women of all risk categories following vaginal birth but prophylactic use in women who have an a priori risk for PPH is being investigated. This article presents a case in which a midwife identifies a woman in active labor who has significant risk factors for PPH. In consultation with the collaborating obstetrician, TXA is given early during the third stage of labor in addition to the recommended components of active management for the purpose of preventing PPH. E.B. is a 20‐year‐old gravida 3 para 2 at 39 3/7 weeks’ gestation admitted to the labor and birth unit in early active labor. Her prenatal course was complicated by iron deficiency anemia with an antenatal hemoglobin of 8.5 g/dL and hematocrit of 27.5%, which was identified one month prior to admission for labor and birth. She endorsed an inability to tolerate oral iron supplements. Her perinatal history was significant for 2 term vaginal births, with the second birth complicated by a postpartum hemorrhage (PPH) that occurred on arrival to the postpartum unit 2 hours after birth. She required a blood transfusion.On admission, her hemoglobin was 8.2 g/dL, hematocrit 27.0%; mean corpuscular hemoglobin 26.0 pg ; mean corpuscular volume 79.5 fL , and platelets 278,000 μL. Based on her risk factors, it was determined that she was at high risk for PPH. The midwife consulted with the collaborating obstetrician and they decided to have additional uterotonics available in addition to those used as standard elements of active management of third stage of labor (AMTSL). In addition, they ordered a type and crossmatch for 2 units of packed red blood cells. The use and timing of tranexamic acid (TXA) administration was also discussed. Based on her history, specifically of later onset PPH, TXA 1 g diluted in 100 mL of lactated ringers (LR) solution was given intravenously at the time of the birth of the newborn's anterior shoulder. The newborn had Apgar scores of 8 and 9. Immediate mild uterine atony in third stage was noted, and per institution policy, E.B. was given oxytocin (30 units in 500 mL of LR solution [200 mL bolus followed by 41 mL/h]), then methergine (0.2 mg given intramuscularly). The total quantitative blood loss was 450 mL. Twenty‐four hours postpartum, E.B.’s hemoglobin was 8.0 g/dL and hematocrit was 26.2%. She did not have orthostatic symptoms and was counseled on increasing dietary iron intake. She was discharged on the second postpartum day with instructions pertinent to anemia.Hemorrhage is the leading cause of maternal morbidity and mortality worldwide. In the United States, 11% of pregnancy‐related deaths were due to hemorrhage in the years 2011 to 2016.Early PPH has most recently been defined as “cumulative blood loss of 1000 ml or more of blood loss accompanied by sign and symptoms of hypovolemia within 24 hours following the birth process.”Historically, most drugs used to treat PPH were uterotonics with a mechanism of action that promoted uterine contraction, as uterine atony was presumed to be the underlying cause. However, the pathophysiology of severe PPH includes coagulopathy, and more recently, TXA, with its antifibrinolytic properties, is increasingly being used worldwide to treat PPH. Thus, a brief review of the relevant physiology is in order.Pregnancy is characterized by physiologic alterations in coagulation and fibrinolytic pathways. During pregnancy, there is (1) an increase in clotting factors , (2) a decrease in anticoagulation activity (protein S and activated protein C) and (3) a decrease in fibrinolysis resulting in a hypercoagulable state.Hemostasis is the typical response to blood vessel or tissue injury.However, when blood loss is severe, the coagulation system and fibrinolysis can be severely dysregulated.TXA is a synthetic derivative of the amino acid lysine that acts by blocking plasminogen‐binding sites and inhibiting the proteolytic function of plasmin, thereby preventing fibrin degradation.P = .0035). The risk of death from bleeding was significantly reduced .In 2010, the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH‐2) randomized controlled trial (RCT) reported the effects of early administration of TXA on outcomes of death, vascular occlusive events, and the receipt of blood transfusion in adult trauma patients.In the United States at present, the use of TXA does not take precedence over the primary steps recommended for managing PPH and therefore it is considered adjunctive therapy.Correct dose, timing, and method of TXA administration are critical. When TXA is used to treat PPH, it should be given as soon as possible (within a 3‐hour