Studies looking at air temperature (Ta) and birth outcomes are rare.We investigated the association between birth outcomes and daily Ta during various prenatal exposure periods in Massachusetts (USA) using both traditional Ta stations and modeled addresses.2.5), random intercept for census tract, and mother’s health.We evaluated birth outcomes and average daily Ta during various prenatal exposure periods in Massachusetts (USA) using both traditional Ta stations and modeled address Ta. We used linear and logistic mixed models and accelerated failure time models to estimate associations between Ta and the following outcomes among live births > 22 weeks: term birth weight (≥ 37 weeks), low birth weight , gestational age, and preterm delivery . Models were adjusted for individual-level socioeconomic status, traffic density, particulate matter ≤ 2.5 μm  in association with an interquartile range increase (8.4°C) in Ta during the last trimester. Ta over the entire pregnancy was positively associated with PT  and LBW .Ta during pregnancy was associated with lower birth weight and shorter gestational age in our study population.http://dx.doi.org/10.1289/ehp.1308075Kloog I, Melly SJ, Coull BA, Nordio F, Schwartz JD. 2015. Using satellite-based spatiotemporal resolved air temperature exposure to study the association between ambient air temperature and birth outcomes in Massachusetts. Environ Health Perspect 123:1053–1058;  The increase in temperatures over the last century and continued increases in emissions of greenhouse gases have focused attention on the effects of increasing heat . Relativin utero growth restriction  also contribute to perinatal morbidity and mortality , early-term delivery (delivery at 37–38 weeks gestation), and ortality . Evidencortality . The patortality . Social ortality . Environortality . Furtherhttp://modis.gsfc.nasa.gov/data/) surface temperature (Ts) over a large area with varying geographical characteristics (covering the entire Northeast and Mid-Atlantic areas of the United States) at a 1 × 1 km spatial resolution. We incorporated land use and meteorological variables to predict daily 24-hr mean Ta for grid cells even when satellite Ts measures were not available. A similar model has previously been developed for PM2.5 on the same resolution  among term births, preterm birth (< 37 weeks), and gestational age.http://www.mass.gov/eohhs/gov/departments/dph/programs/admin/dmoa/vitals/). The term birth weight and LBW  analyses included 453,658 births ≥ 37 weeks gestational age, and the gestational age and preterm birth (< 37 weeks) analyses included 473,977 births. The study and the use of birth data was approved by the Massachusetts Department of Public Health and the human subjects committee of the Harvard T.H. Chan School of Public Health. Informed consent was not required because we used anonymous administrative data.In the analysis we included the entire state of Massachusetts . The stuhttp://www7.ncdc.noaa.gov/CDO/) monitoring stations, and residence-specific cumulative traffic density. We describe each metric in more detail below.For exposure data we used three different indicators: predicted 1 × 1 km Ta from our model, ground Ta from the nearest National Climatic Data Center . Mean out-of-sample R2 values for days with and without Ts data were 0.947 and 0.940, respectively, indicating excellent model performance. Mean out-of-sample temporal and spatial R2 values also were high  (on model . In thesctively) .To estimate Ta exposure, we linked each mother’s residence at the time of delivery to its corresponding grid cell . Daily T2.5.PM Particulate matter ≤ 2.5 μm (PM2.5) was estimated on a 1 × 1 km grid from the same MODIS satellite, using daily measures of aerosol optical depth using a similar methodology  as the temperature model. Further details have been published previously  2002 Road inventory. These data are based on automatic vehicle counts on major highways, periodic counts on other major roads, and estimated counts for all other roads . The percent of each census tract that was open space was then calculated and assigned to birth addresses belonging to that tract.Percent of open space. The percent of open space data was obtained from the office of geographic information Commonwealth of Massachusetts, information technology division MassGIS . The subSocioeconomic indicators. Socioeconomic data at the individual level were obtained from the Massachusetts birth registry. Information included the mother’s race/ethnicity , mother’s years of education, and the Kotelchuck adequacy of prenatal care utilization index (APNCU). The APNCU is based on the number and the time of start of mother’s prenatal visits  and was Median income. Data were obtained from the U.S. Census Bureau 1999 median household income  for everIndividual-level covariates. Maternal age, parity, gestational age , number of cigarettes smoked per day during and before pregnancy, chronic conditions of mother or conditions of pregnancy , previous occurrence of a preterm birth, whether the mother ever had a previous infant weighing ≥ 4,000 g, and sex of infant were all obtained through the Massachusetts Birth Registry  through the index child’s birth certificate.To identify factors affecting birth weight, we used linear mixed regression models to estimate associations between both monitor and modeled Ta during different time windows and term birth weight, and logistic mixed regression to estimate associations with preterm birth (< 37 weeks) and LBW  . SeasonaSpecifically, we fit the following models:ij =BW (α j+ u) + β1iTa + β2i +PM γXi + eij(ju) ~ N and [1]Logit (ij/LBWij = 1|XPT) = (α j+ u) + β1iTa + β2i +PM γXi + eij(ju) ~ N, [2]ijBW, ij,PT and ijLBW represent birth weight, preterm, and LBW, respectively, for the ith subject in census tract j; α and ju are the fixed and random (tract-specific) intercepts, respectively; γXi denote the set of variables included in the model, which include predicted ambient air temperature, predicted ambient PM2.5, cumulative traffic density, percent of open spaces, age of mother, median income, gestational age, chronic conditions of mother or conditions of pregnancy , parity, previous infant weighing ≥ 4,000 g and sex of infant, sine and cosine , APNCU , mother’s race , mother’s education , and previous preterm occurrences. ije is the error term and finally, σ2u is the variance of the tract random effects, and jje ~ N.where We estimated associations between Ta during different time windows and gestational age using an accelerated failure time model (AFT).T) is given bySuch models are a form of survival analysis that model the survival time directly instead of the hazard. Gestational age is used as a continuous outcome in the AFT model. The log-linear form of the AFT model with respect to time . A two-sided p-value < 0.05 was considered statistically significant.where μ is the intercept, σ is a scale parameter, and εWe also ran analyses stratified on subject residence < 30 km or ≥ 30 km of a Ta monitor . Statistical analyses were performed in SAS  and R . Cases wDescriptive statistics are presented in Term birth weights were negatively associated with predicted Ta in almost all exposure time windows . In geneThe OR for low term birth weight with a 2.7°C increase in model-based Ta over the entire pregnancy was 1.04 , compared with 1.07  for monitor-based Ta . The OR A 2.7°C increase in Ta over the entire pregnancy was associated with a 0.26% decrease in gestational age , and an 8.4°C increase in Ta over the last trimester before birth was associated with a 0.15% decrease in gestational age  . For monp-value = 0.26).The association between an IQR increase in predicted Ta during the entire pregnancy and birth weight was stronger among births to mothers with residences in urban areas  compared with births to mothers residing in rural areas , though the differences were not statistically significant , regardless of the distance between a participant’s residence and the closest Ta monitor.We found a consistent negative association between Ta and birth weight for infants who were born full term after adjusting for other potential risk factors, such as previous and current mother’s health conditions, socioeconomic factors, and physical environment risk factors such as traffic density in surrounding grid cells. The association with Ta over the entire pregnancy was stronger in more urban areas (< 30 km from a monitor) than in more rural areas (≥ 30 km from a monitor), though the difference was not statistically significant. In contrast to the associations found with our modeled predicted Ta, associations between birth weight and Ta measured at the nearest ground monitor stations were close to the null, suggesting that predicted Ta classified exposure more accurately than monitor-based estimates. Interestingly, for the AFT analysis we found that an increase in Ta over both periods were associated with a decrease in gestational age; yet in the monitored Ta analysis, these associations were significantly associated with an increase of gestational age. These findings need to be further explored in future studies.A key advantage of the presented study is the exposure assignment. Because our model allows us to predict temporally and spatially resolved Ta, we can assign daily Ta exposure to the entire study population, avoiding potential selection bias that would yield a nonrepresentative sample. It also captures the urban heat island effect, as shown in The literature on the potential impact of Ta on birth weight and its determinants is still very limited. Increased Ta may affect birth weight through direct or indirect means. The causes of preterm birth and LBW are largely unknown, but are likely to be a complex mix of genetic, behavioral, socioeconomic, and environmental factors . Heat stRace, ethnicity, education, and other socioeconomic status factors are often clustered spatially and can act as potential confounders since they do not vary by time but do vary by space. We use a random-effects model with a random intercept for FIPS  code while controlling for seasonality to reduce bias as well.There are several limitations in the present study. First, the spatial resolution of the exposures was 1 × 1 km. As satellite remote sensing evolves and progresses, higher spatial resolution data should become available in the coming years, which will further reduce exposure error. Such increased resolution should enable us to more precisely estimate daily intraurban exposures and how these vary across spatial locations. Other limitations include the lack of some health and personal-level data such as maternal weight, body mass index, differences across different locations in physical activity, and pollen exposure. We also lacked data on indoor temperature exposure and information on air conditioning use in households. Finally, another limitation is the lack of information on road noise as in some recent pregnancy outcome studies .In summary, our findings suggest that higher Ta during pregnancy may be a risk factor for lower birth weight.


