Furthermore, the preterm ex utero environment is hostile to the developing brain with a myriad of environmental, biochemical and excitotoxic stressors. Allopregnanolone is a key neuroprotective fetal neurosteroid which has promyelinating effects in the developing brain. Preterm birth leads to an abrupt loss of the protective effects of allopregnanolone, with a dramatic drop in allopregnanolone concentrations in the preterm neonatal brain compared to the fetal brain. This occurs in conjunction with reduced myelination of the hippocampus, subcortical white matter and cerebellum; thus, damage to neurons, astrocytes and especially oligodendrocytes of the developing nervous system can occur in the vulnerable developmental window prior to term as a consequence reduced allopregnanolone. In an effort to prevent preterm-associated brain injury a number of therapies have been considered, but to date, other than antenatal magnesium sulfate and corticosteroid therapy, none have become part of standard clinical care for vulnerable infants. Therefore, there remains an urgent need for improved therapeutic options to prevent brain injury in preterm neonates. The actions of the placentally derived neurosteroid allopregnanolone on GABAA receptor signaling has a major role in late gestation neurodevelopment. The early loss of this intrauterine neurotrophic support following preterm birth may be pivotal to development of neurodevelopmental morbidity. Thus, restoring the in utero neurosteroid environment for preterm neonates may represent a new and clinically feasible treatment option for promoting better trajectories of myelination and brain development, and therefore reducing neurodevelopmental disorders in children born preterm.Children born preterm are at an increased risk of developing cognitive problems and neuro-behavioral disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. Whilst neonates born at all gestational ages, even at term, can experience poor cognitive outcomes due to birth-complications such as birth asphyxia, it is becoming widely known that children born preterm in particular are at significant risk for learning difficulties with an increased utilization of special education resources, when compared to their healthy term-born peers. Additionally, those born preterm have evidence of altered cerebral myelination with reductions in white matter volumes of the frontal cortex, hippocampus and cerebellum evident on magnetic resonance imaging (MRI). This disruption to myelination may underlie some of the pathophysiology of preterm-associated brain injury. Compared to a fetus of the same post-conceptional age, the preterm newborn loses access to  Preterm birth is the leading cause of death and neurodevelopmental related disability in early life . In resoex utero environment   . Importaem (CNS) . Any decem (CNS) .Birth is necessarily associated with the loss of the fetus from the placenta-maternal unit, and therefore separation from any trophic factors derived from either mother or placenta. Preterm birth results in the premature loss of placentally supplied allopregnanolone during a period when it is critical for optimal neurodevelopment . Whilst Despite only comprising 10% of births, preterm birth is the leading cause of death and neurodevelopmental related disability in neonates, accounting for up to 50% of neonatal deaths . FurtherIn infants that were born <32 weeks’ gestation, it has recently been shown that reductions in white matter volume in areas such as the fornix and the cingulum observed by MRI at the time of birth remained present until 19 years of age and were associated with impairments in memory functions . The StoAttention deficit hyperactivity disorder is characterized by a deficit in behavioral inhibition, inattention, impulsivity and social difficulties, and in a Norwegian cohort of preterm/low birth weight children at 5 years old was more commonly diagnosed in males . In the School-related problems also arise in children following preterm birth, with those born preterm needing more special educational support, having an increased risk of repeating a grade and lower overall reading and mathematics scores compared to children born at full term . These fThe direct impact of preterm birth on cognitive function is hard to quantify as it is confounded by many of the complex socio-economic, environmental and other factors that precipitated preterm birth in the first place. Additionally, given the plasticity of the developing brain, the timing of cognitive assessment needs to recognize the prognostic limitations of early assessment, especially for those born at extremes of gestational age. Studies comparing cognitive delays in toddlers at 2 years of age do not find any significant difference between preterm and term when corrected for prematurity . Alternain utero environment experienced by a fetus of the same post-conceptional age. Organ maturation and function throughout the body changes tempo dramatically in response to this premature separation from the maternoplacental unit. Brain development requires neurotrophic and gliotrophic support during this time and so is vulnerable following preterm birth as it loses placental steroid support, the supply of precursors for fetal neurosteroid production, and other placentally supplied nutrients. In addition, premature loss of these steroids exposes the developing brain to increased stimulation and excitotoxic damage. Damage to oligodendrocytes of the developing nervous system can occur during this vulnerable developmental window prior to term gestation.Preterm birth abruptly removes the newborn from the supportive ex utero environment  no targeted therapies are available in the perinatal period to those infants born late preterm (34–36 weeks). For the less mature infants, maternal magnesium sulfate has been shown to reduce cerebral palsy in extreme preterm neonates, but the number needed to treat remains high, highlighting the need for other therapeutic approaches. A Cochrane systematic review of five large trials comprising 6,145 babies found that the incidence of cerebral palsy in preterm neonates dropped from 5 to 3.4% following antenatal magnesium sulfate therapy . A recenThe antioxidant melatonin has also been investigated for its neuroprotective benefits in animal models due to its roles in modulating neuroinflammation and reducing reactive oxygen species . In neonClinicalTrials.gov Identifier: NCT01793129). The American Academy of Pediatrics committee advises that hypothermia should not be undertaken on preterm neonates due to the associated risks, unless it is performed in a research setting  to pregnant dams reduced the allopregnanolone synthesizing capacity of both the placenta and the fetal brain as demonstrated by a reduction in the expression of the rate-limiting enzyme 5α-reductase type 2 in both tissues . Interesbehavior .A receptors and specifically enhances GABAA receptor mediated inhibition, which results in anxiolytic, anti-convulsant, anesthetic, analgesic, and sedative effects   , 2005. T2 (KCC2) .A receptors are involved in a broad range of functions including controlling the excitability of the brain, modulation of anxiety, as well as cognition, memory, and learning   . The enhA receptor subunits α6 and δ are not altered in these preterm-born animals at juvenility (A receptor subunits expression, or conversely, that levels in the brain of term born animals have dropped to lower levels. Subunits of the GABAA receptor are reported to go through age-related changes in expression, with early development often a period of high expression, followed by down regulation in adulthood (A receptor subunits after birth (A receptors present a common link between initial myelination, ‘catch up’ and remyelination processes, and behavioral state.In juvenile guinea pigs born preterm, altered GABAergic pathway development is evident at juvenility in the cerebellum. Intriguingly, despite reduced expression of both subunits in the preterm neonatal cerebellums  Shaw et mRNA expvenility . These odulthood . This ager birth  (Shaw eter birth . This poer birth , 2003. Ier birth , and whiA neurosteroid sensitive receptor subunits appear to be largely unaffected by preterm delivery with the exception of a decrease in the expression of the α5 subunit mRNA at juvenility (Conversely, the hippocampal GABAvenility . This pavenility . Thus, aA receptors (Steroid hormones, including progesterone, allopregnanolone and potentially other neuroactive metabolites, can exert neuroprotective effects following damage to neurons and glia by preventing excitation, apoptosis, and inflammation, as well as by regenerative mechanisms . Studieseceptors . Both preceptors . Furthereceptors . Followieceptors . Likewiseceptors .The role of progesterone as a precursor of allopregnanolone, and the number of positive studies relating to the use of progesterone, led to us examining the use of progesterone replacement therapy in preterm guinea pig neonates. In contrast to the earlier finding of effects on TBI in rats, we observed detrimental effects on postnatal neurodevelopment particularly in the male offspring. From this preliminary study, it appears that progesterone is metabolized differently by the male neonates and instead of producing allopregnanolone, much of the steroid is converted to cortisol. These males, with high plasma and salivary cortisol concentrations, also had reductions in myelination of the cerebellum and subcortical white matter, highlighting the vulnerability of these male neonates to increased cortisol as a result of increased postnatal progesterone .Previous studies have also investigated the potential use of allopregnanolone to restore neurosteroid deficits. Preliminary findings, however, suggested that allopregnanolone had limited effectiveness due to the very short half-life of allopregnanolone, or other possible metabolic conversion making therapeutic concentration difficult to achieve. To avoid both of these issues with allopregnanolone therapy, as well as potential conversion of allopregnanolone to its less active isomers, we explored a possible postnatal therapy with ganaxolone.A receptors, producing similar anxiolytic and anti-seizure effects. The addition of the methyl group markedly improves oral pharmacokinetics and in addition ganaxolone is not readily metabolized to other steroids that may bind elsewhere and produce unwanted effects (A receptor.Ganaxolone is a 3β-methylated synthetic analog of allopregnanolone initially developed by Edward Monaghan at CoSensys in 1998, however, in 2004 Marinus Pharmaceuticals Inc., acquired the development and commercialization rights . Marinus effects . AllopreAnimal pharmacokinetic studies demonstrate that ganaxolone has a large volume of distribution as administration of radioactively labeled ganaxolone has shown wide distribution, and due to its’ lipophilic nature, it becomes concentrated in the brain with a brain-to-plasma concentration of between 5 and 10 . In addiA number of phase 2 clinical trials have examined the use of ganaxolone for epilepsy and infantile spasms, as well as for posttraumatic stress disorder, migraine, and the developmental problems associated with fragile X syndrome . Daily din utero neurosteroid environment and that this restores neurodevelopment to a normal, term-born, trajectory (In the context of preterm birth, we have recently reported that ganaxolone neurosteroid-replacement therapy given to preterm guinea pigs between birth and term ‘due date’ improved myelination of the CA1 region of the hippocampus and overlying subcortical white matter, in addition to reduction in hyperactive behavior . This waajectory . By combajectory  and the Until recently, the risk of neurodevelopmental impairment in children born moderate-late preterm who required little to no clinical intervention, was thought to be minimal, however, data from large international cohorts clearly demonstrate that this is not the case. Albeit that the effect size is not as great as for those born at extremes of gestational age, the significantly larger number of children born at moderate-late preterm gestations means that this is an increasingly large public health issue, with important implications for the provision of educational and other resources throughout childhood. Currently, there are no targeted therapies available to prevent the development of these neurodevelopmental problems, and as such therapy is limited to symptom management for the most affected children.Through use of studies in our model of preterm birth in the guinea pig we have begun to address these gaps in the knowledge of neurodevelopment following preterm birth. We suggest key pathways involved, targets for intervention, and a therapy for prevention of preterm-associated neurodevelopmental disorders. These studies are in their preliminary stages and whilst we have identified a target for improving outcomes, there are many aspects to this therapy that we are yet to investigate. Our pilot studies are primarily focused on identifying an optimal dose that promotes oligodendrocyte maturation but minimizes adverse side effects. Once we identify an ideal dose, we can then determine whether there are interactions with other therapies that the preterm neonate may be exposed to, such as synthetic glucocorticoids, and potentially in the future, for asphyxiated preterm infants, therapeutic hypothermia as a co-therapy.JS: primary author. MB, RD, and GC: revisions and edits. JH and HP: co-senior authors, revisions and edits, and concept design.