window) after the onset of bleeding and in conjunction with uterotonic medications if uterine atony is suspected.The dose of TXA may be repeated once after 30 minutes if bleeding continues.Given the action of TXA in preventing clot degradation, a key concern has been the potential risk for thromboembolism. Adverse effects include venous thromboembolic events, such as deep vein thrombosis and pulmonary embolism, stroke, myocardial infarction, renal failure or dysfunction, seizures, and mild gastrointestinal symptoms .P = .045). All other causes of death and rate of hysterectomy did not differ significantly between groups.Uterine atony is the cause of 70% to 80% of PPH cases. Less common causes include retained placental tissue, genital lacerations, and inherent or acquired clotting conditions.The findings of the WOMAN trial prompted the World Health Organization to update their treatment recommendations for PPH to include TXA as part of the standard care for women with PPH following vaginal or cesarean birth regardless of etiology.Best practice for prevention of PPH is AMTSL, with the use of uterotonics, specifically oxytocin, as the most critical element.Currently, a large RCT with anticipated enrollment of 11,000 women is underway to assess whether prophylactic TXA lowers the risk of PPH in women undergoing a cesarean birth.P < .001). Additionally, the incidence of PPH (>500 mL) was also lower in the experimental group compared with that in the placebo control group . No episode of thrombosis occurred in the women who received TXA. In another double‐blinded RCT, 120 women received either 1 g of intravenous TXA or placebo in addition to 10 IU oxytocin immediately after birth of the newborn.P = .036) as was the measured blood loss from birth of the placenta to 2 hours postpartum . In addition, the frequency of blood loss greater than 1000 mL was lower in the TXA group .Research on the use of TXA to prevent PPH in women anticipating vaginal birth has been conducted, but results to date are less robust than the positive effects noted for women who have a cesarean birth.P = .07). Secondary outcomes such as severe PPH (blood loss ≥1000 mL), blood transfusion, and postpartum blood count indices did not differ significantly between the groups. With respect to safety of TXA, the incidence of thromboembolic events in the 3 months after birth did not differ between the TXA group and the placebo group .Most recently, 3891 women in France who had a vaginal birth and received prophylactic oxytocin were randomized to receive prophylactic TXA or a placebo.The use of TXA as a preventive measure in women at high risk for PPH is germane to this case. Maternal anemia is a risk factor for PPH Table , and womPPH is a leading cause of maternal mortality and morbidity worldwide.In the case of E.B., the midwife and obstetrician were concerned that E.B. was at particular high risk for PPH secondary to her history of PPH and the presence of anemia (hematocrit <30%). Furthermore, at her prior birth, she had an atypical presentation of PPH 2 hours after birth that required a blood transfusion. E.B. did not possess risk factors for venous thrombosis. By giving TXA with birth of the newborn's anterior shoulder, placental transfer of TXA was mitigated while also allowing the antifibrinolytic properties to take effect early in the third stage. This management illustrates how TXA can be used for prevention of PPH in individual circumstances.The authors have no conflicts of interest to disclose.www.jmwhce.org. A CEU form that can be mailed or faxed is available in the print edition of this issue.Continuing education units (CEUs) are available for this article. To obtain CEUs online, please visit


Intake of food group “eggs” was associated with decreased birth weight . Intake in food groups was expressed in 10 g per 1000 kcal to be able to draw conclusions on clinical relevance given the bigger portion size of the food groups. In particular, preconception intake of “artificially sweetened products” was shown to be associated with increased birth weight. Artificial sweeteners were introduced into our diets with the intention to reduce caloric intake and normalize blood glucose levels, without compromising on the preference for sweet food products. Our findings highlight the need to better understand how artificial sweeteners may affect the metabolism of the mother and her offspring already from preconception onwards.The preconception period has been recognized as one of the earliest sensitive windows for human development. Maternal dietary intake during this period may influence the oocyte