We investigated whether maternal prenatal emotions are associated with gestational length and birth weight in the large PREDO Study with multiple measurement points of emotions during gestation.Altogether 3376 pregnant women self-assessed their positive affect  and depressive  and anxiety  symptoms up to 14 times during gestation. Birth characteristics were derived from the National Birth Register and from medical records.One standard deviation (SD) unit higher PA during the third pregnancy trimester was associated with a 0.05 SD unit longer gestational length, whereas one SD unit higher CES-D and STAI scores during the third trimester were associated with 0.04–0.05 SD unit shorter gestational lengths , corresponding to only 0.1–0.2% of the variation in gestational length. Higher PA during the third trimester was associated with a significantly decreased risk for preterm (< 37 weeks) delivery . Mothers with preterm delivery showed a decline in PA and an increase in CES-D and STAI during eight weeks prior to delivery. Post-term birth (≥ 42 weeks), birth weight and fetal growth were not associated with maternal prenatal emotions.This study with 14 measurements of maternal emotions during pregnancy show modest effects of prenatal emotions during the third pregnancy trimester, particularly in the weeks close to delivery, on gestational length. From the clinical perspective, the effects were negligible. No associations were detected between prenatal emotions and birth weight. Mounting empirical evidence suggests that maternal emotional distress during pregnancy, including depressive symptoms, and state, trait and pregnancy-specific anxiety, may increase the risk of adverse birth outcomes, such as preterm birth  or shorter length of gestation, intrauterine growth restriction (IUGR), and low < 2.5 kg) or lower birth weight at delivery –7. Howev kg or loA small body of literature suggests that maternal positive predisposition or positive attitude towards pregnancy may, independently of emotional distress, decrease the risk of adverse birth outcomes. In a sample of 130 pregnant women, higher levels of self-esteem and optimism measured in gestational weeks 28–30 were associated with higher birth weight, but not with length of gestation . CorrespOur original contribution in this study is to explore the influence of positive affect and the role of the timing of exposures for the birth outcomes. To our knowledge, our study offers the most comprehensive view on maternal emotional state over the course of pregnancy reported thus far, with prospective assessments of emotions at two-week intervals from 12 weeks’ gestation onwards in a large data set. Therefore, the roles of negative affect and its timing were also relevant. Hence, we examined the hypothesis that higher positive and lower negative affect would predict longer length of gestation and higher birth weight in 3376 pregnant women. We also examined whether the associations would vary by the medical risk-status of mothers, since obstetric complications are associated with higher emotional distress during pregnancy [2) . The participants also less often smoked during pregnancy  and more often had tertiary education . The characteristics of the participants are presented in The participants came from the Prediction and Prevention of Preeclampsia (PREDO) Study –15. The The participants filled in well-validated questionnaires –18 on prPositive affect: We used Positive Affect (PA) scale comprising 10 mood states derived from the International Positive and Negative Affect Schedule (PANAS) . The parDepressive symptoms: We used the Center for Epidemiologic Studies Depression Scale (CES-D) 16) for both continuous and categorical variables: CES-D scores were dichotomized at ≥16, which is the cut-off for individuals at risk for clinically significant depressive symptoms [ for bothAnxiety symptoms: To measure state anxiety, we used the Spielberger State Anxiety Scale (STAI) .The partData on gestational length and birth weight came from the hospital birth records for the high-risk subsample and from the national birth register for the community-based subsample. We used the birth outcome variables as both continuous and categorical variables: preterm birth: ≤ 36 6/7 gestational weeks; term birth: 37 0/7-41 6/7 gestational weeks; post-term birth: ≥ 420/7gestational weeks; small for gestational age (SGA): birth weight for gestational age ≤ -2 standard deviations (SD); appropriate for gestational age (AGA): birth weight for gestational age > -2 SD—≤ 2SD; LGA: birth weight for gestational age ≥ 2 SDs, all according to Finnish national growth charts .2; normal weight: BMI = 18.5 to 25 kg/m2; overweight; BMI = 25 to 30 kg/m2; obese: BMI ≥ 30 kg/m2, hypertensive pregnancy disorders , gestational diabetes (hyperglycemia that first emerged or was first identified during pregnancy), and Type I diabetes were derived from patient case records and verified by a clinical jury. For the community-based subsample the data of pregnancy disorders and BMI came from the national birth register. In both subsamples maternal education  prenatal use of antidepressant or other psychotropic medication  and alcohol consumption during pregnancy (yes/no) were self-reported in a questionnaire given at the first ultrasound screening at gestational week 12 6/7-13 6/7. Social support was assessed in at two-week intervals (i.e. biweekly) in the questionnaire with a 65 mm long visual analog scale.Maternal age (years), delivery mode , parity (primiparous vs. multiparous), smoking (no/quit during first trimester/smoked throughout pregnancy) during pregnancy, and infant’s sex (girl vs. boy) were derived from the national birth register for both subsamples. For the medical high-risk sample, maternal pre-pregnancy BMI . The rationale of using trimester means in these analyses instead of the bi-weekly scores was based on the very high inter-correlations between the bi-weekly emotion scores .2) was calculated for prenatal emotions by hierarchical multiple regression analyses. We used logistic regressions to examine whether maternal positive affect decreased and depressive symptoms and state anxiety increased the risk of preterm vs. term, post-term vs. term, SGA vs. AGA, and LGA vs. AGA births. Finally, to test whether the associations varied by the medical risk status of the sample, we added an interaction term ‘high-risk subsample vs. community subsample x trimester-specific PA/CES-D/STAI’ to the regression equations following the main effects. In these interaction analyses, the small comparison group recruited for the high-risk subsample was merged to the community-based subsample.All analyses were adjusted for maternal age at delivery, parity, delivery mode, education and infant’s sex (Model 1) and further for maternal alcohol consumption and smoking during pregnancy, maternal pre-pregnancy body mass index, hypertensive pregnancy disorders, gestational and Type I diabetes, antidepressant and other psychotropic medication, and social support (Model 2). In case of significant associations, the explained variance (RPA (range of Pearson r’s 0.57 to 0.83), CES-D (r’s 0.61 to 0.83) and STAI (r’s 0.55 to 0.79) scores were significantly correlated across the three trimesters . PA correlated negatively within the trimesters with STAI (r’s -0.51 to -0.66) and CES-D (r’s -0.50 to -0.62). STAI and CES-D correlated positively with each other within the trimesters (r’s 0.69 to 0.84), all P-values < 0.001. In terms of mean raw scores shown in PA during the third trimester was associated with a significantly decreased odds for preterm delivery  decreased by 0.8-fold  . CES-D , and STAI  scores during the third trimester, in turn, were higher in women with a preterm delivery, but these associations were not statistically significant. PA, CES-D, and STAI at the first and second trimesters were not associated with a preterm delivery  and PA, CES-D, and STAI at any trimester were not associated with a post-term delivery  or with SGA vs. AGA, or LGA vs. AGA status of the infant .Post-hoc exploratory analyses further highlighted the significance of the trajectories of emotions experienced during pregnancy. Medical risk status moderated significantly the associations between the third-trimester CES-D and gestational length . In the high-risk sample, one SD unit increase in the third trimester CES-D was associated with a 0.12 SD unit shorter gestational length ; in the community sample this association was not significant .We investigated among 3376 women whether prenatal PA and depressive and anxiety symptoms were associated with the likelihood of shorter gestation, preterm birth or lower birth weight. While the issue has been widely studied, the previous literature concentrates mostly on negative emotions and does not cover the effect of the emotions experienced throughout the entire pregnancy. With our data, we were able to overcome these issues with up to 14 measurement points during pregnancy, allowing a trimester-specific approach, with an adjustment for several major confounders. We found statistically significant, but clinically negligible associations between positive and negative emotions during the third trimester and gestational length, and no significant associations with birth weight. In addition, PA during the third trimester was associated with lower odds for a preterm birth.PA was associated with longer gestational length and negative emotions with shorter gestational length. The general pattern of the results was in accordance with earlier studies –7, whichWith regard to prematurity, higher PA during the third trimester was associated with a reduced risk for a premature delivery, in