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Diffusion tensor imaging (DTI) is sensitive technique to detect widespread changes in water diffusivity in the normal‐appearing white matter (NAWM) that appears unaffected in conventional magnetic resonance imaging. We aimed to investigate the prognostic value and stability of DTI indices in the NAWM of the brain in an assessment of disability progression in patients with a relapsing‐onset multiple sclerosis (MS).Forty‐six MS patients were studied for DTI indices , mean diffusivity (MD), radial (RD), and axial (AD) diffusivity) in the NAWM of the corpus callosum (CC) and the internal capsule at baseline and at 1 year after. DTI analysis for 10 healthy controls was also performed at baseline. Simultaneously, focal brain lesion volume and atrophy measurements were done at baseline for MS patients. Associations between DTI indices, volumetric measurements, and disability progression over 4 years were studied by multivariate logistic regression analysis.p < 0.05). Changes in DTI indices over 1 year were observed only in the CC (p < 0.008), and those changes were not found to predict clinical worsening over 4 years. Clear‐cut association with disability progression was not detected for baseline volumetric measurements.At baseline, most DTI metrics differed significantly between MS patients and healthy controls. There was tendency for associations between baseline DTI indices in the CC and disability progression (Aberrant diffusivity measures in the NAWM of the CC may provide additional information for individual disability progression over 4 years in MS with the relapsing‐onset disease. CC may be a good target for DTI measurements in monitoring disease activity in MS, and more studies are needed to assess the related prognostic potential. Conventional magnetic resonance imaging (MRI) detecting T1 and T2 focal brain lesions is not specific to the underlying pathology, and it lacks sensitivity to the microstructural diffuse damage in the normal‐appearing white matter (NAWM)  quantifies the magnitude and direction of water diffusion, and it is sensitive to diffuse microstructural abnormalities in the brain that appears unaffected on conventional MRIs . All subjects provided informed written consent.2.1In total, 56 individuals, 46 patients with relapsing‐onset MS, and 10 healthy subjects were enrolled in this 4‐year follow‐up study (between 2006 and 2012) at the Tampere University Hospital, Finland. The MS diagnosis was based on the revised McDonald criteria from 2005 . Clinical progression was determined as the difference between the baseline EDSS and EDSS 4 years after the baseline. Progression of disability during the follow‐up was defined as an EDSS score increase ≥1.0 when the baseline EDSS was <6.0 or an increase of EDSS ≥ 0.5 when the baseline EDSS ≥ 6.0, and these subjects were assigned to a progression group , and the MRI acquisition and protocol were as follows: T1‐weighted header followed by an axial three‐dimensional (3D) T1‐weighted magnetization prepared rapid gradient echo (MPRAGE), 3D T2‐weighted turbo spin echo, fluid‐attenuated inversion recovery (FLAIR), T1‐weighted spin echo with magnetization transfer contrasts, multidirectional diffusion‐weighted echo‐planar imaging, and gadolinium‐enhanced T1‐weighted MPRAGE when needed. The DTI protocol consisted of a single‐shot spin‐echo‐based echo‐planar diffusion‐weighted imaging with three averages and 12 gradient encoding directions, with b values of 0 and 1,000 s/mm2.32  were positioned on the left and right posterior limbs of the internal capsule (IC), CC genu, left and right CC body, and CC splenium  in all ROIs. The values of the following DTI parameters were obtained: FA, MD, AD, and RD.The DTI data were analyzed with commercial Neuro 3D software  at an offline workstation. Multidirectional diffusion data were assessed visually for the presence of distortions and artifacts. There were no significant eddy current distortions due to the diffusion gradients. Six freehand regions of interest (ROI) of approximately 26–48 mmm Figure . The ROIThe whole brain volume of the T1 hypointense, FLAIR hyperintense lesions, and brain parenchymal fraction (BPF) were assessed blindly using the semi‐automatic segmentation software Anatomatic™ 2.23  to baseline were set as covariates. In Model 2, the covariates were as follows: sex, disease duration (time from MS diagnosis to baseline), baseline EDSS, number of relapses up to 3 years preceding the baseline, immunomodulatory medication status, and volumetric measurements . A resulting odds ratio (OR) is given with 95% confidence interval (CI), and the p‐value <0.05 was considered statistically significant. The Bonferroni‐corrected p‐values for six comparisons (p < 0.008) were also investigated in the analyses concerning DTI. A statistical analysis was performed using SPSS Statistics for Windows version 22 .Means and standard deviations were given for normally distributed variables and medians and ranges for skewed distributed data. For the demographic and volumetric data, groups were compared using independent sample 33.1In total, 22 of 46 (48%) patients showed disability progression over 4 years. The mean age of patients at baseline was 39.6 years (range 18–61). The demographic and clinical characteristics are summarized in Table Incidental findings in the brain white matter were found in four healthy subjects from control group; three subjects had one to two punctate white matter hyperintensities, one subject had several punctate white matter hyperintensities, and none of healthy subjects presented clinical signs of demyelinating disease.p < 0.001) were found in the CC for FA, MD, and RD  in the disability progression group compared to the stable disability group  were found between MRI volumetric measurements and DTI indices. The strongest correlations were found in the CC genu between the T1 brain lesion volume and FA , MD , RD  and between FLAIR lesion volume and FA , MD , and RD . Regarding brain atrophy, the strongest correlations were found between BPF and RD  in the right CC body, RD  in the left CC body, MD  and AD  in the right IC, and MD  and AD  in the left IC  increased in 4/6 ROIs, and RD decreased in 4/6 ROIs . AD showed a significant increase in 3/6 ROIs . The results remained significant except for RD in the CC genu and AD in left CC body after the Bonferroni corrections (p < 0.008). In the IC, the changes were nonsignificant .To assess the intra‐observer repeatability of DTI measurements, the intraclass correlations (ICCs) were calculated for 20 patients. The same observer (U.H.) repeated the measurements for the same scans with a time interval of approximately 3 months. In all ROIs, the ICCs were good and excellent and were 0.77–0.98 (mean 0.91) for FA, 0.75–0.96 (mean 0.84) for MD, 0.64–0.93 (mean 0.85) for AD, and 0.85–0.95 (mean 0.91) for RD.3.2p ˂ 0.05). Moreover, a higher baseline MD in the right CC body and higher MD and AD in the CC splenium were associated with disability progression. The results did not remain significant after the Bonferroni corrections. There were no significant associations between baseline DTI indices in the IC and disability progression over the follow‐up. The age and symptom time had no effect in any of the analyzed ROIs.In logistic regression Model 1 with covariates of age and time from the onset to baseline Table , a lowerIn Model 2, which contained baseline EDSS and relapse number before baseline, an association between DTI and disability progression disappeared in the CC genu, body, and the splenium regrading several diffusivity parameters; however, none of these explanatory variables reached statistical significance (Supporting Information Tables DTI change over 1 year did not relate to disability progression over 4 years in any ROIs (data not shown).4The prognostic assessment of clinical disability accumulation by using conventional MRI is still suboptimal  of patients with RRMS (Kern, Sarcona, Montag, Giesser, & Sicotte, The main observation in our study is the tendency for baseline DTI metrics’ association in the CC with disability progression over 4 years with the most consistent and stable correlation observed in the CC splenium. We observed an increased baseline AD and RD, indirectly representing axonal integrity and demyelination, which is associated with disability progression even after correcting for focal lesion volume. This result corroborates observations in a previous study analyzing only FA maps where decreased FA in the CC splenium in primary‐progressive MS (Bodini et al., The 1‐year longitudinal DTI analysis revealed a significant change of DTI metrics in the CC but not in the IC. In this cohort with active MS (Lublin et al., Altogether, the results of our longitudinal study suggest that DTI is a sensitive tool in monitoring diffuse abnormalities responsible for disability accumulation, and CC may be a good target for DTI analysis. We believe that an assessment of the prognostic value of DTI in an MS cohort with variable clinical characteristics such as ours which is typically encountered in everyday practice has practical value, as suggested by others (Harrison et al., We did not observe any associations in the IC between baseline DTI and disability progression. Moreover, no longitudinal changes in DTI metrics were observed in the IC, although significant differences related to DTI between healthy controls and the MS group were already observed. This result indicates that diffusivity abnormalities may already exist in the IC, but they progress at different rates, and image disability progression distinctly than in the CC (Ge et al., Our results corroborate the observed lack of clear‐cut association between the T1/T2 brain lesion load, brain atrophy, and disability progression expressed by EDSS change in other follow‐up studies for over 2 years in relapsing MS (Enzinger et al., In conclusion, our results among others suggest that diffusivity abnormalities exist in relapsing‐onset MS patients; however, their dynamic change over time is different with respect to anatomical location. Additionally, diffusivity metrics in the normal‐appearing CC may be associated with disability accumulation in relapsing‐onset MS and suggest the crucial role of the CC in monitoring disease progression. Given its high sensitivity in detecting diffuse brain abnormalities, DTI indices may serve as a potential biomarker of disease progression; however, method standardization is needed. Moreover, stability and sensitivity to underlying pathology of DTI metrics have to be confirmed in longitudinal studies (Wattjes et al., We declare that we have no conflict of interest. Click here for additional data file. Click here for additional data file.