quality, as well as placenta and early embryonic development during the first trimester of pregnancy. Previous studies have found associations between macronutrient intake during preconception and pregnancy outcomes. However, as food products consist of multiple macro- and micronutrients, it is difficult to relate this to dietary intake behavior. Therefore, the aim of this study was to investigate the association between intake of specific food groups during the preconception period with birth weight, using data from the Perined-Lifelines linked birth cohort. The Perined-Lifelines birth cohort consists of women who delivered a live-born infant at term after being enrolled in a large population-based cohort study (The Lifelines Cohort). Information on birth outcome was obtained by linkage to the Dutch perinatal registry (Perined). In total, we included 1698 women with data available on birth weight of the offspring and reliable detailed information on dietary intake using a semi-quantitative food frequency questionnaire obtained before pregnancy. Based on the 2015 Dutch Dietary Guidelines and recent literature 22 food groups were formulated. Birth weight was converted into gestational age-adjusted z-scores. Multivariable linear regression was performed, adjusted for intake of other food groups and covariates . Linear regression analysis, adjusted for covariates and intake of energy   showed that intake of food groups “artificially sweetened products” and “vegetables” was associated with increased birth weight (resp. ( The first 1000 days of life are known as a critical window for the effect of environmental influences  . Second,Previous studies have investigated the associations between macronutrient intake and birth weight ,4. AlthoWe investigate the association of 22 food groups, classified based on the food-based 2015 Dutch Dietary Guidelines ,8, and bThis study was part of the Perined-Lifelines linked birth cohort, a cohort established by linking the Dutch national birth registry  and theThe Perined-Lifelines linked birth cohort was created by linking two existing databases; a large population-based cohort study  and theAmong the women in the Perined-Lifelines linked pregnancy cohort, the inclusion criteria for the present analyses were delivery of a live-born baby at term  and availability of information on birth weight of their offspring. Women with unreliable data for dietary intake were excluded from the analyses. Reliability of reported dietary intake was checked using the Goldberg cut-off method, which relies on the ratio of reported energy intake and basal metabolic rate ,13; a raBased on evidence underlying the 2015 Dutch Dietary Guidelines, Vinke et al.  categoriMaternal age was defined as age at enrollment in Lifelines. Maternal education was assigned in three categories: low , intermediate  and high  education. Maternal BMI was calculated based on measured height and weight at the Lifelines research sites at enrollment (baseline) to Lifelines. For the description of food group consumption within the cohort, stratified groups of BMI-quintiles were used. BMI quintiles were generated by use of the distribution within the study, whereby quintile 1 was defined as “low” BMI (lowest 20% in this cohort), quintiles 2 to 4 as “normal” BMI (middle 60% of this cohort and used as the reference) and quintile 5 as “high” BMI (highest 20% in this cohort). Maternal ethnicity was classified as either “white/European” and ”other.” Maternal alcohol use was divided into “alcohol use”  and ”no alcohol use” . Urbanizp < 0.05. Analyses were performed in SPSS version 23 .Continuous variables were summarized by the median and IQR, and comparisons between groups were made by the Kendall’s tau rank correlation test. The associations between food group intake (exposure) and birth weight (outcome) were estimated by linear regression analyses. Maternal characteristics were considered as possible confounders based on a previous study within the Perined-Lifelines linked birth cohort . Adjusten = 427 and n = 168), pre-term births  and unknown sex of the child (n = 1), 1698 women remained available in the analysis. The characteristics of this group of women have been described in detail previously )  . To illuβ = 0.002 )   . Increas= 0.02]) . When liTo investigate which macronutrients from food group artificially sweetened products might contribute to the association found in linear regression analyses, we performed linear regression analysis with the macronutrients from this food group with birth weight. Analysis was performed twice; first only main macronutrients , and second with the sub-macronutrients  from animal and plant protein  and mono- and disaccharides, and polysaccharides  were included.