line with a recent study . HoweverKramer  presenteWe did not observe any associations of PA, prenatal anxiety, or depression with birth weight. These findings are in line with a meta-analysis that noted no associations between depression and birth weight  and withThe current study subject has been under active research, with several biological mechanisms potentially underlying associations between prenatal emotions and gestational length. Increased concentration of corticotrophin-releasing hormone (CRH) in early pregnancy plasma predicts preterm birth –26. MostThe strengths of this study include the large well-characterized sample and the multiple repeated measurements of PA and anxiety and depressive symptoms, enabling us to reliably evaluate the effects of these factors on gestation length and birth size and to assess specific sensitivity periods. We were also able to assess possible confounding by multiple factors known to affect gestation length and birth size.As to limitations, we cannot rule out that the results, especially with regard to prematurity, reflect reverse causality, i.e. prenatal emotions would be then generated as a response to the risk of premature birth. Mothers in Finland are followed intensively during pregnancy, with mothers being well aware of potential risks. Second, PA had a strong inverse correlation with negative emotions. We cannot say whether PA had an independent effect on gestational length or whether the effect could be reduced by a lack of negative emotions (depressive and anxiety symptoms). This is, however, a semantic question related to the core definition of positive emotions and their relation to depression and anxiety. Third, we did not have information about whether mothers with depression and anxiety symptoms received any psychosocial support. Finally, the participants may not be representative of the catchment areas of the study hospitals; these mothers had on average high educational attainment and smoking during pregnancy was rare. This would be expected to cause bias only if the association between prenatal emotions and pregnancy outcomes differs between participants and non-participants.In summary, we used a large sample of pregnant women who rated their prenatal emotions bi-weekly to examine the relationships of PA and depressive and anxiety symptoms with gestational length and birth weight. Experience of PA during the third trimester was associated with longer gestation and lower odds of preterm delivery, whereas higher prenatal depressive and anxiety symptoms during the third trimester were associated with shorter gestation. The associations regarding depressive symptoms and gestational length were stronger among high-risk mothers. We also found that the course of emotions during the last eight weeks of pregnancy is different among women delivering preterm, as they displayed more negative emotions and less PA. Birth weight and fetal growth were not associated with prenatal emotions, and no effects on gestational length were observed for the first two trimesters. Our findings thus highlight the modest effects of both positive and negative emotions during the third pregnancy trimester on gestational length. While this subject has raised intense research interest in recent years, our findings indicate that the effects of prenatal emotions on birth characteristics are very small.per se. Of course, this has to be verified in further studies with as intensive measurements of prenatal emotions.The clinical relevance may be in the message that prenatal negative emotions, including symptoms of depression and anxiety, may not play such a large role for pregnancy outcome However, several studies show that prenatal negative emotions may be harmful to child development, being associated with increased psychopathology in the offspring, often independently of the maternal postnatal emotions –38. As m


History of childhood sexual abuse (CSA) is highly prevalent with as many as one in four American women being victims. Exposure to CSA or other early life traumatic experiences has been associated with adverse reproductive and pregnancy outcomes. However, the effects of CSA on preterm delivery (PTB), a leading cause of neonatal mortality, remain poorly understood. The objectives of this review are (i) to synthesize the available research investigating the relationship between maternal history of childhood sexual abuse (CSA) and preterm delivery (PTB); (ii) to provide suggestions for improving future research on this topic; and (iii) to highlight implications for clinical practice and public health.Relevant articles were identified through searches of four electronic databases  for studies published before March 2014, as well as through reviewing references of published articles.A total of six studies published from 1992 to 2010 were included in this review. Overall, findings were inconsistent. Three studies reported statistically significant associations of CSA with PTB (<37 weeks gestation) or shorter mean gestational age at birth. Women with a history of CSA had 2.6 to 4.8-fold increased odds of PTB as compared with women without a history of CSA. Three other studies did not observe statistically significant differences in rates of PTB or mean gestational age at birth in relation to a history of CSA.Available evidence on this topic is sparse and inconsistent, and limited by a number of methodological challenges. Given the ubiquity of CSA, as well as the clinical and public health significance of PTB, more rigorously designed epidemiologic studies on the association between CSA and PTB are warranted.The online version of this article (doi:10.1186/s12884-015-0606-0) contains supplementary material, which is available to authorized users. Childhood sexual abuse (CSA) is a major public health problem with serious immediate and long-term health consequences –3. Althonon-contact sexual abuse ; (b) contact sexual abuse without penetration ; and (c) contact sexual abuse with penetration  is recognized as the most severe. In addition, CSA may be characterized in terms of frequency, duration, age of onset of abuse, and relationship of the victim to the perpetrator [Generally, CSA is characterized into three broad categories: (a) petrator .et al. reported that the average prevalence of CSA was 19.7 % for girls and 7.9 % for boys [Recent prevalence estimates of CSA, summarized in meta-analyses and multi-country studies confirm high global prevalence, with markedly higher prevalence among girls as compared with boys; see Table for boys . These ffor boys , 11.Tablet al. observed CSA prevalence of 7 % using one question to screen for CSA: “have you been forced to have sexual intercourse ?” [et al. observed a prevalence of 32.2 % using the 14-item Childhood Sexual Assaults Scale [The prevalence of CSA in hospital and clinic based studies of pregnant women, primarily from high-income countries, range from 3.2 to 32.2 % –22. As ws old)?” , whilst ts Scale .p <0.05) and with use of force during CSA  among men [The relation of CSA with a range of health outcomes has been well documented among men and women. Investigators have reported strong associations of CSA with psychiatric disorders including post-traumatic stress disorder (PTSD) , depressmong men . Similarmong men .CSA is linked to increased odds of a host of adverse reproductive characteristics in women including early age at menarche , 28 and Preterm birth (PTB), defined as birth prior to the completion of 37 weeks gestation , is the Although the majority of preterm births occur in low and middle income countries , PTB remDespite its high prevalence, the etiology of PTB is not well understood . HoweverRelevant studies published before March 2014 were identified from four online databases , Web of Science Core Collection and BIOSIS Online). A full list of search terms used can be found in Additional file The exposure of interest was maternal exposure to CSA, and the outcome of interest was preterm birth or gestational age at birth. To be included, studies had to: (1) define CSA as occurring sometime before age 18 years; (2) report quantitative associations between CSA and PTB or gestational age at birth; (3) be observational studies ; and (4) be full-length papers .The electronic database search identified 2,207 titles, of which 1955 were duplicates or rejected upon title review. The abstracts of the remaining unique 252 articles were read. Of these, 34 were selected for full-text screening . Also, the frequency of PTB was higher among abused women as compared with non-abused women . However, the authors reported that when controlling for maternal stress, depression, social support, and substance abuse, the association between abuse and gestational age at birth was not statistically significant (quantitative summary not reported) [Steven-Simons and colleagues analyzed data for 127 women who were <19 years old at the time of conception of pregnancy. History of current or prior physical or sexual abuse was obtained through interviews and was defined as answering “yes” to the question “Have you ever been physically or sexually abused?” or other related questions. Overall, 42 women (33 %) reported exposure to childhood physical or sexual abuse. The authors noted that abused women delivered approximately 1 week earlier, on average, as compared with non-abused women  . It is pp < 0.05, adjusted for minority status and sibling number). Prenatal alcohol use, but not maternal cortisol concentrations, mediated this relationship [In a prospective cohort study of 40 women with CSA history and 31 without a history of CSA, Noll and colleagues reported that the odds of PTB was elevated among women with a