Birth Preparedness and Complication Readiness (BP/CR) is the process of planning for normal birth and anticipating actions needed in case of emergency. Even though there is no adequate evidences on determinant factors, women and newborn need timely access to skilled care during pregnancy, childbirth, and the postpartum period. The aim of this study was to identify factors associated with the practice of birth preparedness and complication readiness plan among women who gave birth in the last 12 months in Farta District, Ethiopia, 2016.A community-based cross-sectional study was conducted among 676 mothers from 1st October to December, 2016. Multistage sampling technique was used to select study participants. Data were collected using structured and pretested questionnaire. Bivariate and multivariable logistic regression models were fitted to identify factors associated with the practice of birth preparedness and complication readiness plan. An adjusted odds ratio with 95% confidence interval (CI) was computed to determine the level of significant.child birth  and postpartum period  were significantly associated with practice of birth preparedness and complication readiness plan.The percentage of women implementing complication readiness plan and practicing birth preparedness was found to be 34%. Residence ; educational status ; Antenatal care follow up ; history of stillbirth ; knowledge of birth preparedness and complication readiness plans ; knowledge of key danger signs during pregnancy , The overall proportion of women who prepared for birth and its complication readiness was found to be low. Educating women, encouraging pregnant women to utilize antenatal care, creating awareness on danger signs during pregnancy and childbirth might increase women’s birth preparation and complication readiness plan.The online version of this article (10.1186/s12884-019-2325-4) contains supplementary material, which is available to authorized users. Globally, Maternal death due to complications during pregnancy and childbirth decreased by 50% from an estimated 523,000 in 1990 to 289,000 in 2013 ,  and  respectively ]. Women who attended secondary school and above were nearly 3 times more likely to prepare for birth and its complication readiness as compared to women who are unable to read and write . Women who had a history of stillbirth were three times more likely to prepare for birth and its complication . Those women who had ANC follow-up visit were nearly four times more likely to prepare for birth and its complication . Those mothers who were knowledgeable for birth preparedness and complication readiness were nearly nine times more likely to prepare for birth and complication readiness compared to non-knowledgeable mothers . Mothers who were knowledgeable for danger signs during pregnancy, This study revealed that the practice of birth preparedness and complication readiness plan was found to be 34%. This is in line with studies done in Goba district that used the same definition for birth preparedness and complication readiness, Southern Ethiopia and Jimma Zone that used the more likely comparable definition for birth preparedness and complication readiness , 18, 19.The study revealed that 21.4% of respondents delivered their last child at a health institution. About eight in every 10 women (79%) received at least once ANC follow-up visit in their last pregnancy. The finding is consistent with the Ethiopian Demographic and Health Survey (EDHS) 2016 result which found that 62% of women who gave birth in the last 5 years received at least once ANC follow-up care and 20% of rural women and 79% of urban women gave birth at a health facility . This fichild birth and postpartum period were significantly associated with the practice of birth preparedness and its complication readiness. Women who were knowledgeable for birth preparedness and its complication readiness were 8.83 times more likely prepared for birth and its complication  as compared to their counterparts and also those who were knowledgeable for obstetric danger signs of pregnancy , child birth  and postpartum period  were more likely prepared for birth and its complication. This is in line with the studies done in Arsi, southern Ethiopia, sub Saharan Africa and Tanzania  weTanzania –25child birth was not associated with the practice of birth preparedness and complication readiness . Mothers who have attended ANC follow-up visit in their last pregnancy were 3.67 times more likely prepared for birth and its complication than those who had no ANC follow up visit . This finding is in line with the study done in Goba district, Oromia region; Adigrat town, northern Ethiopia and Robe woreda, Arsi zone –14. ThisWomen who were urban dwellers were 5.94 times more likely prepared for birth and its complication as compared to rural counter parts . This is consistent with the studies done in Goba district, and Sub- Saharan Africa , 19. Thistill birth were prepared for birth and its complication than mother who did not have a history of still birth . This is similarly reported in Adigrat town, northern Ethiopia [Among the obstetric factors, mothers who had a history of Ethiopia . This cochild birth. This is consistent with the studies done in Adigrat town and Robe woreda [child birth (51.2%) and the postpartum period (71.9%). This is consistent with the studies done in Tsegedie District, Aleta Wondo District and Mapawa district [A significant proportion of respondents were not knowledgeable about birth preparedness and its complication readiness. This finding is in line with other previous studies –14. Amone woreda , 14. Majdistrict , 26, 27.district .The study revealed that a small number of women were well prepared for birth and its complication. Therefore Ministry of health maternal and child health directorate, Amhara regional health bureau and Farta district health office are strongly recommended to work hard to improve birth preparedness and its complication readiness of women.Farta district health office in collaboration with the district educational office should further strengthen their activity to empower women with education. Furthermore, the regional policy makers and program planners are recommended to increase educational access to the women which will make alert them in preparing to birth and complication. This might be due to, as the level of education of increase, women empowerment would increase which might increase birth preparedness and complication readiness plan , 15, 28.The Farta district health officers and the health care providers are recommended to increase awareness about obstetric danger sign, increase quality and accessibility of antenatal care services for every woman at the community and providing adequate information about the risk of lack of birth preparedness through community mobilization during maternal conference, during ANC follow up visit and postnatal follow up visit. This might be due to the fact that women awareness on ANC, and when they got quality of maternal health care service, their practice on birth preparedness and complication readiness plan might increase , 19.Monthly income might be one of the causes that can affect the practice of birth preparedness and complication readiness plan but in this study, the assessment of their revenues throughout data collection was not precise so that it was not reflected during the analysis. Even though we tried to minimize, still there might be recall bias and social desirability bias. In addition, the district surveyed in this study may also not be representative of other districts in Ethiopia or regions beyond Ethiopia.still birth, and educational status were factors significantly associated with birth preparedness and complication readiness practice.The proportion of birth preparation and complication readiness practice among women who gave birth in the last 12 months was found to be low. Knowledge statuses of respondents about birth preparedness and its complication readiness and on key obstetric danger signs were very poor. Knowledge of key obstetric danger signs during pregnancy, delivery and postnatal period, knowledge about preparation for birth and its complication, ANC follow up visit, residence, history of Additional file 1:English version questionnaire: English language questionnaire that used to assess Birth preparedness, readiness planning and associated factors among mothers in Farta district, Ethiopia. (DOCX 25 kb)


Informal street traders are exposed on a daily basis to traffic emissions and biomass fuel smoke containing a variety of pollutants. These exposures are likely to place the female traders at increased risk for adverse reproductive outcomes.The aim of this study was to compare the reproductive outcomes among street traders exposed to pollutants from their work-related activities and traders without such exposure.A cross-sectional study was conducted among 305 female traders selected from exposed and non-exposed areas within the Warwick Junction trading hub, located in Durban, South Africa. Validated reproductive questionnaires and clinical assessments were conducted on all participants. Adverse reproductive outcomes such as low birth weight, spontaneous abortions and infertility were assessed.The mean age of the traders was 43.6 years (SD:12.1), mostly single (63%) and worked in trading hub for an average of 14 years. There were 876 pregnancies reported in the total sample. Traders pregnant while working in this location accounted for 120 pregnancies There was an increased risk of exposed traders having a low birth weight infant as compared to non-exposed traders . Exposed traders were also almost 3 times more likely to be infertile as compared to non-exposed traders .This study has demonstrated that female street traders working within a trading hub in KwaZulu-Natal, South Africa; exposed to occupational pollutants show an association with developing infertility and low birth weight infants. Recommendations to mitigate adverse exposures have been suggested which include short term safety interventions and