β = 0.047 ) and ) ) . For anaThe aim of this study was to investigate the association of maternal diet based on specific food group intake during the preconception period with the birth weight of the offspring in a linked birth cohort of a representative group of women in the north of The Netherlands ,9. We shOur finding that the food group artificially sweetened products was positively associated with birth weight is intriguing given recent studies carried out by researchers at Israel’s Weizmann Institute. They examined three artificial sweeteners  which are often incorporated into low-caloric snacks and beverages . The resThe fact that we show a positive association between preconception intake of artificially sweetened products and birth weight may suggest that artificial sweeteners induce similar metabolic changes during preconception that may affect the offspring’s birth weight. During normal pregnancy, changes in insulin sensitivity are a normal physiological phenomenon that provides increased nutrient supply to the fetus. However, if insulin resistance develops and the beta-cell compensation of the pancreas is inadequate in secreting sufficient insulin to maintain normal glycemia in the mother, gestational diabetes mellitus may occur . It woulWe showed that the intake of artificially sweetened products increased over stratified groups of BMI; however, we adjusted for BMI via linear regression analyses, so our findings cannot fully be explained by the contribution of BMI. Unfortunately, we do not have information on gestational weight gain nor on glucose metabolism or occurrence of  diabetes mellitus available in this population, which could potentially confound the association with birth weight. However, the prevalence of diabetes mellitus (type 1 and 2) in the complete Lifelines Cohort Study is low, e.g., 4% , approxiWithin our study, the food group “artificially sweetened products” consists of two main food items. The first is “light soft drinks/lemonade without sugar,” and the second food item is “dairy drinks without sugar/with artificial sweeteners.” Given the fact that we found that it was  protein within this food group that was positively associated with birth weight, this suggests that it is probably the food item ‘dairy drinks without sugar/with artificial sweeteners’ that is driving the positive association with birth weight as the other food item does not contain any protein. These results are in line with results from the Generation R study, a population-based prospective cohort study in Rotterdam, The Netherlands, who showed that higher intake of protein, especially animal protein, in early postnatal life was associated with a greater height, weight, and BMI in childhood up to 9 years of age in the offspring .Besides “artificially sweetened products,” we also found an association between food groups “vegetables” and “eggs” with birth weight. Results from the Danish National Birth Cohort showed that fruit and vegetable consumption in pregnancy was positively associated with birth weight in well-nourished Danish women, especially among lean women . The assRegarding the association found between food groups, eggs, and birth weight, there is less scientific evidence to support this finding.For many food groups  and overall diet quality (LLDS) we found a clear association with maternal BMI but most were not significantly associated with birth weight. More specifically we showed that mean diet quality (LLDS) slightly decreased with increasing BMI . We alsoAs maternal BMI is a stronger predictor for birth weight than dietary intake , it is pWithin our analysis we have not corrected for multiple testing given the more exploratory background of the analysis. Our results are indicating a direction of association between preconception dietary intake and birth weight. Further research should be performed within large cohorts investigating the association between dietary intake and birth weight to be able to draw more firm conclusions.In summary, the present study provides information on food group intake and its association with birth weight in the linked Perined-Lifelines birth cohort. Our findings highlight the need to better understand how artificial sweeteners may affect the metabolism of mother and her offspring already from preconception onwards. Future research should be performed within large cohort studies to further investigate, confirm, and understand the associations found in the present study.