history of CSA as compared with those who had no such history of abuse  [Recently, Leeners 9, 5.59) .p = 0.68) [In contrast to the studies described above, three other studies did not observe significant associations of CSA with PTB or mean gestational age at birth. In a case–control study conducted in Norway, Grimstad and colleagues analyzed data for 82 women who delivered low birth weight (<2500 g) infants, and 91 women with normal birth weight (≥2500 g) infants. A positive history of CSA was determined on the basis of participants’ response to a single question as to whether they had negative sexual experiences prior to age 18 years. The authors did not observe a significant difference in the prevalence of preterm birth (definition not specified) among women with CSA history (36 %) and women with no CSA history  retrospective cohort study, Jacobs reported no statistically significant association between being a victim of CSA and PTB or gestational age at birth. However, the authors reported a positive correlation between gestational age at birth and maternal history of being sexually touched as a child . Due to a number of methodological challenges, one being an extremely small sample size, findings from this study, particularly those on the CSA sub-category of being sexually touched as a child, should be interpreted with caution [Benedict and colleagues conducted a prospective cohort study to examine the association of CSA with depressive symptomatology, negative life events, and selected pregnancy outcomes, including gestational age at birth among 357 women aged ≥18 years. CSA was defined as ≥ 1 episode of non-consensual and non-experimental contact or non-contact sexual abuse prior to 18 years by a perpetrator ≥ 5 years older than the victim. However, if force was used, women were considered as CSA-exposed regardless of age difference with perpetrator. Thirty-seven percent of participants reported exposure to CSA and prevalence of PTB in the entire sample was 13 %. The authors reported no significant association of CSA with mean number of gestational weeks at birth or PTB observed (no quantitative summary was shown) . Finally caution .These studies on the association of CSA with PTB or gestational age at birth had some common limitations. First, the majority of studies were based on convenience samples with relatively small sizes (range from 28 to 357 women), which limited statistical power and hindered inferences that could be made from the studies. Second, there was significant heterogeneity across studies with regard to the definition of CSA, i.e., level of contact considered, mode of ascertainment of CSA history, and the maximum cutoff age for CSA (range from 16 to 19 years of age). These differences in the operational definition of CSA may have contributed to variations in CSA prevalence and observed associations of CSA with PTB and gestational age at birth. Third, the mode of ascertainment of PTB or gestational age at birth varied, from maternal self-report , to extrPathophysiological mechanisms that may account for observed associations of CSA exposure histories with PTB are not well known. However, investigators have suggested that CSA, an early life stressor, contributes to psychological stress and promotes dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, one of two major neuroendocrine pathways activated in stress response . HPA axiIn their review paper, Horan and colleagues propose that the trauma, stress and fear associated with CSA may stimulate enhanced CRH gene expression and chronic overproduction of CRH in the brain, making a woman susceptible to elevated placental CRH gene expression during pregnancy and consequently, increased risk of PTB . This thCSA is a highly prevalent early life stressor with wide-ranging immediate and long-term biological and psychological sequelae . Among pThe use of detailed CSA questionnaires  in future CSA-PTB studies would allow for more uniform exposure collection efforts and capture of a wide range of CSA severities to enable nuanced analyses and interpretation of findings.Studies should distinguish between sub-categories of preterm birth  to add greater specificity to the existing literature and further inform the development of clinical risk stratification and risk management protocols.Longitudinal studies incorporating the use of biological samples may facilitate understanding of biological mechanisms and identify important mediators and modifiers of the CSA-PTB relationship.Study design and analytical approaches to account for confounders and potential mediators  will improve validity and precision of measured CSA-PTB associations.Efforts should be made to quantify the contribution of CSA to PTB incidence in middle and low-income countries, particularly those countries with high prevalence of CSA. Such efforts would expand current knowledge and may be informative for PTB prevention in these settings.Prevention of both CSA and PTB requires a multi-sectorial response. Prevention and risk management efforts should engage individuals from health services, educational, advocacy, institutions, with better recognition of the social, cultural and environmental milieu within which CSA and PTB occur.As reported in this review of the six published studies on the topic to date, only three studies observed statistically significant associations of CSA with PTB or shorter mean gestational age at birth –54. ThreIn spite of the great strides that have been made towards elucidating the medical, environmental, psychosocial and genetic risk factors of PTB , this re


The small (1-cm) esophageal cyst was left untreated based on a “wait-and-see” policy. Histological analysis showed that the resected cyst was walled by hyperplastic, fibrous tissues and locally lined with gastric mucosa inherent glands. This finding was consistent with a diagnosis of EDC, with ectopic gastric mucosa. The respiratory tract symptoms resolved immediately after the operation. Computed tomography obtained at the 6-month follow-up showed that no disease, residual or recurrence, was present after the resection of the large-sized cyst, and the small-sized cyst remained unchanged in size.Esophageal duplication cyst (EDC) is a congenital malformation of the posterior primitive foregut, which mainly occurs in the thoracic esophagus. Here, we describe a 3-year-old Han Chinese boy afflicted with intermittent fever of acute onset and dry cough. Thoracic computed tomography revealed an 10 cm × 5.4 cm × 5.8 cm oval-shaped, cyst-like tumor located in the extrapleural space, extending along the right paravertebral gutter and compressing the trachea forward. An additional small-sized, oval-shaped cyst was identified in the posterior mediastinum, between the esophagus and the spinal column, at the T1 level. During open thoracotomy, under general anesthesia, an opaque, thick-walled, esophageal cyst was revealed not to be in communication with the esophageal lumen or the trachea. This cyst was subsequently resected in an  Gastrointestinal (GI) tract duplication, or GI duplication cyst, is a rare congenital malformation of the GI tract. The etiology of GI tract duplication is not fully understood; however, an initial developmental abnormality during the gastrulation stage is thought to be the most likely cause . Based oGI tract duplication mainly occurs in the ileum of the small intestine, which accounts for over 40% of cases . EsophagEsophageal duplication cysts may contain ectopic gastric mucosa  and pancvia thoracotomy, whereas the smaller cyst was left untreated, based on a “wait-and-see” policy.In this case study, we described a boy afflicted with intermittent fever of acute onset and dry cough, and diagnosed as having double EDCs containing ectopic gastric mucosa. The larger cyst was resected A previously healthy 3-year-old Han Chinese boy, who presented with intermittent fever of acute onset and dry cough, but without dysphagia, was referred to our Department of Pediatric Respiratory Medicine. He showed no clinically significant abnormalities on physical examination, except for feebleness and pyrexia (39.0°C). Chest radiography and computed tomography (CT) scans at the initial visit revealed a mediastinal tumor with complicating pneumonia. He was subsequently referred to our pediatric thoracic surgery service.Three-dimensional CT reconstruction demonstrated that two oval-shaped cystic masses were located in the posterior mediastinum, which displayed well-defined margins and were fluid-filled, yet free of any air-fluid levels. The larger cyst was 10 cm × 5.4 cm × 5.8 cm in size. It was attached to the middle and lower portions of the esophagus in the extrapleural space and extended along the right paravertebral gutter. The cyst compressed the forelying trachea, the right main bronchus, and the right inferior lobe anteriorly Figure . Therefoen bloc manner. The small esophageal cyst was left untreated based on a “wait-and-see” policy. This cyst was located at the thoracic entrance  and was not easily accessible through the sixth intercostal space incision.Because the cysts were symptomatic and one of them was oversized, elective open thoracotomy was undertaken. A double-lumen endotracheal tube was used to deflate the right lung, and a right-sided thoracotomy was made along the sixth intercostal space. A 10 cm × 5.4 cm × 5.8 cm cyst originating from the right lateral wall of the esophagus at the level of the carina was identified Figure . The cysGross pathology of the resected specimen showed a grayish cystic mass, with a 0.3-cm-thick wall, lined with brownish, rough epithelial-like tissue. Histological analysis of the resected esophageal cyst revealed that