better cooking practices and future long term policy interventions. Adverse reproductive outcomes have long been a cause of concern worldwide. The World Health Organisation (WHO) reported a global estimate of 130 million births annually, 303,000 resulted in maternal mortality. Still births and neonatal deaths account for 2.6 million and 2.7 million respectively . (Table n = 50 (16%)], bovine head market [n = 43 (14%)] and the traditional herb market [n = 75 (25%)]. There were 93 (30%) traders involved solely in cooking practices  within the sample. The remaining traders were considered non-exposed and belonged primarily to the clothing markets [n = 81 (27%)], fresh produce market [n = 34 (11%)], roadside vendors [n = 14 (5%)] and other traders in sales of goods [n = 8 (3%)]. The participants on average were working in WWJ for 14 years with a small minority (5%) working for greater than 30 years in the market. There were no statistical significant differences in demographic profiles between the exposed and non-exposed groups.There were 167 (55%) of the participants in the exposed group. These were the mealie cookers  reported being pregnant at least once. The overwhelming majority (n = 261 (90%)) were multiparous. (Table p = 0.004). Doctor diagnosed infertility also accounted for 6% (n = 17) of the total number of participants.A vast majority of traders [Traders becoming pregnant while working in WWJ was analysed as a subset of the data Table . There wn = 34(28%)]. There was a collective high prevalence of low birth weight (34%) and spontaneous abortions (10%) among traders in the exposed group compared to non-exposed.The majority of the pregnancies during work at WWJ, were among traders in the traditional herb market [p = 0.002) and low birth weight (p = 0.000) were significantly higher in exposed traders compared to those without exposure.  Table  Traders This study among informal street traders provides additional evidence of increased exposure related risk for adverse reproductive outcomes . The finThis is higher than reported in the literature. In Accra, Ghana a cross-sectional study on 105 female street vendors indicated an association between street vending and adverse reproductive outcomes . The aveFuel use amongst pregnant women and the associations with adverse reproductive outcomes have been extensively researched. A fixed effect meta-analyses conducted by Pope et al., described the relationship between use of biomass fuels and birth weight. Use of solid biomass fuels was significantly related to low birth weights  and a reduced mean birth weight  and particulate matter (PM) which was emitted in the smoke. Garbage burning was associated with an increase in the risk of low birth weights  and miscarriages 13.7%). Another 13.5% of the women reported experiencing difficulties in conceiving during their child bearing years [.7%. AnotInfertility was also identified as a significant risk associated amongst exposed street traders in this study . South Africa has been leading the trend of increasing infertility within sub-Saharan Africa, with a national fertility rate of 2.8 . In the We were unable to assess further history of previous pregnancies such as; frequency of antenatal visits, clinical assessments during the pregnancies and other psychosocial factors  that could affect the outcome of the pregnancy. Information bias might have also existed amongst traders who had to recall information on their previous pregnancies which could not be objectively verified.A further limitation is that we were unable to conduct personal exposure sampling while the women were pregnant. However since trading activities seldom change and traders are not in fixed isolated trading areas, we adjusted for crude exposure readings which were based on years working in WWJ.Our findings indicate a risk of adverse reproductive outcomes in the informal sector in South Africa. Access to healthcare and education of traders on reproductive and maternal health needs to be a priority to assist in reducing incidence of adverse reproductive outcomes in this vulnerable group of workers. Short term interventions need to be assessed in this working environment. Control measures; such as engineering, administrative and use of personal protective equipment have been previously implemented such as; designing of separate stalls, chimneys and areas of natural ventilation to mitigate exposure to smoke emissions and dust. Informal street traders form an integral component of the economy and should therefore be accorded inclusion into labour legislation and national policy development.According to statistics released by the ILO, approximately 2.5 billion people, or half of the global workforce are employed within the informal economy . InformaThe primary concern therefore remains the lack of legislation and inadequate health and safety control measures within this rapidly growing economy. Formal sector and informal sector are chiefly viewed as being separate entities however in most developing economies these two sectors overlap .A notable step has been taken by the ILO to address the challenges of the informal economy by adopting Recommendation No.204 in 2015 which seeks to address the Transition from Informal Economy to the Formal Economy . HoweverThe relevant stake holders; governmental and non-governmental need to engage and embark on planning and developing new policies and interventions to be implemented within this sector to assist in reducing the growing burden of disease by ensuring safer working practices.Accessibility of healthcare poses a challenge to these informal traders. In an attempt to mitigate this, it is recommended that local government institute a mobile clinic program within the trading hub specifically for traders. This intervention will assist traders to utilize healthcare facilities whilst at work. By providing this service the burden of diseases prevailing in this community might be minimized. Early diagnosis and prevention of diseases will be encouraged by the implementation of this facility.


Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth.We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect  effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available.Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF . Using causal mediation methods, the total effect of CF on birth weight was estimated to be −178.8 g (95% CI −225.43 to −134.47 g) in the Danish population and −210.08 g (95% CI −281.97 to −141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age.CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation. Does having cystic fibrosis (CF) impact on birth weight and gestational age at birth?CF has a large effect on birth weight, similar to the impact of maternal smoking during pregnancy, and is only partially explained by shorter gestation, indicating that having CF impacts directly on intrauterine growth.Using record-linked data for 2.2 million babies in two countries and modern methods of causal mediation analysis, we show that babies with CF are born about 200 g lighter than babies with no CF, and only around 40% of this effect is explained by reduced gestational age.Cystic fibrosis (CF) impacts negatively on the growth of children. Suboptimal growth is associated with worse lung function and increased risk of premature death in people with CF.In children with CF, as in the general population, those from socially disadvantaged backgrounds are smaller and lighter compared with children from more affluent families, and have worse health outcomes and survival. In children with CF these associations are evident at diagnosis, and they appear to track forward influencing subsequent outcomes.In this study, we aimed to clarify the association of CF with preterm birth and birth weight, and establish whether these associations vary by childhood socioeconomic conditions (SECs), at population level in Denmark and Wales. We further aimed to assess whether any differences in birth weight observed were due to differences in gestational age between babies with CF and babies with no CF, or whether there are separate biological processes linked to CF that lead to reduced birth weight.We undertook a population-level linkage study of all singleton children born in Denmark between 1980 and 2010 and in Wales between 1998 and 2015.In Denmark, we accessed the data from the Danish Medical Birth RegisterIn Wales, we analysed data from the Secure Anonymised Information Linkage databank.Multiple births, individuals with missing birth weight, gestational age, parity, sex or deprivation score were excluded from the analysis. We also excluded individuals with birth weight <100 g or >7 kg or gestational age <21 weeks or >45 weeks, on the basis that these may be data entry errors. See  online 10.1136/thoraxjnl-2018-211706.supp1Supplementary dataThe main outcomes of interest were birth weight and gestational age; and the main exposure of interest was being coded as having CF compared with not having CF in the linked administrative datasets in each country. Selection of covariates in the analysis was informed a priori using a directed acyclic graph , and thiIn Denmark, CF diagnosis was extracted from the DNPR, which includes hospital inpatient and outpatient data, identified by the  International Classification of Diseases (ICD) 8 code 273 in years prior to 1994 and ICD 10 code E84 thereafter. Birth weight, gestational age, date of birth, sex, parity (from 1996 onwards), mode of delivery, maternal age at birth and maternal smoking (from 1996 onwards) during pregnancy were obtained from the Danish Medical Birth Register. A binary variable indicating first-born status was derived from the available parity variable post-1996; parity for births prior to 1996 was estimated as the number of previous live births and stillbirths, which reached gestational age >22 weeks. Additional available covariates in Denmark were pre-eclampsia or eclampsia during index pregnancy , and diabetes during index pregnancy , which were obtained from the DNPR. Highest maternal educational level at birth  