High rate of repeat cesarean section and its complications are the results of cesarean tsunami in the last two decades in Iran. Vaginal birth after cesarean (VBAC) is an important alternative for repeat cesarean. However, the rate of VBAC in Iran is very low subject to some organizational and individual barriers is very low. This study explored the clinician’s and women's perceptions of individual barriers to achieve VBAC.In this conventional content analysis, 28 semi-structured interviews and one focus group discussion was conducted with health care providers including gynecologists, midwives and family physicians as well as prior cesarean section mothers attended one of the women's hospitals in Mashhad, Iran in 2017. Participants were selected through purposive sampling considering the strategy of maximum variation. Data were analyzed according to Graneheim and Lundman (2004) method using MAXQDA.10 software.The theme of “obstacles to acceptance and committed actions” emerged from two categories of “psychological barriers” and “operational barriers". Psychological barriers included 'sense of danger”, “financial displeasure" and "negative attitude"; whereas, operational barriers consisted of 'barriers to decision making' and 'indolence'. Improving women's attitude via maternity care promotion, creating supportive environment, informing mothers about choice of birth mode and empowering them in shared decision making could influence women's VBAC request. Also organizing VBAC care team and creating motivations in medical team and hospital directors through reporting of research project outcomes on safety and benefits of VBAC could affect the VBAC rate. The World Health Organization (WHO) recommends that the rate of cesarean section should not exceed 15% . ComplicThe possibility of cesarean for women who has already given birth vaginally is 10%, while this possibility either as emergency or elective cesarean in the presence of once prior cesarean is 67% . In thisIn October 2016, the Iran’s Ministry of Health and Medical Education announced the VBAC clinical guidelines in accordance with the latest international guidelines . Agency It has been reported that not being informed properly and completely about the next birth options, confusing recommendations about birth options, the limited selection of supportive childbirth environments and the lack of emotional and psychological support provided to women have been known as the factors influencing women's decision about mode of birth after cesarean section . A recenThis study adopted qualitative content analysis with conventional approach as the method of inquiry. In this approach, the researcher tries to extract categories and themes from the data . ParticiThe informed consent form was signed by the participants after providing them the necessary information about the purpose of the study and ensuring the anonymity of the information and the confidentiality of the recorded interviews. Data collection was done by the first author (MF), who is an experienced midwife, through face to face semi-structured individual interviews and one focus group discussion. The mean duration of the individual interview session was 30-90 minutes and focus group discussion lasted 90 minutes. Data collection was conducted in hospitals and health care centers. An interview was initiated by a general question: Please talk about your understanding and experience of vaginal birth after cesarean section. Then more specific questions were asked: What barriers have you  experienced regarding VBAC? Why maternal health care providers do not recommend VBAC to the mothers? Why mothers do not choose VBAC? What strategies could facilitate access to VBAC? Data collection and its simultaneous analysis was continued to 28 interviews when data saturation was obtained. Of those who were invited to the interview, only one physician declined the invitation due to work overload. Focus group discussion was arranged with 10 former interviewees (clinicians) after reaching data saturation in individual interviews with the aim of confirming the data collected already and giving feedback of the analyzed data to the interviewees. Each interview was transcribed verbatim as soon as possible and read through several times to get the insight of the whole story of the participants, then was analyzed by Graneheim and Lundman method (2004)  using MA The analysis of the clinician’s and women's perceptions and experiences towards the individual barriers of vaginal birth after cesarean (VBAC) revealed five sub-categories including: “sense of danger”, “financial displeasure”, “negative attitude”, “barriers to decision making” and “indolence”, which were set in two categories of “psychological barriers” and “ operational barriers”. At the end of analysis, “obstacles to acceptance and committed actions” emerged as the main theme of the study .Sense of danger: The participants stated that fear of complications of vaginal birth after cesarean section, fear of legal accountability and fear of uterine rupture is a barrier to choose vaginal birth after cesarean. Mothers expressed their sense of danger in vaginal birth after cesarean section, including concerns about the health of the baby, fear of death during VBAC, and the non-assurance of birth safety.A mother with a history of VBAC said: I went to the doctor and she said that you have