the cyst wall was composed of hyperplastic fibers and lined with stratified squamous epithelium, containing gastric mucosal simple columnar epithelium Figure . The disThe respiratory tract symptoms resolved immediately after operation. The patient underwent an uneventful recovery. A chest CT scan revealed no residue of the resected cyst on postoperative day (POD) 5. The patient was discharged from hospital on POD 7, and treatment was continued at the outpatient clinic. At the follow-up visit at 6 months, the patient appeared asymptomatic and generally in good health. A follow-up chest CT scan showed that no disease, residual or recurrent, was present after the resection of the large-sized cyst, and the small-sized cyst remained unchanged in dimension  EDCs have been reported ,12. The Most EDCs do not present with debilitating symptoms. Affected children may complain of nonspecific esophagus-related or respiratory tract symptoms, depending on the size and the presence or absence of complicating hemorrhage, infection, rupture, or respiratory tract involvement . EDCs maRadiographic manifestations of EDC are generally nonspecific and similar to those of other common mediastinal non-neoplastic or neoplastic diseases. Non-contrast and contrast-enhanced CT scan can demonstrate esophageal cysts and the neighboring esophagus and tracheobronchial tree . If the Histology offers the best diagnostic tool of EDC. The pathological criteria of EDC are as follows : the cysvia thoracotomy or thoracoscopy for removing thoracic EDC. Complete removal of EDC is required to minimize the risk of disease recurrence. Thoracoscopic resection is believed to be as effective as the conventional open procedure, and offers additional minimal invasiveness and expedited postoperative recovery [Surgical excision is the mainstay treatment for symptomatic EDC. This procedure can be performed recovery . In our recovery  or partirecovery  after EUrecovery . If necerecovery .EDC is an uncommon differential diagnosis in children presenting with posterior-mediastinal cystic masses. The use of a combination of multiple medical imaging techniques, such as esophagography, CT scan, MRI, and EUS, can help characterize EDC in relation to its neighboring anatomy and exclude possible concomitant tracheoesophageal malformations. Ectopic gastric mucosa can be retrospectively detected in EDC resection specimens. Large-sized and/or symptomatic EDCs should be surgically treated, while small-sized and/or asymptomatic EDCs should be closely followed up, especially if the cyst is located in proximity to the superior thoracic aperture or tracheal carina.Written informed consent was obtained from the patient’s guardian for the publication of this case report and any accompanying images. A copy of the written consent is available from the Editor-in-Chief of this journal.CT: Computed tomography; EDC: Esophageal duplication cyst; EUS: Endoscopic ultrasonography; GI: Gastrointestinal; MRI: Magnetic resonance imaging; POD: Postoperative day.The authors declare that they have no competing interests.YBC, study concept and design; ZFZ and FJ, drafting and finalization of the manuscript, preparation of the figures, acquisition of data, and analysis and interpretation of data; HW and SLT, critical revision of the manuscript for important intellectual content and material support; ZT, preparation of the figures, and technical and material support. All authors read and approved the final manuscript.Dr. Youbin Cui, Superintendent of the Institution, surgeon; Zhefeng Zhang, master’s degree, surgical trainee; Feng Jin, master’s degree, research student; Hao Wu, master’s degree, research student; Shulian Tan, master’s degree, research student; Zhuang Tian, master’s degree, technician.


The main objective was to investigate the burden of birth defects among alive infants and explore the impact of maternal lifestyle during pregnancy on the burden of birth defects in Northwest China.A stratified multi-stage sampling method was used to study infants born during 2010–2013 (and their mothers) in Shaanxi province of Northwest China. Socio-demographic information was collected using a structured questionnaire, and medical records from the local hospitals were used to determine the final diagnosis of birth defects. Poisson regression analysis was performed to assess the association between maternal lifestyles during pregnancy and the burden of birth defects, while adjusting for potential confounders.We sampled 29098 infants, of whom 629 (i.e. 216.17 per 10000) were observed to have congenital defects. Cardiovascular system defects (77.32 per 10000) were found to be the most common. Mothers who had ever consumed alcohol during pregnancy were found to have infants with a higher prevalence of some categories of birth defects, including nervous system , cardiovascular system  and oral clefts  in contrast to infants of mothers without any alcohol consumption. Maternal passive smoking during pregnancy lead to the increased burden of malformations of eye, ear, face and neck , cardiovascular system  and respiratory system  in their newborns. Further, tea or coffee consumption during pregnancy was positively correlated with the burden of specific birth defects, such as cardiovascular system  and genital organs  among infants.The prevalence of birth defects was high in Shaanxi province of Northwest China. The unhealthy lifestyles of mothers during pregnancy may increase the prevalence of congenital malformations. These findings in future may have some important implications for prevention of birth defects in Northwest China. Birth defects (BD), defined as a constellation of structural, functional and metabolic disorders, represent a significant global public health problem owing to their substantial contribution to infant and child mortality and morbidity. Around the world, an estimated 3% of the 134 million annual births are thought to be affected by birth defects, with significant variability in their prevalence among countries and regions . AlthougWith the progressive decline in infant mortality in China, BDs have become one of the dominant problems of the country in recent years. Every year, an estimated 800,000 to 1.2 million infants are born with BDs and disabilities in China, accounting for 4%–6% of the country’s total newborns . SimultaThe study employed data from the cross-sectional survey conducted from August to November 2013 in Shaanxi province of Northwest China. The target population of the study were infants born during 2010–2013 and their mothers. Because of the differences in the distribution and fertility rates of population between rural and urban areas in the whole province, a stratified multi-stage sampling method was employed to determine the sampling units. In China, counties, townships and villages in rural areas and districts, streets and communities in urban areas, respectively, were two different three-level administration frames. As a first step, 20 counties and 10 districts were randomly selected from the entire province. In the next step, six townships in the chosen counties, and three streets in the chosen districts, were randomly sampled. Subsequently, six villages from each chosen township and six communities in the chosen streets were selected randomly. In the next stage, a random sampling method was adopted to select 30 babies born during 2010–2013 and their mothers in each sampled village, and, 60 in each chosen community. Approximately 32400 infants and their mothers were expected to be sampled in the study. However, 2374 subjects of the randomly sampled population declined to participate in the study (response rate: 92.7%). Only infants who were alive at the time of sampling were considered for this study. A total of 29098 live infants were eventually selected, and the relative sampling size in relation to the total infant population of the whole province was approximately 9%.All family-level primary data was reported by the mothers of the sampled children in the pre-coded structured family questionnaire, including socio-demographical information, information on maternal lifestyles during pregnancy, and presence of birth defects at the time of visit. The information on birth defects was collected with the pre-coded structured birth defects questionnaire which contained questions on birth outcomes, past diagnostic information at local hospitals, time of diagnosis and the types of defects. In the survey, all questionnaires were designed by Xi’an Jiaotong University Health Science Center. Written informed consent was obtained from all subjects prior to their enrollment in the study. Families having a child were required to complete birth defects questionnaire. Medical records at local hospitals including prenatal diagnostic test results, clinic diagnostic results, findings of physical examination, ultrasound imaging reports and medical history were used as final diagnosis references.Trained field staff from Xi’an Jiaotong University Health Science Center were responsible for the data collection. Ten investigation teams were formed for these counties or districts, with each team comprising of 10–12 members, a supervisor and a doctor from local maternal and child health hospital. As soon as each questionnaire was completed, the supervisors were under obligation to detect any errors and/or incomplete information. The doctor in each team facilitated the collection of information on birth defects. All data collection was completed in the local village clinics and community health service centers. The study was supported by the local hospitals and health administrative departments as well as the Shaanxi province Ministry of