The transition from a fetus to a neonate at birth represents a critical phase in our life. Most infants make this transition without complications, but preterm infants usually require some form of assistance due to immature cardiopulmonary systems that predispose them to lifelong sequelae. As the incidence of preterm birth is increasing, there is now an urgent need for the development of management strategies that facilitate this transition, which will likely include improved strategies for the management of the maternal third stage of labor. For instance, recent studies on the physiological transition at birth have led to the discovery that establishing ventilation in the infant before the umbilical cord is clamped greatly stabilizes the cardiovascular transition at birth. While most benefits of delayed clamping previously have been attributed to an increase in placenta to infant blood transfusion, clearly there are other significant benefits for the infant, which are not well understood. Nevertheless, if ventilation can be established before cord clamping in a preterm infant, the large adverse changes in cardiac function that normally accompanies umbilical cord clamping can be avoided. As preterm infants have an immature cerebral vascular bed, large swings in cardiovascular function places them at high risk of cerebral vascular rupture and the associated increased risk of mortality and morbidity. In view of the impact that cord clamping has on the cardiovascular transition at birth, it is also time to re-examine some of the strategies used in the management of the third stage of labor. These include the appropriate timing of uterotonic administration in relation to delivery of the infant and placenta. As there is a lack of evidence on the effects these individual practices have on the infant, there is a necessity to improve our understanding of their impact in order to develop strategies that facilitate the transition to newborn life. One of the first major interventions that an infant experiences following birth is umbilical cord clamping (UCC) and its separation from the placenta. This signifies a landmark period during which the newborn transforms into an independent entity. Much interest has recently focused on the appropriate timing of UCC, particularly on the risks and benefits of delaying cord clamping for a set period of time after birth. Debate on appropriate timing of UCC following birth has been ongoing for several decades (even centuries), yet the ideal time still remains unknown. As a result, although the potential benefits of delayed umbilical cord clamping (DCC) have been documented, ‘early’ or ‘immediate’ umbilical cord clamping (ICC) is the most widely used procedure and is part of the active management of third stage of labor; i.e., the period extending from complete delivery of the infant to complete delivery of the placenta , 2. AlthThe benefits and risks associated with DCC have been primarily attributed to an increase in neonatal blood volume, secondary to placento-fetal transfusion. But this does not readily explain all observations commonly associated with DCC, for example the lower risks of cerebral hemorrhage and necrotizing enterocolitis . These b“Another thing very injurious to the child, is the tying and cutting of the navel string too soon; which should always be left till the child has not only repeatedly breathed but till all pulsation in the cord ceases. As otherwise the child is much weaker than it ought to be.”  levels caused by the stress of labor are thought to activate epithelial Na channels, which increases Naithelium . This reithelium . Howeverithelium , 23, 24.After birth, airway liquid clearance primarily results from transepithelial pressure gradients generated by inspiration , 23, 24.The fetal pulmonary and systemic circulations are not separate as they are in adults and the placenta is connected in parallel with the fetal lower body, thereby forming part of the fetal systemic circulation . Thus, aDuring fetal life, the left ventricle receives much of its preload from the umbilical circulation via the DV and FO, because PBF is usually low during fetal life Figure . HoweverRecently, published normograms demonstrate that heart rates in normal healthy infants are reduced immediately after birth and rapidly increase within a few minutes . As low After birth, aeration of the lung causes a marked decrease in PVR and increase in PBF . AlthougDespite a marked and persisting decrease in right ventricular output caused by UCC, PBF markedly increases immediately after birth. This is due to both the redirection of right ventricular output into the lungs and the large contribution (~50%) of flow from L-to-R shunting across the DA . This hiAs the supply of preload for the LV must change from umbilical venous return to pulmonary venous return after birth, establishing ventilation in an infant before its cord is clamped allows PBF to increase before umbilical venous return is lost . As a reThese observations underpin the well established and widely taught concept that establishing effective ventilation at birth is the cornerstone of neonatal resuscitation . That isThe maternal third stage of labor is the period of time between delivery of the infant and delivery of the placenta and can be managed in two different ways; either expectantly or actively. The active approach is currently the most commonly employed method and involves administration of an uterotonic agent upon delivery of the infant’s anterior shoulder. This is followed by immediate UCC upon the infant’s delivery and controlled cord traction to separate and deliver the placenta. The aim is to shorten the duration of the third stage, which is a strategy that is thought to be associated with lower rates of PPH. As such, active management is highly encouraged , 43. In Delaying UCC during the third stage of labor is thought to result in “placental transfusion,” allowing a time-dependent net transfer of blood volume from the placenta into the infant , 44. It Although current evidence favors the practice of DCC, particularly in preterm infants , 49, the(1)an increase in systemic blood volume and hematocrit in the immediate newborn period;(2)a reduced risk of anemia and need for blood transfusions;(3)improved iron stores and lower rates of iron deficiency, lasting for 3–6 months after birth;(4)higher birth weights, most likely due to higher neonatal blood volumes;(5)lower risks of IVH  and necrotizing enterocolitis.The reported , 49–54 b(1)higher rates of hyperbilirubinemia (jaundice) in both term and preterm infants although this did not lead to a significantly increased need for more phototherapy;(2)a higher incidence of polycythemia (venous hematocrit > 65%), but no infants were found to develop symptoms or complications related to the condition .Potential risks associated with DCC , 50, 55 While these clinical studies have highlighted an increase in blood volume as the major benefit of DCC, the actual benefits could potentially be far more extensive. To some extent, this is indicated by the lower risk of IVH, which is difficult to explain simply in terms of blood volume. Indeed, the insights provided by recent experimental studies provide a new understanding of the potential benefits of DCC as well as a different approach for determining the appropriate timing of DCC after birth . That isIn addition to the onset of pulmonary ventilation and the associated increase in PBF, there are a number of other physiological factors that could impact on the benefits of DCC. These include uterine contractions and the vertical position of the infant with respect to the placenta.Intramuscular uterotonic injection (either syntocinon or syntometrine) upon delivery of the infant’s anterior shoulder is the recommended practice in Australia . NumerouAlthough uterotonic administration reduces the risk of PPH , the timAs umbilical venous pressures are low, it is commonly assumed that gravity and resistance will influence umbilical blood flow between the infant and its placenta. Thus, it is assumed that placing the infant above the level of the placenta will facilitate flow into the placenta whereas placing the infant below the placenta will facilitate flow into the infant. Previous studies , 48, 58 Milking or stripping the umbilical cord following clamping is reported to have beneficial effects for the newborn by assisting or augmenting the placental transfusion, thereby reducing the time required for DCC –64. IndeAlthough a considerable amount of data have been published on DCC, the absence of rigorous scientific data has made it difficult to reach a consensus upon the precise benefits and appropriate timing of DCC and the factors that influence this. Recent experimental evidence indicates that DCC until after the lung has aerated and PBF has increased greatly increases the stability of the cardiovascular transition at birth . In partDelayed umbilical cord clamping is a subject that has attracted much debate and is clearly a topic that could greatly benefit by the application of further scientific experimentation. Although current guidelines recommend a fixed time interval between birth and UCC, this is unlikely to optimize the benefits for individual infants. Instead, the decision for clamping the umbilical cord after birth should probably be based on the infants’ physiology rather than an arbitrary period of time. This suggestion is based on the markedly improved cardiovascular stability associated with cord clamping after ventilation onset and the increase in PBF. The reasons and logic behind this suggestion has been well documented and described, but further experimentation is required to uncover additional variables that may impact on the benefits of DCC. In particular, we need to understand how gravity and utertonic administration impacts on the infants cardiovascular transition if cord clamping is delayed, which could potentially lead to revisiting the clinical practices for managing the third stage of labor.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.


