Bronchogenic cysts arise from abnormal buds from the primitive esophagus and tracheobronchial tree, which do not extend to the site where alveolar differentiation occurs. Bronchogenic cysts are typically unilocular mucus field lesions arising from posterior membranous wall of the air way. The prenatal diagnosis usually is realized by two-dimensional ultrasound showing the large unilocular cystic image in the chest fetus. The prenatal percutaneous aspiration can reduce the risk of heart compression and permit better respiratory conditions to newborn. We present a case of a primiparous pregnant 23 year-old-woman prenatal ultrasound showed a large unilocular cyst in the left hemithorax with compression of the normal left lung tissue and contralateral mediastinal shift. This cyst was percutaneously aspirated without subsequent reaccumulation of fluid. The newborn did not have respiratory distress and the computed tomography scan confirmed the finding of a fluid-filled cyst in the left chest. The chest X-ray showed the displacement of the heart and the mediastinum from the left to the right. The prenatal diagnosis of bronchogenic cyst is very important to assess the degree of the compression of the normal lung and the mediastinum shift. Furthermore, the prenatal diagnosis permits planning delivery in the tertiary hospital with multidisciplinary team because of the risk of respiratory distress. Bronchogenic cysts arise from abnormal buds from the primitive esophagus and tracheobronchial tree, which do not extend to the site where alveolar differentiation occurs. If this separation occurs early, the system migrates into mediastinum. If it occurs late, it forms an intrapulmonary bronchogenic cyst. Bronchogenic cyst accounts for 20–30% of congenital bronchopulmonary foregut cystic malformation .Bronchogenic cysts are typically unilocular mucus field lesions arising from posterior membranous wall of the air way. The cyst wall has structural elements of the air way including cartilage, smooth muscle, mucous glands, and respiratory epithelium. Malignancies have been reported in these lesions .in utero as an anechoic unilocular intrathoracic cyst and is usually located in the central area of parenchyma [The appearance of bronchogenic duplication cysts has been described renchyma . HoweverWe present a case of prenatal diagnosis of a large bronchogenic cyst by ultrasound confirmed in neonatal period by computed tomography (CT) and the chest X-ray finding.A primiparous pregnant 23-year-old-woman was referred to our service because of suspicion of fetal malformation. A fetus was found to have a large left thoracic cyst on routine prenatal ultrasound at 23 weeks of gestation . This lein utero, resulting in a better understanding of the natural history of many of these lesions and also allowing provision to be made for delivery and postnatal management [Congenital cystic lung lesions are a rare but clinically significant group of anomalies, including CCAM, pulmonary sequestration, congenital lobar emphysema (CLE), and bronchogenic cysts. These conditions can all present on imaging studies as air or fluid-filled cysts. Widespread use of antenatal ultrasound has led to increased detection of infants with congenital thoracic abnormalities nagement . ex utero intrapartum treatment (EXIT) including placement onto extracorporeal membrane oxygenation therapy while the fetus was still under placental perfusion and resection of the obstructing lesion followed by airway reconstruction performed during the first hours of life. In our case, the signals of a good prognosis were the absence of compression of the heart and hydrops. The prenatal diagnosis of bronchogenic cyst is very important because, depending on the size, the cyst can compress the normal lung parenchyma causing pulmonary hypoplasia or compress the heart causing hydrops and fetal death . Levine The main prenatal ultrasonography presentation of bronchogenic cyst is an anechoic image as in our case. However, Lecomte et al. , in a loThe bronchogenic cysts are usually treated by thoracotomy and excision of the cyst. In case of intraparenchymal bronchogenic cysts wedge resection, segmental resection, or lobectomy may be required. The long-term outcome for infants and children with bronchogenic cysts is excellent because they generally do not require sacrifice of significant normal lung parenchyma . In our In summary, we present a case of prenatal diagnosis of bronchogenic cyst confirmed in the postnatal period by CT. The antenatal diagnosis is of great importance to plan the prenatal care and the labor because many neonates can develop respiratory distress, requiring a multiprofessional team.


Objective. To evaluate the rate of preterm birth and low birth weight in the newborns of pregnant women with early and late onset pre-eclampsia according to folic acid supplementation. Study design. Birth outcomes of newborns were evaluated in 1,017 (2.7%) pregnant women with medically recorded pre-eclampsia and 37,134 pregnant women without pre-eclampsia as reference in the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980–1996, in addition these study groups were differentiated according to the supplementation of high dose of folic acid alone from early pregnancy. Results. Pregnant women with pre-eclampsia associated with a higher rate of preterm birth (10.2% versus 9.1%) and low birthweight (7.9% versus 5.6%). There was a lower risk of preterm birth (6.8%) of newborn infants born to pregnant women with early onset pre-eclampsia after folic acid supplementation from early pregnancy though the rate of low birthweight was not reduced significantly. There was no significant reduction in the rate of preterm birth and low birthweight in pregnant women with late onset pre-eclampsia after folic acid supplementation. Conclusion. The rate of preterm birth in pregnant women with early onset pre-eclampsia was reduced moderately by high doses of folic acid supplementation from early pregnancy. Pre-eclampsia (PE) is frequent (2–8%) and severe complications of pregnancy, and this multisystem disorder of pregnancy is characterized by pregnancy-induced hypertension and new-onset proteinuria during the second half of pregnancy –3. PE isTwo important hypotheses have been generated for the pathogenesis of PE during the last decades. The first hypothesis was based on the differentiation of early and late onset PE  or on thThe first objective of our study was to evaluate the birth outcomes of pregnant women with early and late onset PE, while the second aim was to check the effect of folic acid supplementation for the risk of preterm birth and low birth weight in their newborn infants in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) .The HCCSCA is based on the comparison of exposures studied during the pregnancy of mothers of cases with different congenital abnormalities and the mothers of controls without any defect matched to the cases. Cases with congenital abnormalities are selected from the Hungarian Congenital Abnormality Registry  for the Cases were excluded from this analysis because congenital abnormalities may have a more robust effect for birth outcomes than PE. Thus only 38,151 control newborns without any defect of the HCCSCA, 1980–1996, were evaluated in this study. Immediately after the selection of newborns an explanatory letter was sent to the mothers, and they were asked to send us the prenatal maternity logbook and all other medical records regarding the study pregnancy; these documents were sent back after three weeks. Prenatal care was mandatory for pregnant women in Hungary , thus nearly 100% of pregnant women visited prenatal care clinics, an average 7 times in their pregnancies. The first visit was between the 6th and 12th gestational week. The task of obstetricians was to record all pregnancy complications, including PE, maternal diseases, and related drug prescriptions in the prenatal maternity logbook. On the other hand, a structured questionnaire, a list of medicines (drugs and pregnancy supplements), and a printed informed consent form were also mailed to the mothers. The questionnaire requested information on maternal personal  and medical data including pregnancy complications, maternal diseases, and medicine intakes during the study pregnancy according to gestational month. In order to standardize the answers, mothers were asked to read the enclosed lists as a memory aid before they replied and to send back the filled-in questionnaire and informed consent form with their signature in our prepaid envelop.