levels 1–6 and obtained from the Education Register) was used as a measure of childhood SECs at birth.In Wales, we obtained information on diagnosis of CF from CARIS, PEDW and WLGP, identified by ICD 10 code E84 and READ codes 1264., 66 k., 66k0., 9No7., C370. We obtained birth weight, week of birth of the baby and sex from the ADBE. Other covariates in the analysis included a binary variable indicating first-born status (derived from the number of previous live births given in NCCH); information on the mother’s smoking status in the year previous to birth and the mother’s week of birth (through WLGP). The mother’s age at birth was calculated as difference in days between week of birth of the baby and week of birth of mother divided by 365.25. Deprivation quintiles of small area of residence based on the Welsh Index of Multiple Deprivation (WIMD) was obtained for the Lower Super Output Area (LSOA) of the mother’s postcode from the WDSD and used as a measure of SECs at birth. The LSOAs from the 2001 census were used together with the WIMD scores from 2008.We used causal mediation methodsWe modelled the joint distribution of birth weight and gestational age using a two-component mixture of bivariate linear regression models for the two countries separately. Finite mixture models have previously been used for modelling of gestational age and birth weight in order to capture the skewed shape of their distributions.We initially included CF, sex, parity and socioeconomic status as explanatory variables for both gestational age, and birth weight conditional on gestational age. The significance of each of the covariates was tested by backward elimination based on the likelihood ratio criterion with a cut-off for significance of p<0.05. The direct effects of CF on birth weight and gestational age after adjustment for possible confounders were estimated in both subpopulations. The indirect effect of CF on birth weight through gestational age was estimated by the product of the effect of CF on gestational age and the effect of gestational age on birth weight.We performed multiple sensitivity analyses to assess the robustness of our results. We allowed for interaction terms between CF and any of the other covariates and assessed their significance using the likelihood ratio test with cut-off for significance of p<0.05. We repeated the analyses: allowing for an interaction term between CF and gestational age; and including just one child per mother to remove any biases that could be introduced due to correlations between outcomes in children from the same mother. In order to assess the influence of unmeasured confounders in our main analysis, we repeated our analyses in subpopulations in which we have additional data on age of the mother at birth and smoking status in the year prior to birth; in Denmark, we additionally included data on mode of delivery, pre-eclampsia or eclampsia and diabetes during pregnancy. In order to assess the impact of potential misclassification of CF cases, we repeated the analyses using stricter classification criteria for CF. In Denmark, we classified those as CF that had a CF code in the DNPR and that had been seen at a hospital more than once. In Wales, we selected only those individuals that were coded as CF in CARIS. In an additional post hoc analysis using our final model, we estimated the probability for a baby with CF compared with a baby with no CF to be born with low birth weight, since this may also be of clinical interest. See online We use anonymised data in this study, therefore specific ethics approval was not needed.In Denmark, 11.9% of the CF population had low birth weight (<2.5 kg) compared with 4.2% in the non-CF population; in Wales, 11% compared with 5.4% had low birth weight. In Denmark, 12.7% of the CF-coded babies were preterm (<37 weeks) compared with 5% in the non-CF population. In Wales, 9.4% of the CF-coded babies were preterm compared with 5.8% in the non-CF population. Socioeconomic position, first-born status, gender, age of the mother at birth, smoking in the year prior to birth, mode of delivery and rates of diabetes and pre-eclampsia were distributed similarly in the CF and non-CF-coded populations.The estimated whole population effects are discussed in this section; for details on the mixture subpopulations and the estimated effects at the level of the subpopulations, see online In the Danish population, babies with a CF diagnosis were on average born about 3 days earlier than babies with no CF . Parity and sex had negligible effects on gestational age, whereas gestational age increased by about 2 days when comparing babies born to mothers with primary education and those born to mothers with second stage tertiary education .In total, babies with CF in the Danish population were 178.8 g (95% CI 134.47 to 225.43 g) lighter than babies with no CF. Approximately 35% of the effect of CF on birth weight was mediated by gestational age. First-born and female babies were significantly lighter than not first-born and male babies and birth weight increased by almost 150 g when comparing babies from mothers with primary education with those born to mothers with second stage tertiary education .In the Welsh population, CF-coded babies were born approximately 4 days earlier than non-CF-coded babies . First-borns were found to be born slightly earlier than non-first-borns. Sex had a negligible effect on gestational age. The estimated increase in gestational age for babies from the least compared with the most deprived mothers was <1 day  lighter than non-CF-coded babies with approximately 39% of the effect being due to reduced gestation. First-borns and females were significantly lighter than non-first-born and male babies. Birth weight increased by approximately 115 g when comparing the most with the least deprived quintile of babies .Although no interaction effects between CF and any of the covariates were statistically significant (p<0.05), we found that the interaction between CF and first-born status was only marginally above the threshold level in both populations  gene mutation and reduced levels of insulin-like growth factor 1 (IGF1). This association has been demonstrated in CF pig models, with reduced levels of IGF1 associated with reduced bone length and bone mineral content at birth.1% at age 6 increasing by an estimated 1% per additional 100 g birth weight.More research is needed to assess the prognostic value of birth weight for subsequent outcomes in CF. Nutritional status and growth in the early years are closely linked to lung function, which subsequently influences survival in CF.Pseudomonas aeruginosa infection and have lower lung function compared with children with CF from the least deprived areas.Within the CF study population, we found an average difference in birth weight of over 100 g between babies from the least and the most deprived families in both Wales and Denmark. Children with CF from the most deprived areas in the UK have been found to weigh less, be shorter, have a lower body mass index, be more likely to have chronic A key strength is that our study made use of routinely collected data, which led to an unselected population-based cohort of around 2.2 million babies with 852 CF cases. A further strength is that we were able to carry out the analysis in two countries with remarkably consistent findings in both national populations. A wide range of information is collected in the Welsh and Danish registry linkages, allowing us to adjust for a range of variables in our analysis. A further strength compared with previous studies is that we have used modern methods for causal mediation analysis to better understand the role of gestational age in the pathway from CF to low birth weight. Misclassification of CF cases is a potential limitation of our analysis. CF is a lifelong condition that requires intensive healthcare support over the patient’s life, and all patients can be expected to receive hospital-based care at some point. It is therefore likely that all true CF cases are captured in both countries. In Wales, we were able to identify cases on the basis of both hospital inpatient and outpatient data and general practice records. In addition, a universal new-born screening programme was introduced in the UK (but not in Denmark) in 2007 leading to early diagnosis of CF in Wales and capture in the CARIS dataset. Any misclassification of CF cases identified in routine administrative datasets is expected to be independent of birth weight and gestational age and would, as such, lead to a conservative estimate of the effects on birth weight and gestational age. Robustness tests, selecting cases most likely to be true CF cases showed similar results to our main analysis.In order to be able to estimate the direct and indirect effects of CF on birth weight, we made four assumptions to ensure identifiability of the natural indirect effect (see online Birth weight and gestational age are not currently collected in most CF registry datasets, including the UK, the US and Danish databases. Based on our study results, we recommend the addition of birth weight to the list of variables collected in CF registries. This will allow further longitudinal studies to understand the association of birth weight with trajectories of nutritional status and lung function and its association with survival. Further research is also needed to understand the biological mechanisms that lead to reduced intrauterine growth in babies with CF compared with babies with no CF. Finally, our study has shown the merits of data linkage, without which we would not have been able to adjust for all the important confounders and identify the direct and indirect effects. In order to further our understanding of disease progression in CF, linkage of CF registries to other routinely collected data sources should be considered.In conclusion, our findings from the analysis of national populations in Wales and Denmark suggests that CF has a significant effect on birth weight, and that this is only partially due to an effect on gestational age.