Duodenal duplication is a rare developmental abnormality which is usually diagnosed in infancy and childhood, but less frequently in adulthood. We report a case of a 16-year-old female with a duplication cyst in the third part of the duodenum. The patient presented with symptoms of gastric outlet obstruction, including severe anorexia and weight loss. The diagnosis was made preoperatively by CT scan and upper endoscopy. The cyst was successfully treated by marsupialization on the duodenum using a GIA stapler. Duodenal duplication presents with a wide variety of symptoms. Although illusive, many cases can be properly diagnosed preoperatively by using the appropriate imaging modalities. Treatment choices are tailored according to the size and location of the cyst, in addition to its relation to adjacent structures. The outcomes are favorable in the majority of patients. Duplications of the alimentary tract are rare developmental abnormalities. The overall incidence of this condition is 1 : 25,000, and duodenal duplication constitutes 5–12% of all cases .Here, we report a rare case of a duplication cyst that compresses the third part of the duodenum. The cyst presented with gastric outlet obstruction and severe anorexia. To our knowledge, this is the first reported case that presents with severe weight loss and malnutrition in adolescence.A 16-year-old female presented to the emergency department of our hospital complaining of recurrent abdominal pain in the epigastrium especially after meals, with occasional radiation to the left shoulder. She reported a recent history of persistent nausea and vomiting in addition to severe anorexia and weight loss.2. Abdominal examination revealed mild tenderness in the epigastrium without rigidity or palpable masses. Laboratory findings showed anemia (hemoglobin 8.2 g/dL), hypokalemia (potassium 3.1 mEq/L), and hypoalbuminemia . Gastric aspiration yielded about one liter of nonbloody aspirate.The patient looked anxious, dehydrated, and debilitated. She had tachycardia and her BMI was only 15.8 kg/mAbdominal ultrasonography (US) showed severe gastric distension with a big cystic mass in the upper abdomen. Abdominal computed tomography (CT) showed a cystic lesion measuring 8 × 4 × 7 cm, which extends along the third part of the duodenum in the retroperitoneum. The lumen of the third part of the duodenum was completely obscured. The cyst was suspicious for duodenal duplication . Upper eUpon laparotomy, a cystic structure was found behind the transverse mesocolon. An extended Kocher maneuver was performed, and exploration revealed a big cyst along the third part of the duodenum with close relation to the head of the pancreas . The duoThe cyst was opened widely through the common wall, and blood clots were extracted from the cyst. No abnormal pathology was noted inside the cyst. Part of the common wall was resected, and the cyst was marsupialized on the duodenum with the aid of a GIA stapler. Finally, a side-to-side anastomosis was performed between the duodenotomy site and a jejunal loop about 30 cm after the ligament of Treitz .2.Histopathologic examination confirmed the diagnosis by identifying a duodenal mucosa that lines a smooth muscle coat within the wall of the cyst . The patDuplication cysts of gastrointestinal tract were first documented in the mid-19th century by Reginald Fitz . Three cDuodenal duplications represent a low percentage of all duplications. They can be cystic or tubular, and they may communicate with the duodenal lumen, the pancreatic duct, or rarely the biliary system . These cThe abnormality is usually diagnosed in infancy and childhood . HoweverThe clinical features of duodenal duplication cysts vary from asymptomatic cases to nonspecific symptoms such as abdominal pain, abdominal distention, and vomiting , 7. Some2 with severe laboratory derangement, and this was not previously reported in any case of duodenal cysts.Most cysts are 2–5 cm in size. The largest diameter of the cyst in our case was 8 cm, which is relatively large. Only few cases in the literature were larger than 5 cm . This waThe preoperative diagnosis of intestinal duplications is rarely accurate. The differential diagnosis encompasses all cystic lesions in this region, which include choledochoceles, pancreatic pseudocysts, cystic tumors of the pancreas, mesenteric cysts, and duodenal diverticulums .Endoscopic US could differentiate the duplication cyst by the “gut signature” or “the double-layer wall” sign of its wall. CT is valuable in identifying the type, location, and the size of the duplication cyst, and the technetium scan can aid in the detection of heterotopic gastric mucosa in cases complicated with bleeding . MagnetiThe appropriate surgical procedure for a duodenal duplication cyst depends on its type and location. Consequently, several operative choices are feasible . Total ePartial resection of the common wall with internal marsupialization on the duodenum is a good management option to avoid injury to the pancreas, pancreatic and bile ducts, or any related structure as we did in our case. Other possibilities include cystojejunostomy by a jejunal loop or Roux-en-Y anastomosis .The surgeon should judge the best treatment that relieves the symptoms without causing serious complications. Total excision was not possible in our case due to the close relation of the cyst to the head of the pancreas, and marsupialization was a safer option for draining the cyst and relieving the compressive symptoms.Advances in therapeutic endoscopy, such as endoscopic mucosal resection, were recently used in the management of some duodenal cysts . More reAlthough duodenal cysts are considered a rare entity, we believe that further research is needed to design a specific classification system and management criteria for these lesions. Such diagnostic and therapeutic criteria would spare many patients the sequelae of laparotomy by taking advantage of the recent advances in minimally invasive and endoscopic techniques. This would only be possible through accumulation of more cases. Therefore, we encourage surgeons to report any lesion of this type with enough details about location and appropriate treatment options.Duodenal duplication should be considered in the differential diagnosis of vague upper abdominal symptoms, especially when a cystic structure neighboring the duodenum is demonstrated on radiology. Ideal treatment is total excision when feasible. Otherwise the cyst may be treated with subtotal excision and/or internal anastomosis. When treated properly, these lesions usually have favorable outcomes.


Previous research has shown exposure to air pollution increases the risk of adverse birth outcomes, although the effects of residential proximity to significant industrial point sources are less defined. The objective of the current study was to determine whether yearly reported releases from major industrial point sources are associated with adverse birth outcomes.Maternal residence from geocoded Alabama birth records between 1991 and 2010 were used to calculate distances from coke and steel production industries reporting emissions to the U.S. Environmental Protection Agency. Logistic regression models were built to determine associations between distance or yearly fugitive emissions  from reporting facilities and preterm birth or low birth weight, adjusting for covariates including maternal age, race, payment method, education level, year and parity.A small but significant association between preterm birth and residential proximity (≤5.0 km) to coke and steel production facilities remained after adjustment for covariates . Above average emissions from these facilities of volatile organic compounds during the year of birth were associated with low birth weight , whereas metals emissions were associated with preterm birth .The present investigation suggests fugitive emissions from industrial point sources may increase the risk of adverse birth outcomes in surrounding neighborhoods. Further research teasing apart the relationship between exposure to emissions and area-level deprivation in neighborhoods surrounding industrial facilities and their combined effects on birth outcomes is needed.The online version of this article (doi:10.1186/1476-069X-13-85) contains supplementary material, which is available to authorized users. Preterm birth (<37 weeks of gestation) and low birth weight <2500 grams) increase the risk of early death, long-term disability, and several chronic health conditions including diabetes and cardiovascular disease , 2. In a500 gramsPrevious research has associated PTB and altered fetal growth with increased exposure to air pollution and developmental toxicity of various components of air pollution have been identified in animal model research –8. EpideCoke and steel production facility air emissions include a mixture of polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds including benzene, toluene, ethylbenzene and xylenes (BTEX), and metals, all of which have been independently associated with adverse birth outcomes in previous research –15. To oSpatial epidemiology studies have demonstrated the utility of mapping concentric buffer zones in classifying proximity to sources of environmental pollutants . For exaBirth records and geocoding: A total of 517,345 birth records between 1991 and 2010 May-Sept were obtained from the Alabama Department of Public Health (ADPH). Birth records from this dataset reported information regarding date of birth, age of mother, birth weight, gestational age, race and ethnicity of mother, education, method of payment for obstetric fees, birth number (parity), as well as mother’s address, including: state, zip code, city, and street information. Latitude and longitude coordinates of current residence was determined through two rounds of geocoding based on street address and city data using ArcGIS 10.0 (ESRI). Records that could not be linked to latitude/longitude coordinates during geocoding were excluded . Similar to other research regarding birth outcomes, those recorded as having very low birth weight (<200 grams) or short gestation periods (<24 weeks) were also excluded , 23. TheExposure classification: Yearly emissions data was retrieved from the USEPA Toxic Release Inventory (TRI) database for the entire state of Alabama for the period between 1991–2010 . BrieflyStatistical analyses: Logistic regression models were developed to determine associations between LBW or PTB and residence proximity to a coke or steel production facility. For the analysis, births were considered low weight if under 2,500 grams and preterm if gestation was shorter than 37 weeks, following World Health Organization conventions. Covariates for logistic regression models included age of mother, race, education, method of payment for hospital services, and parity. Year of birth was also included as a covariate due to its significant effects on birth outcomes demonstrated in previous work . Age of After geocoding and excluding records with missing information, 412,973 records  were available for analysis  and Resource Conservation and Recovery Act (RCRA) statutes . Based oHigher odds of LBW and PTB were found in neighborhoods within 5 km of coke and steel production facilities after controlling for individual-level covariates available in the present analysis. Furthermore, a stratified analysis suggests increased odds of adverse birth outcomes associated with high versus low yearly fugitive emissions from these facilities. When analyzed by facility, a cluster of 6 facilities in Birmingham, AL was associated with increased odds of PTB. The present analysis detected suggestive trends justifying further research on the potential compounded burden of social, economic, and environmental stressors, particularly for minority populations.Table S2. Adjusted odds ratios for LBW (< 2500 grams), LBW in full term (37 weeks gestation), and PTB births and proximity to specific coke or steel production facilities in Alabama and groups of facilities within close proximity of each other. (PDF 132 KB)Additional file 1: Table S1: Sample characteristics of original, geocoded, and analyzed datasets.