+ 2.9 months. The interval between the end of pregnancy and return of the “information package” including prenatal maternity logbook, questionnaire, and so forth, was 5.2 In addition, 200 nonrespondent and 600 respondent mothers were visited at home by regional nurses as part of two validation studies , 25 becaOverall the necessary information was available on 83.0% of pregnant women (81.3% from reply and 1.7% from home visit). Here the 17 years' data of the HCCSCA between 1980 and 1996 are evaluated because the data collection has been changed since 1997 , and the recent data had not been validated at the time of the analysis. Four types of hypertension in pregnant women were classified: (i) chronic hypertension, (ii) PE, (iii) PE superimposed upon chronic hypertension, and (iv) gestational hypertension , 2, 26. Blood pressure and proteinuria were measured in pregnant women at their visits in the prenatal care clinics. If a new-onset proteinuria was found by the help of dipstick screening test after the 20th gestational week, pregnant women were referred to a detailed laboratory examination (more than 300 mg in 24 h was accepted as proteinuria). PE was diagnosed in pregnant women if they had new onset hypertension and proteinuria. Of course, pregnant women with secondary hypertension were also excluded from the study. The preliminary analysis of data showed that the diagnosis of PE in the questionnaire based on retrospective maternal information was not reliable; therefore, we decided to evaluate only medically recorded PE in the prenatal maternity logbook. There is no consensus in the classification of early and late onset PE, SOGC  and ASH Other pregnancy complications, PE-related drug treatments and other potential confounding factors such as maternal age, birth order, marital and employment status as indicators of socioeconomic status , other mOnly one type of 3 mg folic acid  tablet was available in Hungary during the study period. Gestational age was calculated from the first day of the last menstrual period. Both birth weight and gestational age at delivery were medically documented in the discharge summary of mothers because all deliveries took place in inpatient obstetric clinics. The rate of low (less than 2500 gram) and large (4000 gram or more) birth weight, in addition to the rate of preterm  and postterm (42 completed weeks or 294 days or more) birth was calculated. reference group including all pregnant women without PE. Contingency tables were prepared for the main study variables. First, the characteristics of pregnant women with different study groups were compared with the reference group using chi-square test for categorical variables and Student t-test for quantitative variables. Second, frequency of maternal diseases, pregnancy complications, and related drug treatments was compared between mothers with PE and the reference group by ordinary logistic regression models and odds ratios (OR) with their 95% confidence intervals (CI) being evaluated. Third, the birth outcomes of newborns were evaluated in mothers with PE compared with the reference group using adjusted Student t-test and OR with 95% CI using ordinary logistic regression model. Finally birth outcomes of newborns in pregnant women with PE were stratified according to folic acid supplementation. We used SAS version 8.02  for statistical analyses. The occurrence of folic acid use was compared in pregnant women with PE and the The total number of births in Hungary was 2,146,574 during the study period, thus 38,151 controls represented 1.8% of all Hungarian births. Of these 38,151 newborns, 1,017 (2.7%) had mothers with medically recorded PE in the prenatal maternity logbook. Of these 1,017 pregnant women with PE, 45 (4.4%) had later eclampsia while HELLP was not recorded. Only 580 (57.0%) women out of total 1,017 who were diagnosed as PE had recorded history of taking folic acid supplementation, while this figure was 54.4%  in the reference group, thus pregnant women with PE used somewhat more frequently folic acid. The indication of folic acid supplementation was the prevention of neural tube defects. The distribution of daily folic acid supplementation was the following: 22.5%, 68.6%, and 8.9% of pregnant women used one (3 mg), two (6 mg), and three (9 mg) tablets, respectively. Thus the estimated mean daily dose was 5.6 mg. The onset of folic acid supplementation was in about 10% of pregnant women before conception; however, most women started folic acid use after the first visit in the prenatal care clinic, that is, between the 6th and 12th gestational weeks, thus before the onset of PE. Practically all pregnant women continued folic acid supplementation until the end of pregnancy. Of 580 pregnant women with PE and folic acid use, 440 (75.9%) had medically recorded folic acid use in the prenatal maternity logbook while this figure was 61.3% in the reference group. Our validation study showed that maternal information regarding folic acid use was correct, but some women retrospectively forgot to mention it. Folic acid containing multivitamins was used rarely and it contained different low doses of folic acid, thus these pregnant women were excluded from the study. Maternal characteristics are shown in Acute and chronic maternal diseases did not show significant differences between pregnant women with PE and the reference sample. Among other pregnancy complications, threatened abortion (20.8% versus 17.0%) and placental disorders (2.2% versus 1.5%), particularly abruption placentae occurred more frequently in pregnant women with PE than in pregnant women without PE.Practically all pregnant women with PE were treated with antihypertensive drugs, most frequently nifedipine (15.1% versus 2.2%) and methyldopa (10.5% versus 0.9%) compared with pregnant women without PE. Dihydralazine, metoprolol, clopamide, and furosemide were also more frequently used by pregnant women with PE. However, magnesium sulphate was used only in two pregnant women with PE.The diagnosis of PE according to gestational months is shown in The birth outcomes of newborn infants born to pregnant women with PE and without PE as reference are shown in the lower part of In the next step, newborns were evaluated according to gestational age and birth weight groups in pregnant women with PE and without PE as reference. A characteristic U-shaped curve was shown; the previously mentioned higher rate of preterm birth and low birth weight associated with a higher rate of postterm birth  and