Health.Birth defects were classified into 11 different groups based on the International Classification of Diseases, 10th Revision (ICD-10), including nervous system (Q00-Q07), eye, ear, face and neck (Q10-Q18), cardiovascular system (Q20-Q28), respiratory system (Q30-Q34), oral clefts (Q35-Q37), digestive system (Q38-Q45), genital organs (Q50-Q56), urinary system (Q60-Q64), musculoskeletal system (Q65-Q79), other defects (Q80-Q89), and chromosomal abnormalities (Q90-Q99). The mothers were interviewed in detail for their lifestyle during pregnancy . The alcohol intake frequency of mothers during pregnancy was divided into three categories . Passive smoking frequency was defined as the number of times when the respondent passively inhaled smoke for > 15 minutes per day, and similarly, also classified into three categories . The tea and coffee consumption during pregnancy had two dichotomous outcomes variables (no and yes). The Demographic and Health Survey wealth index based on the principal component analysis was adopted to assess the socioeconomic status (SES) of the households [P value of < 0.05. Prevalence rates (per 10000 live births) of congenital malformations across socio-demographic characteristics and maternal lifestyles in the province were compared using univariate Poisson regression. Poisson regression model was also applied to assess the association between maternal lifestyles during pregnancy and birth defects after adjusting for socio-demographic characteristics. Prevalence rate ratio (PRR) was used as an indication of the magnitude of change, which was not be negative and <1 for a decrease and >1 for an increase.Data were entered into Epidata 3.1 by double entry, and STATA version 12.0  was used for data analysis. The criteria for statistical significance was Written informed consent was obtained from all study participants after a detailed briefing on the purpose, process and confidentiality of the research. The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Xi’an Jiaotong University Health Science Center.The average age of infants was 16.88 ± 11.29 months (range 0–46 months). Of the infants, 98.8% were singletons and boys accounted for 54.4% of total infants. The mean age of mothers was 28.01 ± 4.86 years and approximately 38.2% of them were educated beyond senior high school. Amongst the mothers, the average parity was 1.65 ± 0.82. Based on tertiles of household wealth index, there was an equal distribution of households in the poor, medium and rich category. The demographic profile of the study sample seemed to approximate that of the overall population of Shaanxi province based on the sixth Chinese population census (2010) data . About 1Compared to the floating population, the frequency of alcohol intake during pregnancy was higher in the permanently resident population. The older mothers with lower education and economic level were more likely to be passive smokers. With respect to coffee consumption in pregnancy, our study revealed a greater percentage in young and well educated women. In addition, low parity and better SES might also be two key contributing factors for higher coffee consumption among mothers.The overall prevalence rate of congenital malformations was approximately 216.17 per 10000 alive infants. Cardiovascular system malformations had the highest prevalence , followed by other defects , musculoskeletal system defects , eye, ear, face and neck malformations , and oral clefts . The prevalence of birth defects appeared to have a significant correlation with socio-demographic characteristics such as infant’s gender, fetal number, etc. Among maternal factors, education level and age, parity, economic status and residence during pregnancy  affectedAfter adjusting for socio-demographic characteristics and other lifestyle-related variables during pregnancy, analysis based on Poisson model revealed a higher prevalence rate ratio (PRR) of certain categories of birth defects such as, nervous system , cardiovascular system  and oral clefts  among live infants born to women with a history of alcohol intake in pregnancy as compared to those born to mothers without a history of alcohol intake during pregnancy . FurtherThis large population-based cross-sectional study in Shaanxi province provides a representative picture of the burden of birth defects among alive infants, and explores the likely relationship between maternal lifestyles in pregnancy, and the burden of birth defects in the offspring. Results indicated a high overall prevalence of congenital malformations (approximately 216.17 per 10 thousand live infants) in Shaanxi province. Due to the cross-sectional study design, inferences on causal relationships between maternal lifestyle in pregnancy and the risk of birth defects in the offspring could not be drawn in our study. According to Poisson regression analysis, however, we inferred a potential association between a history of maternal passive smoking during pregnancy and the overall burden of congenital malformations. However, alcohol, tea and coffee intake did not demonstrate a significant association with the overall burden of congenital malformations. Likewise, significantly increased burden could be observed for different categories of congenital malformations among infants born to mothers with unhealthy lifestyles during pregnancy.In our study, 629 infants of 29098 participants (216.17 per10000) were identified as having congenital defects in Shaanxi province, Northwest China. The prevalence of congenital malformations appears to be considerably higher than those reported from other parts of China. In a study conducted in Inner Mongolia, China, for example, the prevalence rate of birth defects was 156.1 per 10000 births 95%CI: 146.3–165.8) . The Gan6.3–165.8There is much variability in the figures reported from different countries. According to Centers for Disease Control and Prevention, birth defects affect one in every 33 babies in the United States . Out of In the present study, cardiovascular system malformations were the most common (77.32 per 10000 live infants), which was at variance with the figures from other recent studies in China ,17. In KAbout two thirds of Chinese male adults are regular smokers, whereas few Chinese women smoke; therefore, women’s passive smoking is more pervasive . Among tIn the present study, maternal passive smoking during pregnancy showed a positive correlation with a higher burden of cardiovascular system, respiratory system and facial malformations among alive infants. Similarly, a significant positive association of maternal smoking with cardiovascular/heart defects ; facial defects ; eye defects  was reported by Hackshaw for . The speIn the current study, alcohol intake in pregnancy was positively associated with the increased burden of congenital malformations, especially those of nervous system, cardiovascular system and oral cleft. Previous studies have demonstrated that high intakes of alcohol adversely affects blood vessels in adults, and especially in pregnant women ,24. GreaWe also observed an association between tea or coffee consumption during pregnancy and the burden of congenital malformations of cardiovascular system and genital organs. The potential effects of caffeine, a natural alkaloid found in tea and coffee, has attracted much attention with regard to its possible effects on birth outcomes. Due to the progressive decrease in maternal caffeine clearance over the course of the pregnancy , caffeinThe multi-stage stratified random sampling methodology adopted for this study is a strength. Moreover, the sample closely matched the general population of Shaanxi province in terms of socio-demographic characteristics. Secondly, the inclusion of 29098 live infants makes our study one of the largest on this subject in Shaanxi province as well as in Northwest China. Thus, the present findings are likely to have a high degree of generalizability to the overall province.However, several limitations should be considered while interpreting our results. The cross-sectional nature of study precluded drawing any cause-effect relationship. Secondly, the information on lifestyles during pregnancy including alcohol intake, passive smoking, tea or coffee consumption were self-reported by mothers. Although recent studies have showed a high sensitivity for self-reported events in pregnancy, the self-reports tend to have low specificity in that some women may under-report ,31. TherThirdly, although the analysis was adjusted for a number of socio-demographic confounders, the influence of other unknown potential confounders such as maternal health status, dietary intake, reproductive history, family history and environmental risk exposure during pregnancy, etc. cannot be ruled out. Therefore, we cannot eliminate the possibility that at least some of the risk estimates in our study were slightly overestimated. This could have contributed to the significant risk estimates reflected in the wide confidence limits in our study.In summary, Shaanxi province of Northwest China appears to have a high burden of birth defects among alive infants. The socio-demographic characteristics had a significant linkage with maternal lifestyles during pregnancy. A substantial proportion of mothers appear to be exposed to passive smoking and its attendant ill effects. A significant increased burden for congenital malformations was observed in infants born to mothers with unhealthy lifestyles in pregnancy. Further investigations are required to understand the mechanisms underlying the impact of maternal lifestyles in pregnancy on the birth defects in the offspring.S1 Dataset(SAV)Click here for additional data file.


Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG. In-vitro and in-vivo studies using slice cultures and rodent models9101112Transcranial electric stimulation (TES) with weak currents is an emerging non-invasive technology for modulating brain function, with the goals of investigating causal influences in neural systems and of effecting beneficial changes in cognition and behavior245Studies focused on the interpretation of local field potentials have successfully measured the electric properties of brain tissues on a small spatial scale 16The goal of this study was to provide comprehensive measurements of the spatial and temporal variations in the properties of electric fields  generated using TES in a non-human primate (NHP) brain. Because our target was the intracranial electric field and the underlying biophysics, rather than the brain’s response to stimulation, we opted to streamline our approach by studying the subjects under anesthesia. The NHP model is ideally suited for such measurements due to the feasibility of strategically implanting stereotactic-EEG (s-EEG) electrodes in a manner that can sample a broad range of brain areas, the ability to perform repeated measurements, and the reasonable approximation of the brain and skull structures of nonhuman primates to those of humans. Complementing these NHP measurements, we capitalized on the availability of neurosurgical patients implanted with the same type of s-EEG electrodes. While the electrode placements were solely based on clinical considerations, the recordings nonetheless allowed us to evaluate how well specific aspects of our non-human primate findings generalize to humans. Although the present study was primarily motivated by the challenges faced by TES, our findings also have broad implications for our understanding of electric field propagation within the brain, and source localization based on EEG/MEG2, Ag/AgCl with conductive gel (SigmaGel)) were used in all sessions and transcranial electrical stimulation was applied using the Starstim system . The position of stimulation electrodes was chosen over the left occipital cortex and middle forehead to create electric fields with a large component along the direction of the implanted electrode arrays. The current output of the stimulator was tested with a linear ohmic resistor and a minimal decrease for high frequencies was corrected for in results  to ensure a similar voltage range, through two electrodes  for 30 s for at each frequency. Intensities were chosen to achieve a high signal to noise ratio while keeping within the dynamic range of the amplifier, as well as to reduce strain on the monkeys for extended measurement sessions. Each measurement series was repeated once immediately following the first series.All procedures were approved by the IACUC of the Nathan Kline Institute for Psychiatric Research. Recordings were carried out in accordance with the approved guidelines. Two Cebus monkeys  were implanted with MRI-compatible (Cilux) headposts. In the first monkey three electrodes (Adtech) with a total of 32 contacts (5 mm spacing) were permanently implanted through a skull incision over the left occipital cortex. In the second monkey, the same three electrodes were similarly implanted, along with an additional 10-contact array. Recording electrodes were oriented from posterior to anterior with medial prefrontal cortex, frontal eye field and hippocampus as target regions. In the second monkey the additional electrode targeted the geniculate complex of the thalamus. Exact electrode positions were identified on a post-implantation MR image and registered to the pre-implantation image. In multiple sessions, s-EEG was recorded during TES using a Brain AMP MR amplifier  with a sampling rate of 500 Hz. The frequency-magnitude response of the EEG system was tested using a function generator and a linear ohmic resistor to derive a correction factor for a slight dampening at higher frequencies see . Ground ults see . To inve2) were attached to the scalp over the left and right temple  and a 1 Hz alternating current of 1 mA was applied in one run (using Starstim) for 2 min with a ramp up/down of 10 s. Electrode locations were chosen in close proximity to areas with good coverage by recording electrodes. Electrode impedance was kept below 10 kOhm during the recordings. Patients were instructed to rest during tACS application. As would be expected, patients reported mild skin sensations during the application of tACS.Two patients  with refractory epilepsy participated in the study while undergoing presurgical monitoring at North Shore University Hospital. All experimental protocols were approved by the Institutional Review Board of the North Shore University Hospital. All recordings were carried out in accordance with the approved guidelines. Both patients provided informed consent as monitored by the local Institutional Review Board and in accordance with the ethical standards of the Declaration of Helsinki. One patient was implanted with bilateral s-EEG electrodes  and one patient with left subdural grid, strip, and depth electrodes (Integra Lifesciences Corp.), with the number and placement of electrodes determined solely by clinical requirements. The reference electrode was placed at midline between skull and scalp for both patients. Electrode positions were identified on post-implantation CT scanData analysis was identical for patient and monkey recordings. First, we subtracted from each channel its mean voltage over a time interval of 1 s right before stimulation onset to correct for possible baseline differences between channels unrelated to stimulation. An example of the baseline correction is shown in In a second analysis we estimated the electric field strength during TES. For that we calculated the numerical gradient using the symmetric difference quotient (using a simple two point estimation leads to similar results) of the potential at its peak up-phase along the contacts for each implanted electrode. For the patient with grid electrodes, we computed the gradient along both grid axes and combined them using vector addition. All values for the potential and electric field strength were scaled to a stimulation current of 1 mA and mean and standard error of the mean were computed over five stimulation cycles. Note that with this method we can only estimate the electric field component along the measurement (electrode) vectors (projection of the electric field). While we tried to use montages that resulted in electric fields with a large component along the electrode directions, the strength of the “true” electric field is likely somewhat larger than the measured field. In addition to field strength, we estimated the spatial extent of intracranial electric fields. First, we identified those electrode contacts that exhibited electric field strengths larger than 50% or 25% of the maximum recorded field strength; this was carried out separately for each implanted linear electrode array or ECoG grid. Then, for each electrode array, we computed the maximum distance between those contacts that met the cutoff criteria.Based on the pre-implantation MR images, we reconstructed the cortical surfaces to visualize the experimental recordings in a 3D model for both monkeys and patients. An overview of the implanted electrodes and the covered brain regions for the monkeys and patients can be found in r(19) = −0.98, p < 0.001 and r(19) = −0.94, p < 0.001 between frequency and magnitude were found for monkeys 1 and 2, respectively. Compared to the magnitude at 1 Hz decreases of 0.5% and 5% were found at 10 Hz and 100 Hz respectively based on a linear fit (r(19) = 0.87, p < 0.001 and r(19) = 0.98, p < 0.001 were found for monkeys 1 and 2. Phase differences in the patients (not shown) were generally in the same small range as in the monkeys. For the scalp electrodes we observed the same mild frequency dependence of the FFT magnitude, and again, we observed only small phase shifts from the scalp electrodes to the intracranial electrodes. The lack of a phase difference between scalp and intracortical measurements suggests that the passage of current through the skull does not introduce appreciable phase shifts.The analysis of the frequency response function indicated that the mean potential magnitude decreases as a function of stimulation frequency , with a near fit  of the mnear fit , indicatS-EEG recordings revealed potential distributions with continuously varying gradients between the stimulation electrodes both in monkeys and humans  and 4, hMaximum electric strengths were found to be 0.358 +/− 0.001 mV/mm for the first monkey (median electric field 0.21 mV/mm) and 1.173 +/− 0.003 mV/mm for the second monkey (median electric field 0.39 mV/mm). The first monkey was a male with a much larger muscle mass overlaying the skull than the second, a female monkey, highlighting the fact that individual anatomical factors result in different electric field strengths. Maximum electric field strengths for the patients were found to be 0.360 +/− 0.008 mV/mm (Patient 1) (median electric field 0.098 mV/mm), 0.163 +/− 0.007 mV/mm (Patient 2) (median electric field 0.059 mV/mm).We evaluated the spatial extent of electric fields (larger than 50% or 25% of the maximum electric field) as follows: Monkey 1: 90 mm (50% of Max) and 110 mm (25% of Max), Monkey 2: 20 mm and 60 mm. Patient 1: 39.6 mm and 45.7 mm, Patient 2: 47 mm and 74.6 mm. The differences in spatial extent observed across cases were predictable given that the electrodes were not placed in the same locations or orientations. However, the findings for the monkey are more notable, as their placement was relatively similar in the two subjects. This again suggests that other factors, such as head size, muscle tissue thickness or skull integrity may contribute to inter-individual differences in field properties.in-vivo with a “4-electrode setup” (two separate stimulation and recording electrodes) minimizing capacitive effects at the electrode-electrolyte interface of the recording electrodes. In line with our results, small phase differences were also reported in Logothetis, Kayser and Oeltermann2531Comprehensive evaluation of the intracranial electric field during TES in nonhuman primates and human neurosurgical patients provided empirical support for common assumptions about the electric properties of the head tissue2326272930Our measurements also have direct implications for interpretation of the EEG signal based on the reciprocity theorem33in-vitro studies13in-vitro and animal studies can be applied to human studies due to the limited field strength induced in human brains. Future efforts could be made to induce higher electric field strengths in a non-painful and safe manner; e.g., using kHz currents as a carrier frequency for low frequency oscillations. Input currents used in human studies could be matched to achieve electric field strengths shown to be effective in in-vitro settings. We found substantial inter-individual differences in electric field strength which might underlie some of the variability in response between participants to TES39Our results show that maximum electric fields in humans reach up to 0.5 mV/mm for 1 mA stimulation currents which is in the range predicted by modeling studies36How to cite this article: Opitz, A. et al. Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates. Sci. Rep.6, 31236; doi: 10.1038/srep31236 (2016).


Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.Please see later in the article for the Editors' Summary Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% , adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% . Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% . But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.We included 13,124 live births between 1994 and 2010, among which, 42% , a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir ; and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.http://dx.doi.org/10.1371/journal.pmed.1001635.Please access these websites via the online version of this summary at PLOS MedicinePerspective by Mofenson and WattsThis study is further discussed in a mother-to-child transmission of HIVThe World Health Organization has a webpage on links to additional information on mother-to-child transmission of HIVThe US National Institutes of Health provides mother-to-child transmissionThe Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on French Perinatal Cohort has a webpage describing the cohort and its main publications The  In France and other industrialized countries, the use of antiretroviral therapy (ART) during pregnancy has led to a spectacular decrease of the mother-to-child transmission rate of HIV-1, from about 20% down to about 1% currently p = 0.02) The risk of birth defects associated with ART has been investigated following an animal study suggesting a teratogenic effect in monkeys exposed in utero to efavirenz The diversity of the results may be due to differences between populations and the variety of follow-up protocols that determine how birth defects are diagnosed . MoreoveOur objective was to estimate the prevalence of birth defects in children exposed in utero to ARV drugs taken by their mothers during pregnancy in the large national prospective French Perinatal Cohort (EPF) , and to assess the association of specific birth defects with each in utero ARV drug, taking several known risk factors into account.The study was approved by the Hôpital Cochin Institutional Review Board and the French computer database watchdog commission .Since 1986, EPF has prospectively enrolled pregnant HIV-infected women delivering in 90 centers throughout France n = 13,124)  . The smaAll clinical events in infants were recorded at each visit . We first coded the birth defects with International Classification of Diseases (ICD-10) codes. We then used EUROCAT inclusion criteria and guidelines in order to assess the overall prevalence of anomalies and to classify them in different organ systems Maternal variables included age, geographical origin, intravenous drug use (IDU), gravidity, parity, CD4 cell count, and HIV-1 viral load closest to the delivery, i.e., the day of delivery or in the 7 d after delivery. Alcohol and tobacco use were recorded only after 2005, and data on concomitant medications were not available in the cohort.All ART combinations administered during pregnancy were recorded, with the dates when started and stopped. For each drug , exposure status was categorized as follows: (1) unexposed to the index drug, but exposed to other drugs (control group), (2) exposed to the index drug since conception or the first trimester, or (3) exposed to the index drug only since the second or third trimester. Another categorization was used in sensitivity analyses concerning only first-trimester exposure: (1) unexposed to any ART in the first trimester, i.e., ART was initiated during second or third trimester (control group), (2) exposed to the index drug in the first trimester, (3) exposed to another drug in the first trimester of pregnancy. Since 1994, the standard of care changed from zidovudine monotherapy (1994–1996), to dual nucleoside reverse transcriptase inhibitors (NRTIs) (1997–1999), to triple-combination drug regimens . We tested 18 ARV drugs for the analysis on overall birth defects and three combinations of drugs: any NRTI, any non-nucleoside reverse transcriptase inhibitor (NNRTI), and any protease inhibitor (PI).Neonatal variables used in the analysis included gender, gestational age, birth weight, and HIV infection status.2 test and Fisher's exact test, as appropriate.The prevalence of birth defects was estimated and compared according to various maternal and neonatal characteristics, using the χWe first studied associations between overall birth defects and each ARV drug using univariate and multivariate logistic regression. Multivariate models included IDU, geographical origin, maternal age, and maternity center. These variables were selected because they were used in the literature and were available for the whole study period. Year of birth was not included in the main analyses because of collinearity with prevention of mother-to-child transmission (PMTCT) strategies; however, it was adjusted for in sensitivity analyses. Alcohol and tobacco use could not be included as adjustment variables because they were not available for the whole study period.p≤0.20 in previous multivariate analysis . In order to evaluate the independent effects of drugs often used in combinations, such as zidovudine with lamivudine, we also adjusted for all drugs found to be associated with the type of birth defect under consideration, with a univariate p≤0.10, in either the EUROCAT or the MACDP classification.We then studied specific associations between birth defects by organ system and (1) efavirenz, zidovudine, didanosine, and nelfinavir, on the basis of prior studies, and (2) any other ARV drugs associated with overall birth defects at For each drug considered, the primary analysis compared neonates exposed in the first trimester and those exposed during the second or third trimester with neonates not exposed to the drug during the whole pregnancy (control group). Women with missing data for any adjustment variables were excluded from multivariate analysis, since they did not exceed 2% of the study population for each variable. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study.Several sensitivity analyses were conducted: (1) exclusion of IDU, (2) inclusion of TOPs and stillbirths, (3) not considering birth defects diagnosed beyond the first week or 6 mo postnatally, (4) using alternative categories for ART exposure status (unexposed to any ART in the first trimester as control group), (5) excluding infants exposed to more than one combination of ART during pregnancy, (6) using more or less parsimonious multivariate models and, particularly, including year of birth, CD4 cell count, or maternal viral load closest to delivery as adjustment variables.p<0.05 was taken as indicating statistical significance. Data were analyzed using Stata 11.0 software (Stata Corp) A two-sided For each ARV drug, we calculated the power to detect an association between overall birth defects and first-trimester exposure (compared with no exposure during pregnancy). Power to show an odds ratio (OR) of 1.5 was >85% for zidovudine, lamivudine, ritonavir, and lopinavir, and was >70% for didanosine, stavudine, abacavir, tenofovir, and nevirapine  were exposed to ART in the first trimester of pregnancy. PMTCT strategies varied over time, and the proportion of infants exposed to ART in the first trimester increased from 19% in 1994–1996 to 52% in 2005–2010. The evolution in time of types of treatment and trimesters of exposure are presented in The analysis was conducted in 13,124 live-born children, born between 1 January 1994 and 31 December 2010, among whom 42% , according to the EUROCAT classification and 7.0% (95% CI 6.5%–7.4%)  according to the MACDP classification. The rate increased from 1994–1996 to 1997–1999 and then decreased slightly afterwards. The presence of a birth defect was significantly associated with male gender and higher maternal age. Neonates with birth defects were more frequently born by cesarean section, preterm, and with low birth weight  , as well as with didanosine , lamivudine  and indinavir  (p = 0.01) and any kind of NNRTI   ; Table 2 = 0.03) . These an = 20/372, AOR = 1.16 [95% CI 0.73–1.85], p = 0.70)  (p = 0.16). The four neurological defects, according to MACDP, reported in children exposed to efavirenz in the first trimester were ventricular dilatation with anomalies of the white substance, partial agenesis of the corpus callosum, subependymal cyst, and pachygyria. Congenital infection or associated non-neurological defects were not reported for these four children. Efavirenz