Several studies have reported associations between restricted fetal development, as shown by birth weight or birth length, and later ischaemic heart disease (IHD). However, few studies have examined the importance of these perinatal factors when taking into account gestational age at birth, hereditary factors, sociodemographic factors and comorbidities. This study investigated the importance of perinatal risk factors for premature IHD and myocardial infarction (MI) in a large Swedish cohort.National cohort study of 1 970 869 individuals who were live-born in Sweden in 1973 through 1992, and followed up to 2010 (ages 18–38 years).The main outcome was IHD, and the secondary outcome was MI.A total of 668 individuals were diagnosed with IHD in 18.8 million person-years of follow-up. After adjusting for gestational age at birth, sociodemographic factors, comorbidities and family history of IHD, low fetal growth was associated with increased risk of IHD  and increased risk of MI  in young adulthood. In contrast, gestational age at birth was not associated with the risk of IHD or MI.In this large national cohort, low fetal growth was strongly associated with IHD and MI in young adulthood, independently of gestational age at birth, sociodemographic factors, comorbidities and family history of IHD. This birth cohort study is the largest nationwide study to examine the associations between restricted fetal development, as shown by birth weight, birth length or fetal growth and later ischaemic heart disease (IHD) or myocardial infarction (MI).Few studies have examined the importance of these perinatal factors when taking into account gestational age at birth, hereditary factors, sociodemographic factors and comorbidities.It highlights the importance of low fetal growth as a predictor for premature IHD and MI, independently of gestational age at birth, sociodemographic factors, comorbidities and family history of IHD.Study limitations include the unavailability of information on blood pressure, cholesterol, body mass index and smoking history. However, data were adjusted for parental socioeconomic factors that are related to life-style factors. Results were also adjusted for diagnosis of hypertension, diabetes, and cardiovascular and chromosomal anomalies.IHD and MI were identified from inpatient and outpatient diagnoses, thus we were unable to identify previously silent and undiagnosed events.et alLow birth weight has been associated with increased risk of ischaemic heart disease (IHD) in adult life in a large number of studies.et alSeveral mediators of the association between low birth weight and IHD have been suggested. Low birth weight has been associated with IHD risk factors such as obesity, hypertension and diabetes in adult life.We conducted a national cohort study in Sweden, to examine the association between perinatal factors and premature IHD and MI. A national cohort of infants born from 1973 through 1992 was followed up until 2010 for IHD and MI. We tested whether birth weight, birth length, standardised fetal growth or gestational age at birth is associated with an increased risk of IHD or MI independently of hereditary factors, sociodemographic factors and comorbidities.We identified 1 984 858 individuals in the Swedish Birth Registry who were live-born from 1973 through 1992 and still living in Sweden at age 18 years. We excluded 4625 (0.2%) persons who had missing information for birth weight, and 6069 (0.3%) others who had missing information for gestational age at birth. To remove possible coding errors, we excluded 3061 (0.2%) who had a reported birth weight more than 4 SDs above or below the mean birth weight for gestational age and sex, based on a Swedish reference growth curve.The study cohort was followed up for the earliest incidence of IHD from age 18 years through 31 December 2010 (maximum attained age was 38 years). IHD was identified using primary and secondary diagnoses from the International Classification of Diseases (ICD), revisions 9 and 10 (codes 410–414 in ICD-9 and I20-I25 in ICD-10) in the Swedish Hospital Registry, Outpatient Registry and/or Cause of Death Registry. The Swedish Hospital Registry contains all primary and secondary hospital discharge diagnoses for six populous counties in southern Sweden, starting in 1964, and with nationwide coverage since 1987; and the Swedish Outpatient Registry contains all outpatient specialty clinic diagnoses nationwide starting in 2001. The Cause of Death Registry includes all deaths nationwide since 1964 for all persons registered in Sweden at the time of death. In secondary analyses, acute MI  was examined separately. The validity of IHD or MI diagnosis in the Hospital Registry has been reported to be ∼95%.30–32Perinatal and familial characteristics that may be associated with IHD were identified from the Swedish Birth Registry and national census data, which were linked using an anonymous personal identification number.Cox proportional hazards regression was used to estimate HRs and 95% CIs for associations between perinatal or familial variables, and IHD. Individuals were censored at the time of death from any cause other than IHD , or at the time of emigration as determined by the absence of a Swedish residential address in census data . Two different adjusted models were used: The first was adjusted for age  and sex, and the second was further adjusted for other variables that were found to be associated with IHD . First-order interactions between sex and other variables were examined using likelihood ratio tests. The proportional hazards assumption was evaluated by graphical assessment of log-log plots and was met in each of the models. All statistical tests were two sided and used an α-level of 0.05. All analyses were conducted using Stata statistical software, V.12.1.Among the 1 970 869 persons in this cohort, 668 (0.03%) IHD cases were identified in 18.8 million person-years of follow-up (35.5 cases per million person-years). The median age at IHD diagnosis was 23.5 years . Males had a higher risk of IHD than females  . HoweverFetal growth was inversely associated with the risk of IHD in young adulthood . AdjustiOther strong independent risk factors for IHD in this cohort included hypertension, diabetes, cardiovascular and chromosomal anomalies or syndromes, parental history of IHD, multiple birth and low maternal or paternal education . Birth oThe findings for MI were overall similar to those for IHD but stronger in magnitude . Low fetA sensitivity analysis that excluded persons with any congenital anomalies  produced very similar risk estimates as the main analysis, including those for fetal growth .In this large national cohort study, we found that low fetal growth was associated with increased risk of IHD and MI in young adulthood, independently of gestational age at birth, sociodemographic factors, comorbidities and family history of IHD. Thus, low fetal growth adds to traditional risk factors for premature IHD and MI.37The associations we observed between low fetal growth and IHD/MI were only partly explained by socioeconomic factors, hereditary factors and common comorbidities. The remaining associations are likely related to other unmeasured long-term complications of restricted fetal growth, although the specific underlying mechanisms are not well-established. One hypothesis is that fetal undernutrition or malnutrition leads to altered gene expression, resulting in physiological alterations such as insulin resistance, vascular endothelial dysfunction and abnormal neuroendocrine stress responses.The most important strength of the current study was its ability to examine the association between perinatal risk factors and risk of IHD/MI in young adulthood using nationwide birth, hospital, outpatient and death registry data for a large national cohort. The results were adjusted for other perinatal risk factors as well as other broadly measured potential confounders. Information on common comorbidities enabled us to examine their influence on the main findings.Study limitations include the unavailability of information on blood pressure, cholesterol, body mass index and smoking history. However, the results were adjusted for parental socioeconomic factors, which are related to life-style factors such as smoking, and for diagnoses of hypertension, diabetes, and cardiovascular and chromosomal anomalies. IHD and MI were identified from inpatient and outpatient specialty clinic diagnoses, thus we were unable to identify previously silent and undiagnosed events. Information on genetic risk factors was unavailable, although the results were adjusted for family history of IHD. It is also unclear to what extent our findings will apply to later birth cohorts or older ages. However, generalisability to other populations seems likely, given the overall consistency of results across different birth cohorts.1–18In summary, among individuals born in Sweden between 1973 and 1992, low fetal growth was a strong independent risk factor for IHD and MI in young adulthood. In contrast, gestational age at birth was not associated with the risk of IHD or MI. These findings call for better awareness of the long-term risk of IHD/MI among growth-restricted infants.