large birth weight . However, these differences reached the level of significance only in low and large birth weight, and the mean birth weight was higher both in term and the postterm births.The gestational age at delivery and birth weight were moderately modified by folic acid supplementation from the early pregnancy . The meaHowever, the effect of folic acid increased the rate of postterm birth (11.9% versus 11.2%) with smaller mean birth weight and the rate of large birth weight (11.6% versus 10.9%) with shorter mean gestational age , though The birth outcomes were evaluated according to the onset of PE . There wFinally the effect of folic acid for birth outcomes was evaluated in pregnant women with early (IV–VI months) and late (VII–IX months) onset PE in the study . Folic aThe primary aim of the study was to evaluate birth outcomes of pregnant women with early  and late  PE. The risk of adverse birth outcomes cannot be differentiated according to early and late onset PE defined in our study, because the onset between sixth and eighth gestational months associated with a higher risk of preterm birth and low birth weight. The secondary aim of the study was to estimate the possible effect of folic acid for the risk of preterm birth and low birth weight of their newborns. On one hand, the high dose of folic acid used in early pregnancy reduced the rate of preterm birth but not modified significantly the higher rate of low birth weight, that is, intrauterine growth retardation in pregnant women with early PE. On the other hand, this preventive effect of folic acid was not observed in pregnant women with late PE; in fact, there was somewhat but not significantly higher rate of preterm birth and low birth weight in pregnant women with late PE after folic acid supplementation.The prevalence of PE was 2.7% in pregnant women without PE superimposed upon chronic hypertension. Eclampsia is defined as the occurrence of tonic-clonic seizures in pregnant women with PE, and recently eclampsia has manifested only in 1-2% of women with severe PE . HoweverThe primary goal is to prevent the manifestation of PE with maternal complications; however, a reasonable secondary goal is to reduce the adverse birth outcomes of pregnant women with PE. The rate of preterm births (10.2% versus 9.1%) and mainly of low birth weight (7.9% versus 5.6%) was higher in the newborns of pregnant women with PE than in the newborns of pregnant women without PE, though these figures were lower than rates found in previous studies , 33. TheThe use of folic acid modified these findings; the mean gestational age was somewhat longer with a lower rate of preterm birth. Similar beneficial effect was not found in the rate of low birth weight newborns. However, an important observation of our study is that the beneficial effect of high dose of folic acid use from early pregnancy occurred only in pregnant women with early  onset PE. Our previous study showed that the high dose of folic acid during pregnancy associated with a minor increase of birth weight but a longer gestational age at delivery and significant reduction in the rate of preterm birth . In thisThe major expected benefit of antihypertensive therapy is the reduction of hypertension of pregnant women with PE  to reducOur study confirmed the role of nulliparity  and the The strengths of the HCCSCA are that it is a population-based large data set including 1,017 pregnant women with prospectively and medically recorded PE in an ethnically homogeneous European (Caucasian) population. We were able to differentiate PE from the other types of hypertension in pregnant women. Additional strengths are medically recorded other pregnancy complications and birth outcomes, in addition to the available data of potential confounders. However, this data set also has limitations. (i) Other pregnancy outcomes, for example, miscarriages were not known in the study pregnancy. (ii) Lifestyle factors could not be evaluated in the total data set due to the unreliability of maternal self-reported data , though In conclusion, a higher risk of preterm births and mainly low birth weight was found in the newborns of pregnant women with PE. The use of high dose of folic acid from early pregnancy resulted in a reduction of preterm birth in pregnant women with early onset PE; however, similar beneficial effect was not found in the rate of low birth weight and in pregnant women with late onset PE. The clinical importance of these statistically significant changes is necessary to be validated in well-controlled prospective studies.


Low birth weight (LBW) is a major public health problem in many developing countries, especially so in India. Although we do not know all the causes of LBW, maternal and environmental factors appear to be significant risk factors in its occurrence.To know the factors affecting the birth weight of a newborn and to estimate the prevalence of LBW.st June 2008 to 31st December 2009.The present study was carried out amongst 1138 pregnant women and their newborns residing in area covered by Kinaye Primary Health Centre in rural Karnataka, India. The study was conducted from 1The mean birth weight of newborns was 2.6 kg with a range of 1.2 to 3.8 kg. The prevalence of LBW was 22.9%. Among the studied risk factors, 25 of them were significantly associated with the birth weight of a newborn on univariate logistic regression analysis. Maternal education [Odds Ratio (OR) 3.2], exposure to passive smoking [OR 2.3], age at first pregnancy ≥25 years [OR 3.6], birth interval <2 years [OR 2.4], previous history of LBW baby [OR 3.3], weight gain ≤4 kg during pregnancy [OR 7.0], maternal weight at last week of gestation ≤45 kg [OR 2.3], pregnancy induced hypertension [OR 3.3], high risk pregnancy [OR 3.6] and late antenatal registration [OR 3.6] emerged as significant risk factors on multivariate analysis.The problem of LBW is multidimensional, and hence, we need an integrated approach incorporating medical, social, economical and educational measures to address this issue. Intrauterine growth and development is one of the most vulnerable process in human lifecycle and its aberrations can result in lasting profound influence in later life. In the context of developing countries, intrauterine growth has been invariably assessed by birth weight. The birth weight of an infant is a reliable index of intrauterine growth and also a sensitive predictor of newborn’s chances of survival, growth and long term physical and psychosocial development. With the availability of fairly accurate infant weighing devices all over the world, birth weight and its determinants have come under intense global scrutiny. As a result, it is now acknowledged that many factors can influence the duration of gestation or the rate of intra-uterine growth.rd of all infant deaths occur in babies with LBW Low birth weight (LBW) has been defined as a birth weight of less than 2.5 kg regardless of gestational age Majority of studies done in India on determinants of LBW are hospital based. Data from hospitals is generally associated with a certain degree of uncertainty and bias. Those which are rural based studies most of them were done in an antenatal clinics situated at Rural Health Training Centres or record based. Hence, this study was undertaken in a rural community to know the risk factors for birth weight of a newborn. Each study has assessed only few or groups of risk factors that might influence the duration of gestation or intrauterine growth. The present study has taken into