Preterm birth and low birth weight are associated with reduced nephron numbers and increased risk of hypertension and kidney disease in later life.We tested the hypothesis that extremely preterm birth and intrauterine growth restriction is associated with decreased renal function in mid childhood.th percentile for GA. Glomerular filtration rate (GFR) was estimated according to the equations by Schwartz, Zappitelli and Gao.At 11 years of age the following measures were obtained in a regional cohort of children born extremely premature  or with extremely low birth weight  and in matched controls born at term with appropriate BW (AGA): Height, weight, abdominal circumference, triceps and subscapular skin fold thicknesses, blood pressure, plasma levels of creatinine, cystatin C and symmetric dimethyl arginine (SDMA). Small for gestational age (SGA) was defined as a BW < 10Fifty-seven of 61 eligible EP/ELBW children, 20 (35%) born SGA, and 54 controls, were assessed. Estimated GFR decreased while plasma SDMA increased from the children born AGA at term through those born preterm AGA to preterm SGA. Systolic BP was correlated to fat mass indices (p<0.03), but not to renal function (p>0.2) and did not differ between the groups.Children born EP/ELBW, particularly those born SGA, had impaired renal function at age 11 years as judged from estimated GFRs and plasma levels of SDMA. Since reduced renal function is associated with an increased risk of later disease, these children should be followed in order to minimize additional risk factors. Preterm birth implies short- and long-term consequences for most organ systems. The fetus might have been subject to adverse intrauterine development leading to preterm birth , and theTh percentile for GA), is associated with smaller kidneys, reduced nephron numbers, possibly morphologically abnormal nephrons and reduced glomerular filtration rate [For the renal system, being born preterm, with low birth weight  or small for gestational age  based on the clearance of the exogenous marker inulin, but also clearance of iothalamate and iohexol are used [The gold standard for assessment of renal function is are used . While tare used . In chilare used , e.g. thare used –16.reatinine, the waste product from creatine and phosphocreatine, found mainly in skeletal muscle, is freely filtered through the glomerulus and secreted through the proximal tubules. Its value as a renal function marker is hampered by biological and analytical variations. There is considerable variation in serum levels due to differences in height, muscle mass, gender and diet [Cystatin C is produced at a constant rate in all cells, and excreted by glomerular filtration followed by catabolism in the tubular cells. As it is less affected by height, weight, muscle mass and diet than creatinin, its plasma concentration has been proposed as a better renal function marker for pediatric patients [Symmetric dimethylarginine (SDMA) is a methylated arginine metabolite produced in all nucleated cells and excreted in the kidneys. The plasma level is correlated to inulin clearance in children, and thus, SDMA has been put forward to serve as an endogenous marker of renal function [Cand diet , the anaand diet . Cystatipatients . Symmetrfunction .We investigated renal function by creatinine, cystatin C, SDMA and estimated GFR in two groups of 11 year old children; term-born children with appropriate birth weight (BW) for gestational age (AGA) and children born extremely preterm (EP) or with an extremely low birth weight (ELBW). Our hypothesis was that being born EP/ELBW and especially SGA within the EP/ELBW group, was associated with decreased renal function.As part of a prospective national study , a cohorThe children were invited for follow-up at 11 years of age. For each EP/ELBW participant, the next-born child of the same gender with GA >37 weeks and BW >3000 grams was identified from birth protocols in the maternity ward and invited as a control. If the parents declined, the next-born child was approached until a match was obtained.th percentile for GA according to Norwegian growth curves [Neonatal data were obtained from compulsory notifications to the Medical Birth Registry of Norway and from registration forms developed for the study and completed by neonatologists during the stay in the neonatal intensive care nursery, and by pediatricians and parents during follow-up . Small fh curves .The Regional Committee on Medical Research Ethics granted ethical approval of the protocol, and the mothers gave written, informed consent.2) and subscapular to triceps skinfold ratio (STR) were calculated as estimates of body fat deposition and truncal fat mass [At 11 years of age (in 2010–2011), the children were assessed at the University Hospitals in Bergen or Stavanger, according to place of birth. Height, weight, waist circumference, triceps and scapular skinfolds were measured. Body mass index  for separation of plasma and in Vacutainer Tubes without additives (Becton Dickinson) for separation of serum. Blood samples for preparation of EDTA-plasma were placed in ice water, and plasma was separated within 4 hours. The samples were stored at –80°C until analysis.www.bevital.no). Plasma levels of cystatin C were measured using immuno-MALDI-MS, with a LOD of 0.003 μg/mL and a within-day CV of 4–6%  [Renal function markers included plasma creatinine, cystatin C, symmetric dimethylarginine (SDMA) and estimated GFR. Plasma levels of creatinine and SDMA were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) . Creatinital.no) .0.003×height)/(Cystatin C0.635 × Creatinine0.547) [2 + 0.48 x age (years)— [Estimated GFR was based on the bedside Schwartz equation, i.e. 0.413*height/Creatinine, the Zappitelli equation, i.e. (507.76 × ene0.547) , 16 and females) .Results are presented as means, standard deviations and 95% confidence intervals (CIs) or as medians and interquartile range (IQR) and compared by ANOVA/Student’s t-test or Kruskal Wallis test. Differences in categorical variables were tested by Chi-Square tests. Trends for differences according to birth status (from term-born via preterm AGA to preterm SGA) were assessed by linear regression. The Spearman’s test was used to calculate correlations, and multiple linear regressions to assess renal function after adjusting for birth status and growth parameters (AGA vs. SGA).The SPSS statistical package (version 23) was used for the statistical analyses and two-sided p-values < 0.05 were considered statistically significant.Fifty-seven eligible EP/ELBW children were examined at a mean age of 11.4 (SD 0.4) years . The GA At 11 years mean height was lower in the EP/ELBW children, whereas mean weight and BMI were similar to that of the term controls. Within the EP/ELBW children, those born SGA were shorter, but their mean weight and BMI were similar to that of those born AGA. STR skinfold thickness increased from the term-born group through the preterm AGA and preterm SGA children .There were no differences in mean systolic or diastolic BP between term and preterm AGA or SGA children . SystoliAll renal function parameters were inter-correlated . The SDMAfter adjusting for age, gender, weight and height in a multiple linear regression model, there was an increase in plasma creatinine , cystatin C  and SDMA  and a reduction in GFR Schwartz , GFR Gao  and GFR Zappitelli  from the term-born through the preterm AGA and preterm SGA groups. The endogenous renal markers (including estimated GFR) did not correlate with systolic or diastolic BP (P>0.13).At 11 years of age, children born EP/ELBW had impaired renal function compared to term born peers, as reflected in lower GFR and higher SDMA. Renal function was more impaired in children born preterm and SGA compared to those born preterm and AGA. Blood pressure was unrelated to GA, BW or SGA vs. AGA status, but systolic BP was positively associated with indices of increased fat mass.There is increasing awareness that adverse intrauterine conditions may lead to developmental programming causing non-communicable diseases later in life, a concept labeled ‘developmental origins of health and disease’ (DOHaD). For hypertension and renal disease, these issues may be related to adverse fetal events that modify the nephron number and/or function .per se or to an adverse intrauterine environment. Moreover, studies investigating cohorts born at different gestational ages may not be directly comparable. Fetal kidney development will have reached different developmental stages at birth and the mechanisms for reduced kidney function are likely to differ. Finally, some studies have investigated only males [Different research groups have reported higher blood pressure or reduced renal function in groups of individuals born preterm and/or at a low birth weight –9, correly males , or founper se, as well as by abnormal nephrons that are formed postnatally, while the preterm infant is exposed to neonatal intensive care [The mechanisms linking preterm birth, fetal growth restriction and impaired renal function are poorly understood. Nephrogenesis begins around the ninth week of pregnancy and terminates around 36 weeks’ gestation in term-born infants. More than 60% of adult nephrons are formed during the last two trimesters of pregnancy; thus, the number of nephrons correlates positively with GA at birth . Nephronive care .as such may also result in lower numbers of nephrons in premature SGA infants, with the number of nephrons increasing by approximately 250.000 per kg birthweight [Fetal growth restriction thweight , 36. A rthweight , a risk thweight , 31, 32.both prematurely and SGA [as such. Nevertheless, it is important to bear in mind that all markers of renal function were within published normal reference ranges [Thus, the present study reinforces concerns expressed previously for those born  and SGA , 38. Thee ranges , 39, 40 Hypertension is both a major cause and a result of chronic kidney disease. Both prematurity and LBW has been shown to increase the risk of later hypertension . In metaApart from height, growth parameters were similar in preterm and term-born children. The preterm SGA children had the shortest stature, but the highest subscapular to triceps skinfold ratio, suggesting a relatively higher truncal fat mass. Similar observations have been made in many –46, but In line with the DohAD concept, most epidemiological studies suggest that being born SGA is associated with higher percentages of body fat and truncal obesity in later childhood and adulthood –46. The This was a population-based study. It included three endogenous markers of renal function, including SDMA, which has not previously been evaluated in a preterm population. The attendance rate was high, and the recruitment of the control group followed a strict algorithm based on the ‘next-born-subject’ principle, minimizing risks of selection bias. The study design prescribed inclusion of all subjects born EP (GA < 28 weeks), but also those with ELBW (< 1000 gram) irrespective of GA. Thus, the results indicate that extreme prematurity, and in particular early intrauterine growth restriction, may be risk factors for early renal impairment and related health consequences. However, the results do not necessarily generalize to all preterm-born children. The low number of participants is an obvious weakness, impacting statistical power and opening for type I as well as type II statistical errors, although the size of the study population is comparable to that of most follow-up studies on children born EP/ELBW. Lack of data on urine albuminuria, urine albumin-creatinine ratio or 24 h ambulatory blood pressure, represent additional weaknesses of the study.Eleven year old EP/ELBW children, and in particular those born SGA, had poorer renal function than peers born at term. The findings indicate that being born preterm and SGA implies an increased risk of developing kidney disease later in life.