Unconventional gas drilling (UGD) has enabled extraordinarily rapid growth in the extraction of natural gas. Despite frequently expressed public concern, human health studies have not kept pace. We investigated the association of proximity to UGD in the Marcellus Shale formation and perinatal outcomes in a retrospective cohort study of 15,451 live births in Southwest Pennsylvania from 2007–2010. Mothers were categorized into exposure quartiles based on inverse distance weighted (IDW) well count; least exposed mothers (first quartile) had an IDW well count less than 0.87 wells per mile, while the most exposed (fourth quartile) had 6.00 wells or greater per mile. Multivariate linear (birth weight) or logistical  and prematurity) regression analyses, accounting for differences in maternal and child risk factors, were performed. There was no significant association of proximity and density of UGD with prematurity. Comparison of the most to least exposed, however, revealed lower birth weight (3323 ± 558 vs 3344 ± 544 g) and a higher incidence of SGA . While the clinical significance of the differences in birth weight among the exposure groups is unclear, the present findings further emphasize the need for larger studies, in regio-specific fashion, with more precise characterization of exposure over an extended period of time to evaluate the potential public health significance of UGD. Unconventional gas development (UGD), characterized by advances in engineering, including horizontal drilling and high volume hydraulic fracturing, enables extraction of large amounts of fossil fuel from shale deposits at depths that were previously unapproachable . In PennSeveral recent reviews summarizing the evolving UGD process describe the potential for adverse health effects and delineate challenges that have contributed to as yet minimal understanding of public health impact , 3–4. UGWells can be hydrofractured intermittently on multiple occasions to stimulate product flow. A more continuous process of product development occurs in region-specific patterns. This includes condensate tanks and glycol dehydrators to separate dry (methane) and wet (higher carbons such as ethane) gas components of product and diesel fuel operated compressors (to liquefy gas for shipping via pipelines) . As suchMajor challenges in assessing and quantifying environmental, ecological and human health related effects  of UGD exist largely due to the dynamic and complex nature of the evolving UGD process itself as well as differences in geology between site locations, UGD technique and community demography. Together, these factors make it difficult to compare experiences, historically and concomitantly, within and between regional efforts. Several recent studies have provided measurements of likely pollutants, focusing on hydrocarbons found in air  or on th2.5 and ozone [2.5 [The embryo/fetus is particularly sensitive to the effects of environmental agents . A host nd ozone , 23–24. nd ozone . Xu et aone [2.5 . McKenzione [2.5 . They foWe adapted the epidemiological and geographic information systems (GIS) approaches of McKenzie et al.  to exploNatural gas well and birth data were collected for Butler, Washington and Westmoreland counties in PA for the years 2007 to 2010. The UGD locations were obtained from the Pennsylvania Department of Environmental Protection (PADEP), that defines UGD as wells having both a lateral component and hydraulic fracturing, a process relatively new to Pennsylvania until 2005 . Multipln is the number of existing unconventional wells within a 10-mile radius of maternal residence in the birth year, and di is the distance of the ith individual well from the mother’s residence. For example, a mother’s residence that has two wells, both 0.5 mile away, would have an IDW well count of 4. Mothers were categorized into exposure quartiles according to their IDW well counts:Group 1: IDW Well Count >0 but <0.87Group 2: IDW Well Count ≥0.87 but <2.60Group 3: IDW Well Count ≥2.60 but <6.00Group 4: IDW Well Count ≥6.00We calculated an inverse distance weighted (IDW) well count for each mother living within 10-miles of UGD to account for both the number of unconventional wells within this buffer as well as distance of each well from the mother’s residence . This meThree indicator variables were created, using the first quartile (Group 1) as the referent group. The 10% of births that did not live within 10 miles of UGD were eliminated from the analysis due to notable sociodemographic differences; these mothers were more African American (7% compared to 3%), smoked more during pregnancy (25% versus 20%), and had a higher proportion receiving WIC assistance (41% versus 32%).th grade or less; 9th-12th grade, no diploma; high school graduate or GED completed; some college credit, but not a degree; associate degree; bachelor’s degree; master’s degree; doctorate or professional degree), pre-pregnancy weight, prenatal care , smoking , gestational diabetes , WIC ; African American  and parity . The model for continuous birth weight was also adjusted for gestational age to account for the downward shift in birth weights accompanying shorter gestational ages due to earlier obstetric intervention observed in our dataset from the PADOH as well as nationally [The outcomes assessed were continuous birth weight, small for gestational age (SGA), and prematurity . To identify SGA births, birth weights were normalized to gestational age and estimates of SGA were deduced from nomograms identifying elements of fetal growth  . Mean bitionally . All staThis analysis included 509 active unconventional natural gas wells in Butler, Washington and Westmoreland counties from 2007 to 2010, representing 18% of the state-wide total of 2,864 [We accessed public records of UGD and birth and used a geographic information system that enabled proximity and density of nearby UGD to be used as a surrogate for exposure. Based on this latter estimate, we identified four groups of mothers of comparable size that gave birth in the study period (2007–2010) in three counties in Southwest Pennsylvania with high levels of UGD activities. These four groups were relatively similar in various determinants of maternal and child risks for perinatal outcomes but had different levels of exposure (i.e. IDW well count) . The infThis analysis adds to possible health impact concerns recently described by McKenzie et al. in which there was an increase in birth defects associated with proximity to UGD in rural Colorado . In contGeological differences are known to account for differences in flowback water composition in different shale gas areas . A notabMcKenzie et al.  establisLike McKenzie et al. , we wereTwo other concomitant studies have findings similar to ours concerning birth weight. The PhD thesis of Elaine Hill at Cornell University compared birth outcomes for mothers who resided in regions in Pennsylvania in proximity to wells as a function of time (before and after permit and SPUD) . Their mIt is only in recent years that drilling technology has rapidly advanced to be able to obtain substantial levels of natural gas tightly bound to deep underground shale layers. This continually evolving technology greatly differs from the past in using perhaps 5 million, rather than 50,000 gallons of hydrofracturing fluid under much higher pressures for each well; in having an evolving suite of hydrofracturing chemicals, with over 500 having been used; in laterally bending the well within the shale layers for greater than a kilometer; in drilling in multiple directions from the same well head from larger drill pads for sequential periods of six months or longer; and in many other technological advances. Recent reviews of shale gas issues in the United States, Canada and Europe have been consistent in commenting on the lack of health-related information , 4.This investigation is semi-ecological in nature. We had individual data on birth outcomes and risk factors; however, the final analysis grouped mothers into exposure categories to provide a clearer picture of possible dose-response relationships. In addition, there may be a number of unknown factors that led to our conclusion that well density was associated with lower birth weight and greater odds of SGA. As in any epidemiological study, these associations do not imply causation and are hypothesis generating only. The observed associations could be due to a contaminant related to UGD, an unknown confounding factor we were unable to account for in our analyses, or chance. Moreover, we assumed that the residence on the birth certificate was synonymous with exposure during the entire pregnancy, as we have no ability to evaluate transient occupancy of the pregnant mother. However, the counties under study have relatively stable populations. US Census data (2008–2012) for living in the same house one year and over for Butler, Washington and Westmoreland Counties shows 88.6%, 88.1% and 91.0% respectively as compared to 84.8% for the US and 87.8% for Pennsylvania .Proximity is a primitive surrogate for exposure itself and is uninformative of route  or etiologic agent. Our observations were based on data deduced from the Department of Environmental Protection (DEP) of Pennsylvania and assignments of longitude and latitude only from birth certificate data. Twenty percent of the birth certificate records did not have a corresponding geocode and, since no further information on address or zip code was available, these births were excluded from the analysis. However, the sociodemographic characteristics of this group were similar to those that were geocoded . Up untiOther limitations in the birth dataset included the lack of a birth month and day; we were therefore only able to identify those wells drilled during the birth year of the infant. Active drilling of a well occurs over a period of only a few months, so incorporating more specific timings of exposure will be critical in future work as further data become available as to the time period during which air or water exposures are most likely. Birth weight data are reasonably precise as derived from birth certificates, but such certificates appear less reliable for gestational age , so deriThe relative monotonic increase in SGA  and oddsIf the association of lower birth weight and proximity to well is indeed secondary to environmental exposure, then identifying the route of exposure and the agents, alone or in combination, is a critical and challenging next step. In the preliminary study of Currie et al. , no diffIn conclusion, a small but significant association between proximity to UGD and decreased birth weight was noted after accounting for a large number of contributing factors available from birth certificate data in Southwest Pennsylvania. Although the medical and public health significance of this is unclear, it was noteworthy that there was a significant increase in incidence of SGA in the most exposed group. Along with the first published study on the association of increased incidence of birth defects and proximity and density of nearby wells in Colorado , there i