was not associated with other birth defects.Exposure to efavirenz during the first trimester was not found to be associated with birth defects overall in the EUROCAT classification  ; Table 2 +1.3%]) . This asp = 0.003) , but four of them were also exposed to zidovudine during the first trimester. The association between zidovudine and heart defects remained the same when (1) limited to diagnoses made in the first 6 mo or in the first week of life, or to infants exposed to only one combination of ART during pregnancy, (2) adjusted for prematurity, parity, CD4 count, year of birth, and gender , (3) using alternate categorization for zidovudine exposure , (4) using the MACDP classification (p = 0.23). Among the 74 children with a diagnosis of CHD and exposed to zidovudine during the first trimester, the most frequent heart defects were ventricular septal defects (n = 43), atrial septal defects (n = 13), and persistence of the ductus arteriosus (n = 9). We found no significant association between heart defects and any of the other ARV drugs included in the multivariate model, which were lamivudine, zalcitabine, emtricitabine, and indinavir. No interaction was found between zidovudine and lamivudine.Exposure to zidovudine during the first trimester was associated with CHDs according to the EUROCAT classification  . The absfication , and (5)n = 5/927, for first-trimester exposure versus 0.2%, n = 18/11,651, in the unexposed group, AOR = 3.4 [95% CI 1.1–10.4], p = 0.04) and with indinavir   . DidanosThe association between birth defect by organ system and each ARV drug is described in The prevalence of birth defects in our study population was 4.4% as assessed using the EUROCAT guidelines and 7% using the MACDP classification. This is higher than the rates reported in most large studies including patients exposed to ARV drugs, which were 1.5% in the European Collaborative Study, published in 2005 and thus including different drugs than those used in more recent studies An important result is that no association was found between birth defects and lopinavir or ritonavir with a power >80% for an OR of 1.5, and for tenofovir, nevirapine, and abacavir with a power >70%. For all these drugs, the power was >95% for an OR of 2. This result is very reassuring in view of the fact that several of these ARV drugs are currently being increasingly used.We found a specific association between exposure to zidovudine during the first trimester and CHDs, for both classifications. It persisted after adjusting for potential confounding variables, including other ARV drugs, and in all sensitivity analyses, including adjustment for year of birth. The association with heart defects was of a larger magnitude than that with birth defects overall, and no association was found between zidovudine and other types of defects, suggesting a specific association. We found the same risk factors  for heart defects as in general population p = 0.13) because this classification excluded a case with a subependymal cyst. The neurological defect rate among children exposed to efavirenz in the first trimester was 1.1%. There has been concern about a teratogenic effect because a preclinical study found three birth defects among 20 monkeys exposed to efavirenz We found a significant association between exposure to efavirenz during the first trimester and neurological defects, using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5). This association did not reach significance using the EUROCAT classification .Finally, a significant association was found between indinavir and head and neck defects. Birth defects associated with PIs have been less studied, because the placental transfer is low. Nevertheless, an increased risk of birth defects was reported in rats exposed to indinavir p<0.001) among live births, with the same classification (EUROCAT) and during the same period. However, interpretation of this difference is difficult and cannot be attributed solely to treatments and/or HIV infection, because of the longer follow-up of children in our cohort and because of potential confounding factors and regional disparities. The rate of birth defects in our cohort changed over time, with an increase between 1994 and 1996, and a slight decrease afterwards. This decrease is unlikely to be due solely to changes in the general population, since the trend in the birth defect rate among live births in the Paris registry was a regular decrease from 2.4% in 1994–1996 to 2.1% in 2005–2009. We chose not to include time period in the main analysis because of collinearity with PMTCT strategies. However, when included in sensitivity analyses, adjustment for year of birth did not change the association between zidovudine and heart defects.There is no nationwide description of the birth defect rate in the French general population, but there are exhaustive regional registries. The birth defect rate observed in our study was higher than in the Paris Birth Defect Registry Our study presents many strengths. To our knowledge, it is the largest national cohort of live births among HIV-infected women, with homogeneous prenatal and postnatal follow-up via standardized questionnaires, and thus has higher power than most studies to date, which is reassuring for drugs found to be not associated with birth defects. Women were included prospectively during pregnancy, before any detection of birth defects. Clinical examinations of children were performed during the first 2 y of life, such that it is unlikely that many birth defects were missed. We used the EUROCAT classification, which excludes most minor anomalies and contains very few decision trees, minimizing the need for additional details for classification, which seems to make it more reproducible. We also used the APR-modified MACDP classification in secondary analyses to facilitate comparisons with previous studies. We studied birth defects by organ system, which is a more specific approach than considering the overall incidence of birth defects. Indeed, teratogenic agents generally affect particular developmental pathways and not several pathways randomly. Therefore, although the number of defects per organ system is lower than the total number of defects, the power for finding an association can be higher. Finally, many characteristics of the mother and neonate were available for adjustment for potential confounders.Our study also presents some limitations. Gestational age at inclusion varied over time, and early TOPs were not captured before 2005. We then decided to exclude stillbirths and TOPs from the main analysis. The reasons were to avoid false associations of major defects with drugs prescribed more often in recent years, and to limit underestimation of major defects likely to be detected earlier in pregnancy for efavirenz than for other drugs. In sensitivity analyses including TOPs and stillbirths, as expected, the association remained unchanged for zidovudine with CHDs, but decreased for efavirenz with neurological defects. We also excluded the small group of women not treated with ART, as relevant variables to adjust for this very precarious situation were not available in the EPF study. Another concern is the risk of false positive associations due to multiple testing. We chose not to perform adjustments for multiple testing because such an approach is questionable for exploratory studies such as this from a methodological standpoint Another limitation, common to most studies of birth defects and ART, is the lack of data on concomitant medication and alcohol and tobacco use, which in the case of the current study were not available for the whole study period. Cotrimoxazole use was indirectly accounted for by adjusting for CD4 cell counts in sensitivity analyses. Exposure to tobacco and alcohol during pregnancy was reported by 5% and 1.9% of women, respectively, between 2005 and 2010. Whatever their impact on birth defects, these factors were unlikely to be related to the prescription of any particular ARV drug, and thus should not bias the results.In conclusion, we found a higher rate of CHDs in children exposed in utero to zidovudine, which should be taken into consideration, given the large number of children exposed to perinatal zidovudine in the world. Potential mechanisms underlying this association must be investigated. This alert reinforces recent recommendations for PMTCT, which no longer consider zidovudine to be the first-line ART during pregnancy