to choose caesarean because you have had one cesarean section four years ago and it is possible that the sutures will break during the vaginal childbirth...!"An obstetrician and gynecologist with 25 years of experience, in relation to the complications of VBAC commented: "The complication that the physician anyway knows about is uterine rupture. If rupture happens, it causes the mother to lose her uterus, lose the baby, and so on and you know, as a result physicians refuse to do it..."Financial displeasure: This sub-category with the codes such as: lack of financial motivation for the physician in vaginal birth after cesarean section, lack of financial encouragement for midwife’s participation to the care of mother, and the lack of effectiveness of financial encouragement of the physician are the barriers in vaginal birth after cesarean section. An obstetrician and gynecologist with 8 years of work experience in this relation said: “The financial issue is not my hundred percent priority. The fee the doctor gets for vaginal birth after cesarean is higher than cesarean section, but this is not an incentive for the physician, because as compared to the time spent and the stress the physician endures, the wage is very low...”Negative attitude: The negative attitudes toward vaginal birth after cesarean section was expressed in different aspects including: mother’s negative attitude towards skills of birth attendants, the birth environment, maternal safety in vaginal birth and VBAC outcomes. These are important barriers to vaginal birth after cesarean section. Mothers who have had cesarean section at their request and those who believed in vaginal birth after cesarean as a high-risk and challenging mode of birth, also did not choose VBAC.A midwife with 22 years of work experience in healthcare center showed her negative attitude in such a way: “I don’t agree with vaginal childbirth currently. I believe that the complications of vaginal birth are high. I worked for a while in a private hospital, a famous doctor there told me: you have to manage a multiparous woman from dilation of 3 centimeters and a primiparous in the same stage, so that both of them get full dilated at 4 o'clock… when she came in the afternoon, both of them gave birth and then she came back. Because I worked in a private hospital, I believe the patient’s safety is not the target in many cases. Indeed, in the patient management process, late maternal complications are not important to them...”A midwife with 30 years of work experience in maternity hospital, similarly commented: "...Whatever I saw here was not good at the end. That is, the patient has progressed even to the stage of full cervical dilatation and eventually has gone through cesarean section with a decrease in fetal heart rate or lack of or no progress of labor".A mother with prior cesarean section declared her negative view as such: “…vaginal birth is not suitable for our country, these (physicians) cannot manage it properly! They tell us: I will come for your childbirth, but they don’t come. They don’t support mother in giving birth….”Barriers to decision making: One of the most important barriers to achieve vaginal birth after cesarean section was to decide about the mode of birth by the mothers. Mothers had no competence in decision making due to the lack of awareness, and lack of effective consultation. They were affected by the cultural atmosphere including physician, spouse and those who influenced their choice and the misconceptions about mode of birth instead of choosing the mode of birth consciously.A pregnant mother with previous cesarean section said: "...These days, vaginal birth has decreased to some extent, you know, women think that there is only one option for giving birth and that's cesarean section. Indeed the tendency of people to cesarean section has increased..."A midwife with 29 years of experience in healthcare center referring to the lack of right of decision making for the mothers commented: "... Mothers don’t have the right to choose. Prior cesarean section mothers due to fear of vaginal birth and worries about the complications that may occur during birth, choose repeat cesarean. Most doctors do not accept VBAC and they tell to the women that you already had cesarean in your past pregnancy and now you have to choose repeat caesarean. In fact, mothers are forced to accept cesarean delivery because there is no support for the choice of vaginal birth after cesarean..."A midwife with 30 years of experience in maternity hospital concerning the role of most health professionals as barriers elaborated: "Our mothers are not aware. If we talk a little bit with them, and say that your first birth was cesarean due to this and, you know, you are in good position now and you can do normal delivery and so on…. The next person come and say no, you cannot do it, you have had cesarean section, so vaginal birth is dangerous for you, it has complications, etc…and in such a way her opinion changes. Mothers are not so aware of making decision for themselves. If they analyze the situation and say that I had cesarean section in my first birth because of that reason but now I want to have vaginal birth…. Naturally, the midwife and the physician are the people who could change a mother’s mind…. Mothers don’t know that they could be responsible for decision making..."Indolence: Participants