consideration all the risk factors and highlightened important independent factors of LBW through multiple regression analysis adjusting for gestational age.2, where n = sample size, p = prevalence of history of low birth weight = 26%, q = 100–p = 100–26 = 74, d = relative error, 10% of p, 10% of 26 = 2.6, therefore n = 4X26X74/2.6X2.6 = 7696/6.76 = 1138. The Ethical clearance was obtained from KLE University Ethical Committee. Data collection: Training of Health Worker  [HW (F)] was undertaken for a period of 3 months and the aim was to make them get acquainted with the study protocol and was conducted in two sessions. The first session was held at the Kinaye PHC. The training components were: completion of data collection instrument, obtaining informed consent, antenatal examination, recording birth weight and investigation. The second training session was held in the respective sub-centre of the HW (F). Three antenatal women were selected from each sub-centre and the HW (F) was made to demonstrate all the elements of training in front of the researcher. When all the components of training were found satisfactory by the investigator as per the check list, the training was taken as completed. During the study period, at the end of every 3 months 10% of data collected by HW (F) was selected randomly for cross-checking the reliability, validity and accuracy.The present study was carried out amongst the pregnant women and their newborns residing in an area covered by Kinaye Primary Health Centre (PHC) in rural Karnataka, India which caters to a population of 58,980. Sample: In our study 61 risk factors were studied together and each factor had different prevalence rate. Among them history of low birth weight was one of the important risk factor The pregnant women were enrolled before 16 weeks of gestation. Written Informed consent was obtained from all the study participants at the time of enrollment. For illiterates the informed consent form was read to them in their vernacular language. After understanding the study and if they agreed to participate then left thumb impression was obtained. The data was collected by interview using a pre-designed and pre-tested proforma. Every enrolled woman had 3 contact examinations. During the first visit maternal socio-demographic information was collected along with obstetric history and antenatal care. Maternal height and weight, blood pressure recording and haemoglobin estimation was also done. Second visit was carried out in the third trimester (36 to 37 weeks). The data was collected regarding antenatal care, weight gain, development of high risk pregnancy, dietary history  and medical illness. Blood pressure was recorded and haemoglobin estimation was done again. The last visit was after the delivery for recording of birth weight and other relevant information. Investigator ensured that the weighing machines and the weighing procedure were standardized before the start of the study. Software SPSS 12  was used for data analysis. Best fit model was used to access the independent effect of the factors using stepwise method.Out of 1138 pregnant women studied, 981 (86.2%) were between 20–29 years, 78 (6.9%) ≥30 years and 79 (6.9%) were teenage pregnancies. Majority 976 (85.8%) were Hindus and most of them 769 (67.6%) belonged to classes III and IV according to Modified B G Prasad’s socio-economic status classification st trimester. Majority 922 (81.0%) women had made ≥3 AN visits. Among 1125 who received iron & folic acid (IFA) tablets, 765 (68.0%) pregnant women took ≥100 tablets. Under Reproductive and Child Health program 100 tablets of iron and folic acid  are given to pregnant women during the course of pregnancy. In our study, 290 (25.5%) women gained weight ≤4 kg and only 21 (1.8%) more than 10 kg. Out of 304 pregnant women who were high risk pregnancy, 259 (22.8%) had one high risk factor, 43 (3.8%) had two and 2 (0.2%) had three high risk factors. The important high risk factors noted in our study were: bad obstetric history in 76 (21.7%), previous caesarean section among 54 (15.4%), Rh. negative status in 52 (14.9%), pregnancy induced hypertension (PIH) among 40 (11.4%), etc. The mean ± SD birth weight of newborns was 2.6±0.4 kg with a range of 1.2 to 3.8 kg. The prevalence rate of LBW in our study was 263 (22.9%).Among 1131 registered pregnant women, 740 (65.4%) had done antenatal (AN) registration in the 1Review of various studies st trimester. Similarly, the birth weight of babies seemed to be influenced significantly by the number of antenatal visits made by the mother . Unregistered mothers had 11 times higher risk of having a LBW baby in comparison to those who had 3 or more visits. If the women did not consume IFA tablets during pregnancy the chances of having LBW baby was 8 times in comparison with those who consumed ≥100 tablets and it was reduced to 2 times if they consumed 50 to 100 IFA tablets. Maximum 80.0% (n = 4) number of LBW babies were born to mothers’ with haemoglobin level <7 g/L (severe anaemia) in the 3rd trimester. When compared with mothers’ who had severe anaemia in the 1st trimester, the risk of having an LBW increased from 5 to 20 times. These 25 risk factors identified were subjected for multivariate logistic regression analysis and 12 factors emerged as the most important risk factors for birth weight in our study area (The percentage of LBW babies was 50.0% (n = 9) in the ≥35 years age group, followed by 33.3% (n = 20) in 30–34 years age group. The least percentage of LBW was noted in the age group of 20–24 years 19.9% (n = 130). As the maternal age increased the chances of having LBW baby also increased . A statistically significant relationship was found between the calorie intake  and birth weight of the newborn when compared with protein intake . Out of all the registered mothers’ outcome was better in mothers who got booked in the 1udy area .The prevalence rate of low birth weight in the study was 22.9% and the mean birth weight was 2.6±0.4 kg. Majority of the studies done in rural areas of India had the same magnitude of the problem of LBWs Different studies have revealed that significantly associated risk factors for the birth weight of a newborn vary according to the geographical location and the study population. A prospective longitudinal study was carried out in the rural areas of district Ambala, Haryana. The bivariate analysis showed a significant association between the birth weight of baby and the maternal age, maternal education, per capita income of the family, time of antenatal registration, number of antenatal visits, physical work during pregnancy, height and weight in pregnancy. A significant association between the calorie and protein intake with the birth weight of babies was also observed The present study revealed that maternal illiteracy, exposure to passive smoking, late child bearing, shorter inter-pregnancy interval, previous LBW baby, maternal weight, weight gain during pregnancy, PIH, high risk pregnancy and late antenatal registration were the risk factors significantly associated with the birth weight of a newborn. Interventions to reduce LBW should be specific for the targeted population and directed at the quantitatively important modifiable determinants of intrauterine growth and gestational duration. So in conclusion, comprehensive approaches which institute a combination of interventions to improve the overall health of the women are needed. Such approaches are likely to be most effective in reducing the LBW problem in India.