Background: Persistent organic pollutants (POPs) are developmental toxicants, but the impact of both maternal and paternal exposures on offspring birth size is largely unexplored.Objective: We examined associations between maternal and paternal serum concentrations of 63 POPs, comprising five major classes of pollutants, with birth size measures.Methods: Parental serum concentrations of 9 organochlorine pesticides, 1 polybrominated biphenyl (PBB), 7 perfluoroalkyl chemicals (PFCs), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs) were measured before conception for 234 couples. Differences in birth weight, length, head circumference, and ponderal index were estimated using multiple linear regression per 1-SD increase in natural log-transformed (ln-transformed) chemicals. Models were estimated separately for each parent and adjusted for maternal age, maternal prepregnancy body mass index (kilograms per meter squared) and other confounders, and all models included an interaction term between infant sex and each chemical.n = 117), birth weight was significantly lower  in association with a 1-SD increase in ln-transformed maternal serum concentrations of DDT, PBDE congeners 28 and 183, and paternal serum concentrations of PBDE-183 and PCB-167. Among boys (n = 113), maternal  and paternal (PCBs 172 and 195) serum concentrations of several POPs were statistically associated with lower birth weight , whereas paternal concentrations of PBDEs  were associated with higher birth weight. Differences in offspring head circumference, length, and ponderal index were also associated with parental exposures.Results: Among girls (Conclusions: Preconceptional maternal and paternal concentrations of several POPs were associated with statistically significant differences in birth size among offspring.http://dx.doi.org/10.1289/ehp.1308016Citation: Robledo CA, Yeung E, Mendola P, Sundaram R, Maisog J, Sweeney AM, Barr DB, Buck Louis GM. 2015. Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE Study. Environ Health Perspect 123:88–94;  Researcelopment , polychlelopment , perfluoelopment , and orgelopment . Althougelopment .Inconsistences may be attributed to several key limitations of prior studies. Past research has focused on pre- and postnatal exposures to POPs, despite evidence that the preconception period may be a critical window of exposure for fetal growth and development . Given tWe aim to address these gaps in knowledge by estimating the associations of maternal and paternal preconceptional serum concentrations of POPs on birth size. We hypothesize that preconceptional serum concentrations of both maternal and paternal persistent environmental chemicals are associated with reduced birth size measures .Study population. The Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective cohort study conducted between 2005 and 2009 to assess the impact of persistent environmental chemicals on reproductive outcomes (n = 501) who resided in Michigan and Texas with reported or presumed exposure to persistent environmental chemicals. Married couples or those in a committed relationship who were planning a pregnancy in the subsequent 6 months were targeted for recruitment. Couples were ineligible to participate if either partner was medically/surgically sterile; they had discontinued contraception for > 2 months; the female’s menstrual cycle was not between 21 and 42 days or she had received injectable contraceptives within the previous 12 months; they were not of reproductive age ; or they could not communicate in English or Spanish. Couples were followed until a positive human chorionic gonadotropin (hCG) pregnancy test or through 12 months of attempting pregnancy. Following conception, women were followed daily for 8 weeks and then monthly until a pregnancy loss or delivery. Analyses were restricted to couples for whom a singleton delivery was observed (n = 247), regardless of a previous loss, and for whose child birth weight was reported (n = 234). In doing so, we excluded data for two sets of twin births.outcomes . BrieflyInstitutional review board approval was obtained from all collaborating institutions, and informed written consent was obtained from all couples before their participation.Assessment of fetal growth outcomes and covariates. Couples were asked to report birth size characteristics for the index birth using standardized birth announcements specifically designed for the LIFE study that were included in the pregnancy diary (available on request). Women were trained in their use and completed them after delivery. Information recorded on the delivery cards included infant sex, birth weight (in grams or pounds and ounces) (n = 230), length (in centimeters or inches) (n = 229), and head circumference (in centimeters or inches) (n = 181). Ponderal index (n = 229), a marker of asymmetrical growth retardation thought to be a result of fetal insult, was defined as 100 × [birth weight (grams)/length (cubic centimeters)] (n = 2) or head circumference (n = 2) exceeded the 99th percentile.meters)] . AnalyseBaseline questionnaires were administered to each partner separately and were used to collect medical and reproductive histories. Information on lifestyle factors such as the use of alcohol and tobacco in the previous 12 months was also collected. Participants then underwent an anthropometric assessment  for measDaily journals captured data on lifestyle factors, sexual intercourse, and home pregnancy test results. A fertility monitor captured data on peak luteinizing hormone concentrations indicative of ovulation. These data combined with information on sexual intercourse and positive hCG pregnancy test results allowed for the estimation of day of conception and, thereafter, gestational age. Pregnant women were asked to complete daily pregnancy journals that captured information on weight gain and gravid diseases .Exposure assessment. Biospecimens were collected from each partner during the baseline home visit. Approximately 20 mL of nonfasting blood were collected to measure concentrations of environmental chemicals. For quality control, blood collection equipment was tested and determined to be free from contaminants under study. Quantification of serum toxicants was conducted by the Division of Laboratory Sciences in the National Center for Environmental Health at the Centers for Disease Control and Prevention (CDC). A list of all congeners measured and their abbreviations can be found in Statistical analyses. We assessed the distributions of all exposures and relevant covariates. Normality of continuous variables was assessed using Kolmogorov–Smirnov tests. Missing covariate values and missing chemical, cotinine, and lipid data (< 4%), due to insufficient blood for analysis, were imputed under the missing at random assumption, using Markov chain Monte Carlo methods , and serum cotinine concentrations (p < 0.05). Evidence of interaction between chemical exposures and birth outcomes by infant sex was observed for some chemicals and models by significant interaction term (p-interaction < 0.05), so all associations were estimated stratified by sex for consistency. We report associations for chemicals for which at least one statistically significant association was estimated with birth size measures. Statistical significance was set at p < 0.05.We used multiple linear regression to estimate the mean difference in each outcome per 1-SD increase for all ln-transformed chemicals. The mean differences in growth outcomes for each chemical and parent were estimated separately. Models were adjusted trations . The sumWe conducted a sensitivity analysis that excluded pregnancies complicated by gestational diabetes or hypertension because of their known effects on fetal growth . ResultsStudy population. Partners for whom a singleton delivery occurred were very similar in their sociodemographic characteristics (2). Women reported having gestational diabetes mellitus (n = 27), hypercholesterolemia (n = 18), and preexisting hypertension (n = 7). The majority of infants were girls (51%). The mean (± SD) postconception gestational age and birth weight of infants at delivery was 36.2 ± 2.2 weeks and 3382.3 ± 487.5 g, respectively.eristics . The majp,p´-DDE (dichlorodiphenyldichloroethylene) , mirex , and several PFCs were markedly higher among males . Preconceptional parental concentrations of POPs were found to be associated with changes in birth size measures.Serum concentrations of most POPs among couples were similar for partners. However, geometric mean concentrations of pesticides such as OCPs and PBB. Statistically significant differences in birth size measures were estimated in association with both maternal and paternal preconception serum concentrations of OCPs among girls, but virtually no significant associations were observed among boys  was associated with lower birth weight , driven perhaps by smaller head circumference . Smaller head circumference was also seen with increasing maternal concentrations of β-HCH (hexachlorocyclohexane) . Length among girls was inversely associated with maternal concentrations of γ-HCH (lindane) and subsequently higher ponderal index . Similarly, paternal concentrations of γ-HCH were associated with shorter length and higher ponderal index among girls, despite mutual adjustment for mean partner concentrations of other organochlorine exposure. A higher ponderal index among girls was also seen with increasing paternal concentrations of p,p´-DDE. Except for larger head circumference observed with increasing maternal concentrations of HCB (hexachlorobenzene), preconceptional parental concentrations of OCPs were not associated with birth size among boys. Parental preconceptional concentrations of PBB-153 were not found to be associated with birth size measures.ong boys . See SupPFCs. The mean birth weight of boys was 104.23 g lower  for every 1-SD increase in ln-transformed maternal concentrations of PFOSA (perfluorooctane sulfonamide). Maternal concentrations of the Et-PFOSA-AcOH [2-(n-ethyl-perfluorooctane sulfonamide) acetate] metabolite were associated with a smaller mean ponderal index among girls . We did not observe associations between preconceptional paternal concentrations of PFCs and birth measures. Furthermore, preconceptional parental concentrations of PFCs were not associated with length or head circumference at birth.PBDEs. Maternal concentrations of PBDEs were associated with significant differences in mean birth weight in boys and girls. Maternal concentrations of PBDE congeners 28 and 183 were associated with lower birth weight among girls; the largest negative association was estimated for PBDE-28 . Maternal concentrations of PBDE-28 were also statistically associated with smaller length and head circumference among girls. On the contrary, for every 1-SD increase in ln-transformed maternal concentrations of PBDEs 66 and 99, mean birth weight among boys was 125.04 g  and 133.39 g  higher, respectively. Among boys, PBDE congeners were also statistically associated with larger length (PBDE-99) and head circumference . As seen with maternal concentrations, paternal concentrations of PBDE-183 were also significantly associated with lower birth weight among girls .PCBs. Among girls, maternal concentrations of PCBs were not associated with significant differences in birth weight. However, for every 1-SD increase in ln-transformed concentrations of paternal concentrations