explained the indolence of the maternity staff with terms such as convenience of cesarean section for a physician, lower stress with cesarean section, refusing to take care of the mother in VBAC, and less time and energy spend in caring of the mother. Also, birth management without any intervention in the process of VBAC is not compatible with the comfort of the staff during labor and birth. Besides Mothers, in their minds, provide more comfortable conditions for themselves and their relatives with scheduled cesarean. An obstetrician and gynecologist with 29 years of work experience in this regard commented: “…Even in our governmental centers, when the mother is going to do VBAC, physicians don’t accept her demand for vaginal birth. Here , although senior supervisors worked before but now they do not spend enough time some of the midwives like the doctors seem lazy; they even do not spend time to talk to the patients ...”A midwife with 23 years of experience in managerial position indicated: “Our doctors like to plan scheduled childbirth, it’s the most crucial problem. If we want the vaginal birth to begin spontaneously and end without intervention, certainly, it takes time and is not scheduled and it can occur at any time of the day and night and it may interfere with their plans, while cesarean section could be scheduled at a specified time by the physician ...”A 29 year old mother with prior cesarean section said:“In my opinion; some physicians disagree with VBAC for their own convenience…” Total rate of cesarean section and repeat cesarean are high in Iran and trial of labor after cesarean (TOLAC) is one of the important strategies to decline it. Despite the fact that it has been two years since the Ministry of Health of Iran has been issued the VBAC instruction, but clinical observations indicate that it is not being widely implemented. As a result of few cases of TOLAC, there are few studies about this topic in Iran. This article has explored the perceptions and experiences of health care providers and prior cesarean section mothers about individual barriers to VBAC. Based on the results, individual barriers towards VBAC included “sense of danger”, “financial displeasure”, “negative attitude”, “barriers to decision making” and “indolence”, which were set in two categories of “psychological barriers” and “operational barriers” and finally abstracted in the theme of “obstacles to acceptance and committed actions”.“Sense of danger” was one of the individual barriers experienced both by the clinicians and mothers. Clinicians were quite afraid of complications of VBAC for the mother and her fetus and also had fear about their legal responsibility. Mothers with prior cesarean section was not also sure about the safety of VBAC and their uncertainty prevents them to make decision for VBAC. Marrero 2012) also reported the concerns about medical malpractice as one of the reasons for the lack of VBAC from the perspective of health care providers in her study . The sen12 also rAnother individual barrier was the financial displeasure, because VBAC had no financial gain for midwives. In relation to the physicians, despite the fact that fee of VBAC is more than cesarean section, but physician’s higher responsibility and investment of more time for VBAC decrease the physicians’ motivation. Marrero (2012) also states that, time spent in caring of VBAC, and the imbalance between time spent and fee are reasons for physician’s unwillingness . In Canada, a specialist, a family physician and a midwife all receive the same fee, regardless of mode of birth. In the financial performance, there is no monetary motivation to perform cesarean section, similar to health management organizations of California that physicians are salaried or receive a steady amount regardless of birth . In factNegative attitude was another individual barrier for both mothers and clinicians. Mothers were reluctant to choose VBAC because of unpleasant experiences, inappropriate interaction of hospital staff during childbirth, unfavorable delivery environment and false beliefs regarding the safety of cesarean section. Maternal health care providers also considered VBAC as a challenging birth. They considered VBAC as a high risk birth with adverse outcome and having a negative attitude towards normal delivery, had a negative attitude toward VBAC. Chaillet 2007) reported the attitudes and beliefs of health care providers as well as mother’s motivation as barriers in implementation of clinical guidelines to decline cesarean section 07 report, previouIn addition, decision making in the atmosphere of lack of informed choice for mode of birth was understood as another individual barrier to VBAC. Participants understood incompatibility of current cultural patterns with vaginal birth as a barrier to VBAC. While Renee 2012) reported that the sense of female control on the decision making process is one of the important factors to choose VBAC . In the 12 reportIn conclusion policy makers, healthcare planners, hospital administrators and maternity healthcare providers should plan to remove the individual barriers and identify facilitators to choose VBAC for mothers with prior cesarean delivery. Additionally, maternity healthcare providers should be encouraged to support this choice. Improving maternity care, shared decision making, create supportive environment  and the