A number of studies have examined the effects of prenatal exposure to stress on birth outcomes but few have specifically focused on psychosocial job strain. In the present protocol, we aim to examine if work characterised by high demands and low control, during pregnancy, is associated with the risk of giving birth to a child born preterm or small for gestational age.We will use the Danish National Birth Cohort where 100.000 children are included at baseline. In the present study 49,340 pregnancies will be included. Multinomial logistic regression will be applied to estimate odds ratios for the outcomes: preterm; full term but small for gestational age; full term but large for gestational age, as a function of job-strain . In the analysis we control for maternal age, Body Mass Index, parity, exercise, smoking, alcohol use, coffee consumption, type of work , maternal serious disease and parents' heights as well as gestational age at interview.The prospective nature of the design and the high number of participants strengthen the study. The large statistical power allows for interpretable results regardless of whether or not the hypotheses are confirmed. This is, however, not a controlled study since all kinds of 'natural' interventions takes place throughout pregnancy . The analysis will be performed from a public health perspective. From this perspective, we are not primarily interested in the effect of job strain per se but if there is residual effect of job strain after naturally occurring preventive measures have been taken. One in eight Danish woman recently reported that she was often stressed in daily life, and workplace factors contributed significantly to the daily stress . Nearly Pregnant women, who experience distress  are more likely to deliver preterm -6 and haSeveral have examined the association between prenatal exposure to stress on pregnancy outcomes, but relatively few focus on the impact of the psychosocial work environment. These suggest that work characterized by high demands and low control during pregnancy is associated with preterm delivery and low birth weight infants -19, althThe present project therefore aims to examine if maternal exposure to psychosocial job strain (high demands and low control) measured by questionnaire early in pregnancy is associated with preterm birth, being born small or large for gestational age (SGA/LGA), in a large and prospective Danish birth cohort.In accordance with Guidelines for Good Epidemiological Practice , this prPopulation and data material are the Danish National Birth Cohort (DNBC), which has been approved by the Danish National Ethics Board . The DNBPrimary data was collected from 1996-2003. General practitioners invited the women to participate in the cohort study at their first antenatal visit. About 50 percent of all general practitioners in Denmark agreed to take part in the DNBC and about 60 percent of the invited women agreed to participate. The design of DNBC implied four interviews; in week 12-14 and 30-32 of pregnancy and when the child was 6 and 18 months old. The women were, by phone, asked about health, work environment, habits, medication and development and well-being of the child. An English version of all interview guides is available at the DNBC homepage . For furAccording to Danish regulations only studies involving human beings or any kind of human tissue needs approval from the Ethics Committee. As this study is based on data from questionnaires we do not have nor need to have an ethical approval or informed consent .Information on the woman's psychosocial work environment during pregnancy was obtained from the first of the four interviews. Data on pregnancy course and children's health are available partly from interviews and partly from the Danish Medical Birth Register.In total, 100,418 pregnancies were included in the DNBC. In the presented protocol the first inclusion criteria is confirmation in the baseline interview, that the woman is still pregnant and working, which results in 63,739 pregnancies. In order to avoid recall bias, we want the women to answer the question regarding psychosocial work environment before they know the outcome of the pregnancy. This is especially relevant for preterm birth, which is defined as a child delivered after 22 and before 37 completed gestational weeks. Thus 8,694 pregnancies will be excluded because baseline interviews were carried out later than 21 completed weeks of gestation. Subsequently, 815 pregnancies will be excluded because they ended before 22 completed weeks of gestation and therefore per definition (in Denmark) are considered a miscarriage and not of primary interest in this study. Since lowered birth weight and preterm birth may arise from different causes in singletons and multitons, we will only include singleton pregnancies . To avoid over-representation of gene material by inclusion of siblings, a woman is only allowed to contribute with her first pregnancy in the cohort . An additional 186 pregnancies will be excluded from the study population due to no response to the question regarding exposure to psychosocial job strain. Finally information on covariates is lacking for 1,145 cases: the final study population will therefore include 49,340 pregnancies. A flowchart of the exclusion process is given in Figure Exposure data concerning psychosocial work environment are collected as self-reported information from the first telephone interview , with the response categories: often, sometimes and seldom:• A172: Do you have too many tasks at your work? (Demand dimension)• A173: Do you have the opportunity to influence your tasks and working conditions? (Control dimension),The questions allow assessment of psychosocial load in the working environment according to the dimensions of the Demand Control Model (Job Strain Model ).Based on the answers the women are divided into four job categories related to the dimensions of demand and control: low strain , active , passive  and high strain . The hypothesis relates to the Job Strain Model by Karasek which has been used previously in DNBC to discuss effects of work-related stress ,27.To maximise contrast in exposure, the high strain group is defined by those who answered 'often' to high demands and 'seldom' to the question relating to control. The combination of high demands and low control is the primary interest of this study as it predicts mental strain according to the Job Strain Model . The higFor explorative purposes there are furthermore the possibility to study social support in relation to the Job Strain model as introduced by Johnson and Hall in 1988 in the Demand-Control-Support model . This caIn the present study we aim to examine the potential relationship between psychosocial job strain and perinatal outcomes as SGA, LGA and preterm birth. All the outcomes are defined relative to gestational age. Gestational age (GA) will be calculated as the number of days from "the first day of the last normal menstrual period (LMP)" to the day of birth. LMP is used because the precise time of conception is rarely known . Data coth percentile.Low birth weight (LBW) is usually defined as a birth weight below 2500 g . Of all th percentile or above is used.In the present study, SGA is defined as the 10% smallest babies at each gestational week in each gender within the present study population. For gestational weeks with less than 10 children in each group (week 22-24), SGA is equal to the lowest birth weight in the group. The same applies to LGA, just the 90Preterm birth is defined as a delivery occurring before 37 completed gestational weeks. It accounts for approximately 5% of all births in Denmark . PretermIn the present study, preterm birth will be defined as a delivery after 22 and