of PCB-167, the mean birth weight among girls was 97.49 g lower , and mean length  and head circumference  were smaller. Significant associations between parental concentrations of PCBs and birth size were more frequent among boys. Birth weight among boys was lower by 99–170 g per 1-SD increase in ln-transformed maternal  and paternal  concentrations. Maternal concentrations of PCBs were statistically associated with smaller head circumference in girls (PCB-138) and boys . Paternal concentrations of PCBs were also significantly associated with smaller head circumference among girls (PCB-167) and boys . Maternal concentrations of PCBs 201 and 206 were associated with larger head circumference. Maternal concentrations of PCB-138 were associated with lower mean birth weight among boys and smaller mean head circumference and ponderal index among boys and girls. Paternal concentrations of PCB-138 were estimated to be associated with smaller mean ponderal index among boys. Additionally, in girls, paternal concentrations of PCB-156 and in boys maternal  and paternal  PCB concentrations were associated with smaller ponderal index .Persistent organic pollutants associated with multiple birth size outcomes. Both maternal and paternal concentrations of several persistent organic pollutants were associated with statistical differences in the same birth size measure among their offspring. The statistical differences associated with increasing parental concentrations of these pollutants were often of similar magnitude and direction. We briefly highlight these compounds here.Lower mean birth weight was observed in association with increasing preconception maternal and paternal concentrations of PBDE-183 among girls and PCBs 128 and 195 among boys. Maternal concentrations of PCB-167 were associated with lower mean birth weight among girls only, but paternal concentrations were associated with lower birth weight in boys. Increasing maternal and paternal concentrations of γ-HCH were associated with smaller head circumference and higher ponderal index among girls.In this prospective pregnancy study with preconception enrollment of couples, we demonstrated that both preconception maternal and paternal serum concentrations of persistent organic pollutants were significantly associated with birth size measures among their offspring, even after taking into account their partner’s serum concentrations. In addition, we also report several statistically significant differences in birth size measures by infant sex and between and within classes of pollutants. We observed decreases in infant birth weight between 85 and 195 g with 1-SD increases in preconception maternal and paternal serum concentrations of POPs.This reduction is similar in magnitude to what has been reported for other prenatal maternal environmental exposures. Compared with nonsmokers, lower mean birth weight has been reported for infants born to women who reported cigarette smoking during the first trimester or throughout pregnancy  . Meta-anOur findings underscore the importance of designing epidemiological studies that ascertain preconception parental exposures in relation to birth size measures. In addition, given that paternal environmental exposures are often overlooked when examining the associations between parental exposures and fetal growth, there is a need for more comprehensive investigations of the associations between preconception paternal exposures and fetal growth and development. Both maternal and paternal serum concentrations of several pollutants  were associated with birth size measures, but more research is needed to investigate whether associations that were specific to paternal serum concentrations are relevant and can be confirmed in other populations.n = 50) born to mothers with the highest concentrations of antiestrogenic PCBs [interquartile range (IQR): 0.23–0.33 ng/g serum] was approximately 471 g  lighter than infants born to mothers with the lowest concentrations (IQR: 0.13–0.15 ng/g serum). This study also examined the association between infant birth weight and maternal antiestrogenic PCB concentrations from serum measured during the prenatal period . The mean difference in infant birth weight between women with the highest (IQR: 0.15–0.21 ng/g serum) and lowest (IQR: 0.07–0.09 ng/g serum) prenatal concentrations of maternal antiestrogenic PCBs was approximately 260 g less  than what was reported for preconception levels , we found that maternal concentrations were significantly associated with lower birth weight and head circumference in boys; for another, shown to be antiestrogenic (PCB-156), we found paternal concentrations to be associated with lower ponderal index in both boys and girls . We alsoOur study also reports several positive associations between pollutants and birth size measures. Maternal concentrations of PBDEs 66 and 99 were associated with increased mean birth weight, length, and head circumference among boys only. Maternal concentrations of PCBs 201 and 206 and maternal and paternal concentrations of OCPs were associated with increased mean head circumference and ponderal index among girls only. Although they are not comparable to our study, other studies have reported positive associations between maternal prenatal levels of environmental chemicals. Maternal prenatal concentrations of total PCBs and PBBs (congener specific information not available) have been associated with higher birth weight . PositivOur study addressed several key limitations of prior studies with equivocal findings of the association between prenatal exposure to POPs and birth size. For one, many studies ascertained prenatal exposure to POPs during late pregnancy using maternal serum concentrations at the time of delivery or using umbilical cord serum concentrations. These studies may not be capturing exposure during relevant windows of fetal growth and development. Prospective pregnancy cohort studies that recruit couples discontinuing contraception to become pregnant are rare, and this is the only way to examine the association between preconceptional exposures to POPs and human birth size. Despite their long half-lives, maternal serum concentrations of PCBs and selected POPs can vary across critical windows of human reproduction and development during pregnancy . Preconcin utero or after birth  PDFClick here for additional data file.


High lipoprotein(a) [Lp(a)] levels are a major risk factor for the development of atherosclerosis. However, because apolipoprotein(a) [apo(a)], the unique component of Lp(a), is found only in primates and humans, the study of human Lp(a) has been hampered due to the lack of appropriate animal models. Using somatic cell nuclear transfer (SCNT) techniques, we produced transgenic miniature pigs expressing human apo(a) in the plasma. First, we placed the hemagglutinin (HA)-tagged cDNA of human apo(a) under the control of the β-actin promoter and cytomegalovirus enhancer, and then introduced this construct into kidney epithelial cells. Immunostaining of cells with anti-HA antibody allowed identification of cells stably expressing apo(a); one of the positive clones was used to provide donor cells for SCNT, yielding blastocysts that expressed apo(a). Immunohistochemical analysis of tissue sections and RT-PCR analysis of total RNA from organs of cloned piglet revealed that apo(a) is expressed in various tissues/organs including heart, liver, kidney, and intestine. More importantly, a transgenic line exhibited a high level (>400 mg/dL) of Lp(a) in plasma, and the transgenic apo(a) gene was transmitted to the offspring. Thus, we generated a human apo(a)–transgenic miniature pig that can be used as a model system to study advanced atherosclerosis related to human disease. The anatomical and physiological similarities between the swine and human cardiovascular systems will make this pig model a valuable source of information on the role of apo(a) in the formation of atherosclerosis, as well as the mechanisms underlying vascular health and disease. The Lin vivo functional roles of Lp(a) in atherosclerosis is the lack of appropriate experimental animals [The major difficulty in defining the  animals . This sc animals –9. Howev animals .By contrast, pigs have a cardiovascular system that is similar to that of humans, and therefore have the potential to serve as an effective animal model for cardiovascular disease . The pigIn the present study, we produced a cloned Clawn miniature pig expressing high levels of human apo(a) in plasma through the transfection of somatic cells combined with nuclear transfer. The studies using the cloned pig will contribute to understanding of the mechanism(s) by which higher levels of Lp(a) affect the development of human cardiovascular disease.Experiments with recombinant DNA technology were performed in agreement with the guidelines of Kagoshima University Committee on recombinant DNA security. All animal experiments in this study were approved by the Animal Ethics Committee, Kagoshima University. The committee defines the timing to give humane endpoints and the method of sacrifice. The criteria used in the present study to determine when the animals should be humanely sacrificed include following activities. 1) Whether it can move? 2) Whether it can eat (drink milk)? 3) Body temperature. Immediately after cesarean section, we carried out the veterinary care for maintenance of body temperature, moisture retention, nutrient supply and oxygen supply of miniature clone piglets using the neonatal incubator. In the first series of experiments, when piglets stopped drinking milk and moving, and their body temperature become low, we decided to sacrifice them. Throughout the experiments using animals, there was veterinary care. In the first series of experiments, after birth pigs were monitored directly every 30 min. In the second series experiments, pigs were monitored every one-hour using an Internet camera equipped in the house and monitored directly by the technicians of the house. Before administration of pentobarbital to sacrifice the piglets, neither analgesics nor anaestetics was used.C-terminus by PCR using the primers ATCCCTCTCTGTGCATCCTCT and CGAATTATTTCTCATCATTCCCTCAA and apo(a) cDNA as a template. After generating blunt ends using T4 DNA polymerase, the PCR product was digested with the PvuI restriction enzyme and cloned into the EcoRV site of the pC-SnailHA vector [EcoRI–KpnI fragment of apo(a) was cloned into the vector, yielding pC-apo(a)HA.The plasmid vector used in this experiment, pC-apo(a)HA, is shown in A vector . Then, tPrimary kidney epithelial cells were isolated from the kidney tissue of a Clawn miniature boar as described in . GrowingA rat mAb against HA was purchased from Roche Applied Science . A goat anti-apo(a) (anti-lipoprotein(a)) antibody was purchased from Applied Biological Materials . A mouse anti-apo(a) mAb  was obtained from GeneTex, Inc . Mouse anti–E-cadherin antibody and anti-cytokeratin 5 and 8 were obtained from Transduction Laboratories  and Chemicon International , respectively. A chicken anti-apoB mAb, which recognizes apoB of multiple species, was obtained from Hiroshima Bio-medical Co. Ltd. . All secondary antibodies were obtained from Jackson ImmunoResearch Laboratories .2, 5% O2, and 