Atrazine, a common water contaminant in the U.S., has been associated with adverse birth outcomes in previous studies. This study aimed to determine if atrazine concentrations in drinking water are associated with adverse birth outcomes including small for gestational age (SGA), term low birth weight (term LBW), very low birth weight (VLBW), preterm birth (PTB), and very preterm birth (VPTB). This study included 14,445 live singleton births from Ohio communities served by 22 water systems enrolled in the U.S. Environmental Protection Agency’s Atrazine Monitoring Program between 2006 and 2008. Mean gestational and trimester-specific atrazine concentrations were calculated. Significantly increased odds of term LBW birth was associated with atrazine exposure over the entire gestational period , as well as the first  and second trimesters  of pregnancy. We observed no evidence of an association between atrazine exposure via drinking water and SGA, VLBW, PTB, or VPTB. Our results suggest that atrazine exposure is associated with reduced birth weight among term infants and that exposure to atrazine in drinking water in early and mid-pregnancy may be most critical for its toxic effects on the fetus. Atrazine is the second most widely used herbicide in the United States, primarily applied to corn and sorghum crops . Much ofAtrazine is an endocrine disruptor ,4,5, andThere is limited epidemiologic evidence of an effect of prenatal exposure to atrazine on adverse birth outcomes in humans. Winchester et al.  observedThe United States Environmental Protection Agency (USEPA) defines the legal limits for water contaminants and water testing schedules, as mandated in the Safe Drinking Water Act. The maximum contaminant level (MCL) for atrazine in drinking water is 3 µg/L . Public The primary objective of this study was to examine the association between atrazine concentrations in drinking water and selected adverse birth outcomes among those communities receiving drinking water from community water systems that were part of USEPA’s Atrazine Monitoring Program between 2006 and 2008 in the state of Ohio. This study also aimed to explore the utility of environmental and health data collected through routine monitoring by state and federal agencies for addressing epidemiologic questions, in line with the Centers for Disease Control and Prevention Environmental Public Health Tracking Program .n = 428,804) during this time period. Individual-level, de-identified birth certificate data for children born in Ohio were provided by the Ohio Department of Health.This study used birth certificate data from all births occurring within the 22 Ohio communities receiving drinking water from a CWS in the USEPA’s AMP between 2006 and 2008. There were 14,897 births in these cities, of which 14,445 (97%) were singleton births. This analysis was restricted to singleton births as multiple births  have smaller birth weights and shorter gestational periods . The sinThe birth outcomes of interest in this study were small for gestational age (SGA), term low birth weight (term LBW), very low birth weight (VLBW), preterm birth (PTB), and very preterm birth (VPTB). SGA was defined as the smallest 10% of infants, according to birth weight, at each gestational age in the population . Small fDrinking water measurements of atrazine in finished water from 2005 to 2008 were obtained from the USEPA’s AMP public data portal  for all Monthly mean estimates of atrazine in each AMP water system were calculated from the weekly and biweekly samples in the AMP data. Using the mean monthly estimates, we calculated the mean atrazine concentrations for the entire gestational period of the pregnancy  as well as for each trimester of pregnancy, based on date of birth and gestational age at birth. The limit of detection for atrazine was 0.1 µg/L in 2006 and was 0.05 µg/L in 2007 and 2008 . MeasureThe covariates examined in this study included infant sex, maternal age at birth, maternal race/ethnicity, maternal educational attainment, marital status, prenatal care status, socioeconomic status, parity, cigarette use, and maternal pre-pregnancy body mass index (BMI). Maternal age was categorized as <20, 20–34, and ≥35 years of age. Maternal race/ethnicity was defined as non-Hispanic white, non-Hispanic black, Hispanic, and other/unknown. Maternal educational attainment was categorized as less than a high school degree, high school degree, some college, and college degree or higher. Marital status was dichotomized as married or unmarried. The unmarried category includes mothers who responded single, widowed, or divorced. The Kotelchuck index was used to define the adequacy of prenatal care utilization, based on the month of entry into prenatal care and total number of prenatal care visits . Women wThis is a cross-sectional study of dichotomous birth outcomes among singleton births in Ohio cities served by AMP CWSs. Bivariate associations between atrazine concentrations, outcomes, and covariates were assessed using t-tests for continuous variables, Rao-Scott Chi-Square tests for dichotomous variables, and ANOVA test for covariates with >2 categories. Potential confounders were considered as those variables that were associated with both the exposure measures and outcome measures and were not conceptually in the causal pathway.®, Version 9.4 [We developed generalized estimating equation (GEE) logistic regression models, with an exchangeable working correlation structure and robust standard errors, to estimate the association between atrazine in drinking water and each birth outcome—SGA, term LBW, VLBW, PTB, and VPTB—while accounting for clustering at the city level. Models of continuous and categorical (tertiles) atrazine exposure were tested. Maternal age, maternal race/ethnicity, and year of birth were included in all adjusted models based on a priori knowledge. We assessed confounding throughout the model building process and in an effort to maximize parsimony, we retained only those variables that had a substantial (>10%) effect on the estimate of the effect of atrazine in the models. Final adjusted models were built using the gestational atrazine exposure measure. The covariates identified as confounders in these models were applied to models of trimester-specific atrazine exposure. Third trimester models were not performed for the outcome VLBW because only two of the VLBW births in this population were delivered at full term. Linear GEE regression models of birth weight and gestation in weeks were performed controlling for those covariates identified in the logistic regression model-building procedures. Between 0.5 and 3.5% of observations were not used due to missing data on covariates, exposure, or outcome status. All analyses were performed using SASsion 9.4 .n = 10 water systems). Additionally, we restricted the data set to those with a gestational atrazine concentration ≤3 µg/L to evaluate the relationship between atrazine in drinking water and selected birth outcomes when exposure is below permissible levels in public drinking water.We performed a sensitivity analysis to further reduce exposure misclassification by restricting the analysis to only those water systems where we had confirmation from on-site representatives that the service boundaries of the water system corresponded to the city limits in which it was located and that >95% of the population was likely to be receiving their public water from the AMP water system in question  and the Institutional Review Board of the Ohio Department of Health (#2016-17).Monthly mean atrazine concentrations in Ohio’s AMP water systems ranged from 0 to 15.7 µg/L between 2006 and 2008 . AtrazinThere were 14,445 live singleton births within the 22 cities which received their public drinking water supply from AMP water systems in Ohio between 2006 and 2008, of which 51% were males . The majWe found weak and statistically non-significant evidence of a positive association between gestational averages of atrazine and SGA in either crude or fully covariate-adjust models  . In our p = 0.0007).Mean gestational atrazine exposure was associated with significantly increased odds of term LBW birth in both crude and adjusted models . In catep = 0.77) and gestational age in weeks among all infants , but these findings were non-significant.Results from linear regression analyses indicated that an increasing gestational atrazine exposure was related to decreased birth weight among term infants , but the association was not significant . We obseMean exposure to atrazine in the first trimester was significantly associated with an increase in the odds of term LBW in these restricted models  . Atrazinn = 12,980), the current MCL set by the USEPA. Used as a continuous measure in the models, mean gestational atrazine exposure was associated with a significant increase in the odds of term LBW . Odds of term LBW increased across tertiles of mean atrazine exposure, but only those in the highest tertile of gestational atrazine exposure were at significantly increased odds of term LBW compared to those in the lowest tertile .In a separate sensitivity analysis of term LBW, we restricted the data set to include only those term births with a mean gestational atrazine concentration ≤3 µg/L  of missing data on the key covariates used in these analyses. A notable exception is the high level of missing data on prenatal care (26%). Those who were missing data on their prenatal care status were more likely to be non-Hispanic black, “Other” race/ethnicity, and young. We chose to only use those covariates that are considered to be well-reported and highly accurate on birth certificates, such as maternal age, race/ethnicity, marital status, parity, plurality, infant gender, birth weight, and gestational age ,43,44,45We lacked information on whether or not the mothers of the infants in these analyses had moved at any point during their pregnancy and assumed that the residence listed on the birth certificate was the residence throughout the entire pregnancy. Rates of pregnancy mobility are estimated between 12 and 32% ,47,48,49Our study was restricted to a small percentage of births (3%) in the state of Ohio for this analysis of AMP water systems. The population in these AMP communities differed from the state population in important ways. A much higher percentage of infants were born to mothers who were non-Hispanic white (86%) compared to the state as a whole (76%). Additionally, these AMP communities had a higher proportion of births from women enrolled in WIC (50% versus 42%) and who reported smoking (35% versus 26%). The small sample size relative to the state population and the demographic differences between the AMP communities and the state as a whole limit the generalizability of the study results. Ideally, future research on the association between atrazine in drinking water and adverse birth outcomes would include a representative sample of births to increase the generalizability of study findings.Despite these limitations, the study had several notable strengths. The exposure estimates used in this study are highly geographically and temporally refined, which allowed specific exposure windows, such as trimesters, to be examined. The large number of births included in this study allowed the examination of two rare outcomes, very preterm birth and very low birth weight, which have not been reported previously. Furthermore, this study also benefited from individual-level data on important covariates.Our findings suggest that additional epidemiologic research should examine the reproductive effects of exposure to atrazine in areas of relatively low contaminant exposure. Ideally, future research would employ biomarkers of exposure or individual assessment of drinking water exposures rather than relying on the ecologic exposure measures presented in these analyses. Despite the limitations in the exposure ascertainment, our findings demonstrate that linking environmental monitoring data with health outcomes data, such as vital statistics databases, holds promise for identifying potential associations, which can subsequently be investigated using with more refined exposure and outcome ascertainment.We found an association between atrazine concentrations in drinking water and the odds of term LBW births within communities served by water systems enrolled in USEPA’s Atrazine Monitoring Program in Ohio. This is the first study to show such an association for term LBW by linking maternal residence to a specific water system. Water systems are enrolled in the AMP as a result of repeated exceedances of the 3 µg/L MCL for atrazine, but only 4% of samples from the water systems in this study exceeded the MCL. We observed an increase in the odds of term LBW births among those with average gestational atrazine below the current MCL. While further epidemiologic research is needed, these results suggest that the current MCL for atrazine may not be protective against some adverse birth outcomes such as term LBW.


Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis.We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach.p = 1.1 × 10− 6) and a 0.168 SD increase in birth weight (p = 7.1 × 10− 5), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights . However, HIP was not associated with head circumference (p = 0.172).In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length  contains supplementary material, which is available to authorized users. Overweight has become a world epidemic affecting women of childbearing age. Up to 50% of reproductive age women were overweight or obesity in Europe and the USA , 2. MateHowever, waist circumference (WC), waist-to-hip ratio (WHR) and hip circumference (HIP), as indicators of central obesity have been suggested as being superior to BMI, given the relationship with visceral adiposity and the natural pregnant process –14. ObseMendelian Randomization (MR) analysis has become widely used to assess the potential causal relationship between environmental risk factors and diseases. MR studies have often been likened to natural randomized trials, in which genotype plays the role of random treatment assignment, avoiding the possibility of confounding and reverse causation –22. It hAn MR analysis is free of confounding and reverse causation compared with observational studies. There are three assumptions of MR analysis Fig. . First, P < 5 × 10− 8) from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, which have been downloaded from http://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files.Genetically predicted maternal central obesity including of waist-to-hip ratio adjusted for BMI (WHRadjBMI), waist circumference adjusted for BMI (WCadjBMI) and hip circumference adjusted for BMI (HIPadjBMI) were based on single nucleotide polymorphisms (SNPs) of genome-wide significant (https://www.broadinstitute.org/snap/snap) for the same reference catalogue and population [r2 > 0.05) were discarded based on larger P value. We used 35 SNPs from GIANT consortium as an IV for WHRadjBMI, 25 SNPs for WCadjBMI and 41 SNPs for HIPadjBMI. Full details of the selected SNPs are provided in Additional file r2 > 0.8).GIANT consortium is an international collaboration that seeks to identify genetic loci that modulate human body size and shape, including height and measure of obesity. This genome-wide association meta-analysis (GWAS) included 224,459 individuals of European ancestry . We assepulation . Highly http://egg-consortium.org. The EGG Consortium represents a collaborative effort to combine data from multiple GWAS in order to identify additional human genome loci that have an impact on a variety of traits related to early growth. EGG birth weight data were imputed up to the reference panels from the 1000 Genomes Project (Phase 1 v 3) or combined 1000G and UK10K Project. Birth weight was z-score transformed in males and females separately. The birth weight dataset was generated by a European-ancestry GWAS meta-analysis ; the birth length, head circumference and puberty height growth datasets were generated by performing a meta-analysis of 22 European population-based studies , a meta-analysis of 7 population-based European studies  and a meta-analysis of 9 European cohort studies , respectively.Genetic associations with birth weight , birth lThe study design of the present MR was to explore the causal effect of maternal central obesity uponoffspring birth size Fig. . SNPs weMendelian randomization analyses are becoming more powerful and efficient to perform based on summary public data. However, when using multiple genetic variants from different gene regions as IVs in an MR study, it is almost impossible that all the SNPs could meet the MR assumptions as mentioned previously . Even ifIf the causal association depends only on a single genetic variant and the estimate is heterogeneous with other variants’ estimates, then the results may be driven by a pleiotropic effect rather than the biology causal effect. We repeated the analyses excluding SNPs (26 SNPs left) that could influence WHRadjBMI and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), adiponectin adjusted for BMI, fasting insulin adjusted for BMI, T2D, and height manually .We also conducted sensitivity analyses to assess whether the estimates were robust to methodological choices. Weighted median method and MR-Egger regression were performed as complementary methods to ensure the robustness of the results. Weighted median estimate defines that each instrumental variable estimate appears with probability proportional to the inverse of its variance , which iMR-Egger regression based on Egger regression to examine publication bias in the meta-analysis was also used to test directional pleiotropy effects given no assumptions about the genetic variants but under an assumption that pleiotropic effects of genetic variants are independent of instrument strength. Using the MR-Egger regression method, the effect of IV on the exposure is plotted against its effect on the outcome, and an intercept distinct from the origin provides evidence for pleiotropic effects. The slope of the MR-Egger regression can provide pleiotropic-corrected causal estimates. If the intercept is zero, it suggests that there is no violation of the exclusion restriction criteria . It provides an estimate of the average pleiotropic effect across all of the genetic variants, because it reflects the effect of the joint instruments on outcome, when there is zero effect of the genetic variants of the risk factor –36.P < 0.00142 (0.05/35 SNPs = 0.00142), P < 0.002 (0.05/25 SNPs = 0.002) and P < 0.00125 (0.05/41 SNPs = 0.00122), using Bonferroni test.Informed consent was obtained from all participants of contributing studies. Contributing studies received ethical approval from their respective institutional review boards. The statistical analyses were conducted using R version 3.2.4 . All statistical tests were 2-sided. The thresholds of statistical significance for WHRadjBMI, WCadjBMI and HIPadjBMI as exposures were r2 > 0.05.Based on the results of meta-analyses of GWAS, 35 SNPs, 25 SNPs and 41 SNPs reaching genome-wide significance for waist-to-hip ratio adjust for BMI, waist circumference adjust for BMI and hip circumference adjust for BMI were selected [We used the inverse-variance weighted method as the primary approach to examine the causal effect in the present MR study. Tables p = 1.1 × 10− 6) and 0.392 SD increase in birth length , respectively. We also found that one SD increase in HIPadjBMI was causally associated with a 0.835 SD increase in sex-combined puberty height , a 0.747 SD increase in puberty height among females at 10 years old  and a 0.828 SD increase in puberty height among males at 14 years old . However, HIPadjBMI was not associated with head circumference . The results of the weighted median based method were consistent and even more significant than IVW method. The intercept term estimated from MR-Egger regression was centred at the origin with a confidence interval including the null showed that no evidence of pleiotropy effects.Table We used the weighted median based method and MR-Egger method to estimate the causal effects of WHRadjBMI, WCadjBMI and HIPadjBMI on birth weight, birth length, head circumference and puberty height. The results consistently supported the robustness of our findings. The results of the causal effects of WHRadjBMI and outcomes were consistent with or without the 9 SNPs which had potentially pleiotropic effects.In the present study, we used MR analyses to test the causal effect of maternal central obesity on offspring birth size and puberty height growth. We found that genetic predisposition to higher hip circumference independent of maternal BMI was associated with increased level of birth weight, birth length and puberty height. We observed one SD increase in HIPadjBMI (cm) was associated with 0.168 SD increase in birth weight, 0.392 SD increase in birth length and 0.835 SD increase in sex-combined puberty height. However, HIPadjBMI was not causally associated with head circumference. There was no evidence of causal effects of maternal WHRadjBMI and WCadjBMI on the birth size.Observational studies have shown that maternal overweight and obesity were associated with many maternal and neonatal complications . HoweverThe findings from this study were inconsistent with the results from the observational studies that showed women with increased WHR or WC were more likely to give birth to macrosomia , 38. Li The pathophysiological mechanisms underlying the causation relationship between HIP and birth size is not fully understood. The potential mechanism could be explained below. Larger HIP potentially reflects increased gluteofemoral muscle mass. As muscle mass increases with weight even in the overweight and obese women, HIP increases with WC as well. The side effects of larger WC might be counteracted by the increased muscle mass to some extent . In addiOur large two sample MR study using public data provided more precise estimates with greater statistical power because of the large sample size. The consistency significant causal effects estimates from different approaches showed no evidence of a violation of the MR assumption and suggested robustness of our findings. Additionally, we used three genetic IVs as indicators of central obesity  to test the associations of maternal central obesity independent of maternal BMI and offspring birth size and puberty height. However, there are several limitations of our study. Firstly, we used two-sample MR to explore the causal effect of maternal exposure on later offspring outcomes. Though in theory two-sample MR could be used to explain this issue; in general it is impossible to assess many questions related to intrauterine effects on offspring outcomes. Therefore, individual participant data of maternal genetic variants on offspring outcomes are warranted replicating the results. Second, the causal relationship between maternal hip circumference and offspring birth size could be violated via the offspring’s genetic variants . This isIn this MR study, a genetic predisposition to higher maternal hip circumference was potentially causally associated with higher offspring birth weight, birth height and puberty height.Additional file 1:Table S1a. WHRadjBMI loci achieving genome-wide significance (P < 5 × 10–8) in European women-specific meta-analyses. Table S1b. WCadjBMI loci achieving genome-wide significance (P < 5 × 10–8) in European women-specific meta-analyses. Table S1c. HIPadjBMI loci achieving genome-wide significance (P < 5 × 10–8) in European women-specific meta-analyses. (XLSX 22 kb)