up to 36 completed weeks of gestation. If analysis indicates statistically significant difference between preterm and term birth in relation to psychosocial strain - the variable will be further divided into three subgroups; extremely preterm (22-27 completed weeks of gestation), very preterm (28-32 completed weeks of gestation), or moderately preterm (33-36 completed weeks of gestation).Pregnancies that terminate before 22 completed gestational weeks is defined as a miscarriage in Denmark , and wilThe included births will divided into the following categories:1. Full term and normal weight for gestational age2. Preterm3. Full term but small for gestational age (SGA)4. Full term but large for gestational age (LGA)With the category 'full term and normal weight for gestational age' as reference (category 1), multinomial logistic regression will be used to estimate odds ratios (OR), with 95% confidence interval (CI), for being in outcome category 1-3 as a function of job-strain . The analysis will be conducted with the procedure proc logistic in the computer package SAS version 9.1. A likelihood ratio test will be used to test the overall null-hypothesis, which states that the outcome vector is independent of job-strain. There will be controlled for age, BMI, parity, gestational age at interview, exercise, smoking habits, alcohol habits, coffee consumption, type of work , maternal serious chronic disease as class variables and parents' heights (continuous variable). The categorisation of variables is described below.Some children will in addition to being preterm also be defined as SGA or LGA. However as only 5% of all cases are preterm and 10% of all cases are SGA, a total of 0.5% of the cases are both preterm and SGA. The expected number of preterm*SGA in the high strain group  is therefore less than the number of parameters in the model. Hence, further division of the preterm category is not feasible. An advantage of this outcome categorisation is a clean reference outcome  with which the three types of cases can be contrasted. In other words the aim is to look at the odds of being preterm versus full term and normal weight for gestational age, the odds of being full term and SGA versus full term and normal weight, and the odds of being full term and LGA versus full term and normal weight. These three separate outcomes will be analyzed together by multinomial logistic regression rather than by separate binomial logistic regressions (one for each outcome). Table The null-hypothesis will be rejected if P ≤ 0.05. To guard against mass-significance, an estimated odds ratio will only be accepted as statistically significant if i) the overall null-hypothesis has been rejected and ii) the 95% confidence interval of the odds ratio does not include one.-1). The same holds for the outcome LGA, since the prevalence of LGA, by definition, is the same as it is for SGA, i.e. 10 percent. For preterm birth, the corresponding power is 93.2%.The presented power calculations focus on the contrast in the high strain versus low strain groups, which is our primary interest. Figure Below we list, motivate and describe the covariates that will be included in the analysis. In Table Women older than 35 years have an elevated risk of giving birth to children with low birth weight ,44. InfoGenerally women deliver lighter babies in their first pregnancy compared to the following pregnancies ,46. As pSeveral studies show that cigarette smoking is causatively related to low birth weight or SGA; and cigarette smoking is the single most important risk factor for SGA in developed countries . AccordiCross-tabulation of the smoking variable from the first and the second interview during pregnancy shows that 89 percent of the women, who were smoking daily in the first part of the pregnancy also smoked daily during the last part of the pregnancy. The smoking variable is therefore only based on the questionnaire from the early pregnancy where the exposure question also derives from.It is documented that a large alcohol intake during pregnancy increases the risk of adverse birth outcomes ,51. AlcoA high caffeine intake (>300 mg per day) during pregnancy has been associated with a reduction in birth weight of 100-200 g compared to that in women with a low caffeine intake  althoughIn the DNBC questionnaire, the questions immediately prior to coffee consumption had answer categories relating to consumption per week. In contrast the categories for coffee consumption were to be given per day. Such shifts between answer categories may create faulty answers, i.e. the women answered per week, but answers were categorised per day. In the present survey, it was obvious that some of the responders meant coffee consumption per week instead of per day as the number of cups ranged between 0 and 69. Due to miscategorization, it was decided to construct a dichotomic yes/no variable.Health authorities in several countries recommend physical exercise during pregnancy, due to its beneficial effects on adverse health outcomes as pre-eclampsia  and gestThe applied variable is constructed on the basis of the work of Juhl et al . Here seAn increasing number of women are overweight when they become pregnant. Numbers from the Danish National Board of Health show that more than one third of the pregnant women in 2008 had a BMI above 25 . MaternaWomen with manual work might have a different risk of adverse pregnancy outcomes than those performing non-manual work. In addition this factor is associated with a person's opportunity to influence work tasks and working conditions . The varSome diseases may affect pregnancy or foetal development either as a result of the disease itself or due to pharmacological treatment. Diabetic women display increased risk of congenital malformations, obstetric complications and neonatal morbidity -65) regath week. To crudely control for potential differences due to the healthy worker effect, a variable 'gestational age at interview' is constructed, with categories <16 weeks and 16 - 21 weeks.One of the inclusion requirements was that the women should be working at the time of the interview. Such requirements are associated with a healthy worker effect. To require that a women should be working in e.g. the tenth week of the pregnancy is however not the same as requiring that a women should be working in the 19We assume that the probability that a child is LGA or SGA at birth depends on how tall the parents are. For control of this parameter a variable will be constructed as follows:First the heights of each parent are normalized by the equations: m xis the height of the mother, m σis the standard deviation. The variables f σrefer to the corresponding values among the fathers .where Then a combined variable is formed by averaging the two z-values. This combined variable will be used in the analysis. The father's height is missing in approximately 10% of the interviews. In these cases the z-value of the mother is used as a proxy for the combined z-value. The mean height among the mothers was 168.7 cm with a standard deviation of 6.09 cm. For the fathers these values are 181.9 and 6.98 cm.We have chosen to present the protocol before undertaking the actual analyses. This is done to improve the quality and integrity of the study by including reviewers' comments prior to analysis in order to ensure that design is not to be changed once data analysis has been performed.The aim of the presented protocol is to examine the relationship between psychosocial job strain and preterm birth, SGA and LGA. The analyses will be made from a public health perspective. We want to know if women with a work characterised by high demands and low control are at increased risk for the above mentioned pregnancy outcomes, compared