90% N2 at 38.5°C, in a 100 μl droplet of modified PZM-3 (mPZM-3) [2, 5% O2, and 90% N2 at 38.5°C. Then, the embryos were transferred into 50 μl of mPZM-3 for further culture. In the second series of experiments, the embryos were cultured in the presence of 500 nM scriptaid, a histone deacetylase inhibitor, which enhanced the cloning efficiency of miniature pig [SCNT miniature pig embryos were produced as described previously  and acti(mPZM-3)  until ac(mPZM-3) , and theture pig , insteadFemale Clawn miniature pigs, aged 6–12 months, were used as recipients. Animals were pre-medicated with a cocktail of ketamin, medetomidine, and butorphanol tartrate mixture. Once sedated, animals were intubated and maintained with 1–4% isoflurane continuous inhalation. Embryo transfer was performed under general anesthesia through a midline incision 31 h after hCG injection , as described previously . MorpholGenomic DNA was extracted from piglets’ umbilical cord, donor cells, and from uterine tissue using the DNeasy Total DNA kit . We genotyped 12 microsatellite markers on the USDA swine linkage maps: S0038, S0091, S0227, SW1378, SW1434, SW1681, SW1954, SW2108, SW2494, SWR153, SWR1941, and TNFB . PCR was5’-TCCCTCTCTGTGCATCCTCT-3’ (forward) and 5’-GCCTCCACAGAAGTGCTTTC-3’ (reverse) [5’-GGACTTCGAGCAGGAGATGG-3’ (forward) and 5’-GCACCGTGTTGGCGTAGAGG-3’ (reverse) [Portions of tissues isolated from three cloned piglets were collected. All samples were immediately frozen in liquid nitrogen and stored at −80°C until RNA isolation. Total RNA was isolated from tissue samples using the Fast Pure RNA Kit . The RT reaction and PCR reaction were carried out using a GeneAmp RNA PCR Kit (Applied Biosystems). The primers for apo(a) were reverse) . Pig β-areverse) . RT-PCR 2O2. The sections were stained in hematoxylin, briefly washed in water, and gradually dehydrated through an ethanol gradient followed by xylenes. Mounted samples were examined using a Nikon (ECLIPSE 80i) microscope .Tissues were collected from each cloned piglet and fixed with 10% (w/v) formalin-PBS. After fixation, tissues were processed for immunoperoxidase staining as described in . PeroxidAnalyses of Lp(a), total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol were performed by SRL .p values < 0.05 were considered to be statistically significant.Data are presented as means ± standard error of the mean (SEM). All percentage data were arcsine-transformed. Transformed values and number of cells in the blastocysts were assessed by one-way analysis of variance followed by Fisher's protected least significant difference (LSD) as a post hoc test; In a line of mice expressing the human apo(a) transgene under the control of the murine transferrin promoter, apo(a) circulating in the plasma associates with human LDL injected intravenously . TherefoUsing pulse-chase experiments, Wang et al. established that more than 80% of apo(a) synthesized by hepatocytes was degraded prior to secretion, independently of coexpression of human apoB . Thus, lPrior to attempting to establish pig cells stably expressing human apo(a), we introduced the expression vector into MDCK cells. MDCK cells are epithelial cells derived from dog kidney, and have been used for isolation of stable transfectants expressing various different proteins . We coulExperiments were repeated four times. The fusion rate of SCNT embryos reconstituted with transgenic kidney epithelial cells was 77.8% (n = 200). The rate of cleavage, blastocyst formation rate, and mean blastocyst cell number were 80.2 ± 4.3%, 18.8 ± 3.9%, and 39.7 ± 9.4, respectively. Furthermore, all blastocysts (n = 38) expressed human apo(a) as assessed by immunohistochemistry . Thus, tIn the first series of experiments, cloned embryos were transferred into the oviducts of five recipient gilts . Two recAs shown in In the second series of experiments, we finally succeeded in obtaining a piglet that is PCR-positive for human apo(a) and exhibited a high level of Lp(a) in plasma . This piC-terminus of apo(a) and the HA immunoreactive material in pig plasma also migrated to the position of apoB. Co-migration of apo(a) and apoB strongly suggested that they were in the same complex. To determine whether apo(a) was disulfide linked to pig apoB, the pig plasma were subjected to electrophoresis on a 4% denaturing polyacrylamide gel (SDS-PAGE) after boiling in the presence 2.3% SDS alone (nonreducing conditions) or in the presence of 2.3% SDS and 5% 2-mercaptoethanol (reducing conditions) (In the human Lp(a) particle, apo(a) is covalently linked to apoB-100 by the presence of a single disulfide bridge . It has Apo(a)-transgenic mice and rabbits have been successfully used in studies addressing the role of Lp(a) in atherosclerosis and thrombosis. However, large-animal models that recapitulate human disease pathophysiology are needed for translational research in atherosclerosis, and genetic engineering of well-characterized miniature pig strains has the potential to generate such models. In this study, we created a porcine model that expresses human apo(a) in Clawn miniature pigs, which showed high levels of human Lp(a) in plasma.Previous studies have identified elevated plasma Lp(a) concentrations (> 30 mg/dL) as a risk factor for a variety of atherosclerotic and thrombotic vascular diseases including peripheral vascular disease, venous thromboembolism, recurrent thrombotic stroke in children, and coronary heart disease (CHD) . Lp(a) lIn humans, a blood Lp(a) level higher than 50 mg/dL is regarded as a very high risk. In the current model, Lp(a) levels are higher than 400 mg/dL. At present we can not discuss the relevance of the model's high Lp(a) level to human's scenario. Further studies are required.in vitro developmental capacity of SCNT embryos were comparable to those other genetically modified somatic cells used as donors in our laboratory [Transgenic pigs have been produced by SCNT techniques using donor cells derived from fetuses and young pig fibroblasts ,38. In tboratory . This obThe advantage of using SCNT to make genetically modified cloned animals is that precise genetic modifications can be accomplished and confirmed in cultured cells prior to generating the animal. This is very important, because true embryonic stem cells have not yet been isolated from any domestic animal . ExpansiRecently, Wei et al.  reportedS1 FigA, Immunoblot detection of E-cadherin in MDCK and PKE cells. Cells were directly lysed in SDS-sample buffer, subjected to SDS-PAGE, and examined by immunoblotting with E-cadherin antibodies. B, Immunofluorescence staining of MDCK and PKE cells with cytokeratin antibodies. Cells were cultured on coverslips for 24 h and then examined by immunofluorescence microscopy for cytokeratin 5/8. Bars, 25 μm.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Anemia in pregnancy is associated with increased rates of maternal and perinatal mortality, premature delivery, low birth weight, and other adverse outcomesA prospective study was conducted on 1405 Iranian pregnant women who delivered during 2015. Blood was collected from all the subjects to measure the hemoglobin (Hb) during 16-19 weeks, 22-24 weeks, and 34-36 weeks of gestation. According to the level of hemoglobin, it is divided into 4 groups. Group 1; Hb > 10.1 gm/100ml (control group), Group 2; Hb= 8.1-10 gm/100ml (mild anemia) Group 3; Hb= 6.5-8 gm/100ml (moderate anemia) Group 4; Hb <6.5 gm/100ml (severe anemia). After delivery, the neonates were weighted within 24 hours after birth. Maternal hemoglobin and birth weights were compared. The anemia prevalence was 20.2% (Hb<10g/dl). Out of them, 16.2 % hadmoderate anemia (Hb=6.5-8 g/dl) and 83.8% had mild anemia (Hb=8.1-10 g/dl). Severe anemia did not detect in pregnant women. The hemoglobin levels in non anemic group showed a drop in the second trimester. Pregnant women with hemoglobin less than 10 g/dl, considered as anemic gave birth to neonates with birth weight of 2.6kg, while pregnant women with higher hemoglobin level (>10 g/dl), considered as normal gave birth to heavier and normal babies (3.3 kg). The severity of anemia during three trimesters was closely associated with birth weight of newborns.The low hemoglobin values during three trimesters of pregnancy were associated with low birth weight in Iran. The anemia can lead to intra uterine growth retardation. Anemia is a major health problem that affects 25% to 50% of the population of the world and approximately 50% of pregnant women . Anemia During pregnancy, anemia increased more than fourfold from the first to third trimester . It is aResearch has shown that Hb and Hematocrit (Hct) concentrations typically decrease during the first trimester and reach the lowest levels at the end of second trimester and increase again during the third trimester of pregnancy . AccordiThis study was conducted in health care centers which are located in Urmia. At the end of pregnancy, they referred to hospitals for delivery. A total number of 1405 healthy women, aged between 17 - 45 years, after pregnancy confirmation and undergoing prenatal care during the three trimesters of pregnancy, were registered as subjects for the present study. The study was approved by the Human Ethical Committee of Urmia Medical Science University. Written consent letters were obtained from all subjects. The inclusion criteria of the current study are the pregnant women without diabetes mellitus, cardio vascular disease (CVD), parathyroid, thyroid, bone, multiple pregnancies, mothers with placenta previa and placenta abruptia. Blood was collected from all subjects to measure the hemoglobin concentration during 16-19 weeks, 22-24 weeks and 34-36 weeks of gestation. The selected method for hemoglobin assessment was Cyanomethemoglobin . According to the level of hemoglobin. patients were divided into 4 groups; Group 1; Hb > 10.1 gm/100ml (control group), Group 2; Hb= 8.1-10 gm/100ml (mild anemia) Group 3; Hb=. 6.5-8 gm/100ml (moderate anemia) Group 4; Hb <6.5 gm/100ml (severe anemia).The weight of patients were measured using standard procedure within 24 hours after birth . A baby In the present study, 1405 pregnant women were selected and changes in hemoglobin concentration during 3 trimesters and its relation to birth weight of neonates were studied. Mothers' demographic profile has been shown in This study demonstrated that the prevalence of anemia is 20.2% (n=1405) among Iranian pregnant women in Urmia. Other studies have shown a higher degree of anemia in pregnancy such as 87% in India  , 58.6% The low prevalence of anemia in the present study may be related to more frequent iron supplementation consumption. Since the women had more visits for prenatal care so in each visit they were encouraged to take their supplements. Therefore, it seems that iron deficiency anemia is relatively lower in this study in compared to other studies. Based on the results, the hemoglobin levels in the non anemic group showed a drop in second trimester. Again the hemoglobin level increased in third trimester and it was realized to be similar to the first trimester. These are comparable with the mean hemoglobin level reported in pregnancy in other studies -29, whicThis study showed that low prenatal hemoglobin status is associated with low birth weight in neonates.