to women whose work is characterised by low demands and high control. All kinds of interventions take place throughout the pregnancy, planned as well as incidental. At work, initiatives may be taken, both by colleagues and management, to relieve some of the strain associated with the work of the pregnant woman. Other interventions might originate from the woman herself (e.g. absence from work) or by people in the health care system as a consequence of the repeated health examinations that are offered during the pregnancy in Denmark. From a public health perspective the primary interest is not if job strain has an effect per se but if an effect of job strain resides after preventive measures have been taken, i.e. does the preventive system work, and are the measures taken sufficient to protect the woman. Furthermore we have chosen to initiate the statistical analysis with a single overall multinomial logistic regression. Although the investigated endpoints do probably arise for different underlying mechanisms such an approach is associated with several advantages. The most important advantage is increased power . The mulThe prospective nature of the design and the high number of participants strengthen the study. The large power allows for interpretable results regardless of whether or not the hypotheses are confirmed. By handling all outcomes simultaneously in a single model, mass-significance problems are eliminated. The hypotheses are theoretically grounded for preterm birth and SGA. Reviews indicate a relationship between severe maternal stress and reduced birth weight , and assIt can be discussed if some of the included covariates might be mediating factors in a causal path between work-environment and risk for adverse birth outcomes. Psychosocially strenuous work will, for example, make it more difficult for a person to stop smoking . It has In summary, the validity of the results and conclusions of the project will be strengthened by this protocol. Since the hypotheses, statistical model and significance level are defined and peer-reviewed before we look at any results, the analysis will be free from hindsight bias.BMI: Body Mass Index; CI: Confidence Interval; DNBC: Danish National Birth Cohort; GA: Gestational Age; HPA-axis: Hypothalamic-Pituitary-Adrenal axis; LGA: Large for Gestational Age; LBW: Low Birth Weight; LMP: The first day of the Last normal Menstrual Period; OR: Odds Ratio; SGA: Small for Gestational AgeThe authors declare that they have no competing interests.ADL, KSH and HHA designed and wrote the first draft. This has been modified and adapted by AMT, CO, JPB. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/255/prepub


The development of the central nervous system is complex and includes dorsal and ventral induction, neuronal proliferation, and neuronal migration, organization, and myelination. Migration occurs in humans in early fetal life. Pathogenesis of malformations of the central nervous system includes both genetic and environmental factors. Few epidemiological studies have addressed the impact of prenatal exposures. All infants born alive and included in the Swedish Medical Birth Register 1980–1999 were included in the study. By linkage to the Patient Register, 820 children with a diagnosis related to a neuronal migration abnormality were identified. Through copies of referrals for computer tomography or magnetic resonance imaging of the brain, the diagnosis was confirmed in 17 children. Median age of the mothers was 29 years. At the start of pregnancy, four out of 17 women smoked. Almost half of the women had a body mass index that is low or in the lower range of average. All infants were born at term with normal birth weights. Thirteen infants had one or more concomitant diseases or malformations. Two infants were born with rubella syndrome. The impact of low maternal body mass index and congenital infections on neuronal migration disorders in infants should be addressed in future studies. Development of the central nervous system (CNS) is a complex process, which requires integration of many cellular processes including neural stem cell proliferation, migration, and neuronal differentiation. The major neuronal migration occurs in humans between the 12th and the 24th weeks of gestation and results in the formation of the cortical plate [Classification of neuronal migration disorders is based on morphological criteria and includes schizenccphaly, porencephaly, lissencephaly, argyria, macrogyria, pachygyria, microgyria, and micropolygyria . PathogeThe aim of this population-based study was to describe perinatal characteristics in infants diagnosed with neuronal migration disorders aiming at identifying potential risk factors.The infants included in the study were identified as those hospitalized with a diagnosis related to a neuronal migration abnormality and confirmed by a computer tomography (CT) or magnetic resonance imaging (MRI).All Swedish residents are assigned a unique 12-digit national registration number, which is used for official population-based registers. This number makes it possible to identify individuals and collect certain information within registers and also to link information between different registers .The inpatient register is held by the National Board of Health and Welfare, and it records information concerning hospitalizations, including date of admission and discharge and primary and secondary diagnoses together with the national registration number. From 1987 and onwards, the coverage is approximately 99% of all patients hospitalized in Sweden. All diagnoses are classified according to the current ICD classification .The Swedish Medical Birth Register was established in 1973 and includes data on more than 99% of all births in Sweden. A standardized set of medical records is used by all antenatal care clinics and delivery units and at the examination of the newborn infant. Selected information from the records is computerized and forwarded to the register, which is held by the National Board of Health and Welfare. For all births, medical information on maternal demographic data, the reproductive history, maternal smoking habits, the pregnancy and delivery, and neonatal factors is included. The registration starts at the first visit to the antenatal clinic and is completed when the mother and newborn infant are discharged from the hospital .The medical records are stored at local and regional hospital and department archives. The records, which include copies of referrals for radiologic examinations, were used to identify the children who had been examined with CT or MRI and to validate the diagnosis of a neuronal migration disorder.2, normal weight ≥18.5 kg/m2 and <25 kg/m2, overweight ≥25 kg/m2 and <30 kg/m2, and obesity ≥30 kg/m2. Smoking was classified as no smoking, smoking 1–9 cigarettes/day, and >10 cigarettes per day. We also obtained information on maternal diseases during pregnancy and mode of delivery . As chronic diseases we included kidney failure, celiac disease, epilepsy, ulcerative colitis, diabetes mellitus, asthma, and systemic lupus erythematosus. The information was retrieved by the International Classification of Diseases as ICD-9 or ICD-10 codes, and all ICD-9 codes were manually transformed into ICD-10 codes.Information concerning factors that might influence neuronal migration disorders was obtained through the Swedish Medical Birth Register. For the mothers we obtained information about age, body mass index at first antenatal visit , chronic diseases prior to index pregnancy, reproductive history , and smoking in early pregnancy. BMI was classified according to WHO definition as underweight <18.5 kg/mFor the infants we obtained information on sex, gestational age at birth, birth weight and birth length, and the Apgar scores at one and five minutes. Gestational age was primarily estimated from the start of the last menstrual period. Small for gestational age (SGA) was defined as birth weight more than 2 standard deviations (SDs) below the mean birth weight for gestational age and sex according to a Swedish birth weight curve . ApproprAll infants born alive from 1980 through 1999 and diagnosed with a neuronal migration disorder according to MRI or CT scan sometime during this period were eligible for inclusion in the study. A total of 820 infants had been hospitalized with a diagnosis such as congenital myopathies and malformations of the CNS that could be related to a neuronal migration disorder . We requested information on performed CT or MRI scans by a letter sent to all paediatric and radiological clinics in the country, and about half of the 47 clinics responded to our request. In 120 of the patients, a CT or MRI scan of the brain had been performed. The diagnosis of neuronal migration was confirmed by the local radiologist in 17 subjects, 9 boys and 8 girls, all of whom were included in the study.As the study was purely descriptive, no formal testing was possible. For certain characteristics , mean and/or median values are presented together with ranges.The mother's median age was 29 years, and most women were born in Sweden . Four ouOther diagnoses, without any relation to the pregnancy, were also reported. One woman suffered from chronic multifocal osteomyelitis and necrosis and another was involved in a motorbike accident. Maternal care for (suspected) damage to the fetus by radiation was reported in one case.Nine male infants and eight female infants were born after mean 39.3 gestational weeks and with a mean birth weight of 3327 grams. All children were born as singletons and were AGA, and all had a full Apgar score.Most infants were classified to have an undefined migrational disorder, a disturbed migration of the immature brain or a migrational disorder of unknown type. Thirteen infants had one or more concomitant disorders at birth. Congenital malformations of the spleen or the heart, Potter's syndrome, and facial asymmetry were reported, including malformation of the eye and lens, microphthalmus, and cleft palate. Hereditary haemolytic anaemia was reported in one infant. Two infants had convulsions and peripheral neuropathy.Congenital infections were reported in three infants. Two infants had rubella syndrome, and one had congenital pneumonia. Two infants had skin problems at birth, and one infant suffered from obstruction of the intestine by gallstones or meconium .All infants were born at term and of ordinary birth weight to healthy mothers with normal or subnormal BMI and after normal pregnancies. Most of the infants had a concomitant malformation, and two infants were diagnosed with congenital rubella infections.A failure of normal migration may result in neurons accumulated in unusual areas . PreviouEpidemiological studies and experimental data have demonstrated the importance of nutritional factors in fetal brain development and the deleterious effects of nutritional deficits –11. BMI Different maternal conditions can interfere with fetal growth. It is well known that maternal diseases during pregnancy, such as diabetes and nontreated phenylketonuria, and conditions where the placental blood flow is reduced, such as preeclampsia, could interfere with the fetal brain development , 13, 14.Neuronal migration disorders have been described in humans and/or in animal models following in utero exposures to infections. Some viruses, such as herpes simples, cytomegalovirus (CMV), or HIV, are potentially capable to persist in a latent form within the central nervous system. Several studies have described the teratogenic effect of CMV infection and the relation to neuronal migration disorders –18. AdveInformation on infections during pregnancy was missing in this study. However, two children were reported with rubella syndrome at birth, which is more than expected. The percentage of susceptible pregnant women with rubella was gradually reduced from 12% in 1975 to just below 2% in 1994. Rubella syndrome is very uncommon, and between 1975 and 1985, only a mean of two cases per year were recorded in Sweden. Since 1985, no child with the rubella syndrome has been registered . It can It is well known that maternal smoking increases the risk of intrauterine growth restriction and affects the fetal brain by inducing intrauterine hypoxia or by acting directly on the developing brain –23. SmokThe detection of cases was difficult mainly because of our strict criteria for eligibility, which included a CT or MRI scan confirming the diagnosis. In 120 of all hospitalized children, a CT or MRI scan of the brain was preformed, and only 17 of them were confirmed with a neuronal migration disorder.Despite several reminders, only 50% of all hospitals in Sweden responded to our request to send in CT and MRI scans. None of the hospitals actively rejected participation in the study. The cause of this dropout is not known but was evenly distributed between level I, II, and III hospitals over the country. It can be speculated that journals from the study period were not easily found, and the time for searching these journals was regarded as too expensive for the hospitals.The study refers to a time of great medical advances, and the use of CT and MRI scan is more widely used today. The cases were identified through the national patient register, and the responding hospitals were evenly spread over the country. Considering the increasing use of CT and MRI scans, a study performed in more recent years might detect more children with neuronal migration disorder.This descriptive study indicates that there might be an impact of low or subnormal maternal BMI before and during pregnancy, maternal infection, such as rubella, and maternal smoking on fetal brain development, including neuronal migration. The roles of maternal BMI and congenital infections should be tested in future analytical studies.


Background. The etiology of motor impairments in preterm infants is multifactorial and incompletely understood. Whether corpus callosum development is related to impaired motor function is unclear. Potential associations between motor-related measures and diffusion tensor imaging (DTI) of the corpus callosum in preterm infants were explored. Methods. Eight very preterm infants  underwent the Hammersmith neonatal neurological examination and DTI assessments at gestational age of 42 weeks. The total Hammersmith score and a motor-specific score (sum of Hammersmith motor subcategories) were calculated. Six corpus callosum regions of interest were defined on the mid-sagittal DTI slice—genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. The fractional anisotropy (FA) and mean diffusivity (MD) of these regions were computed, and correlations between these and Hammersmith measures were sought. Results. Anterior midbody FA measures correlated positively with total Hammersmith  and motor-specific scores . Total Hammersmith scores also negatively correlated with anterior midbody MD measures . Discussion. These results suggest the integrity of corpus callosum axons, particularly anterior midbody axons, is important in mediating neurological functions. Greater callosal maturation was associated with greater motor function. Corpus callosum DTI may prove to be a valuable screening or prognostic marker. Preterm infants are at a high risk of motor deficits in later life, with approximately fourteen percent of very preterm infants developing cerebral palsy (CP) , and up The corpus callosum is vital for communicating and integrating motor and somatosensory information between the hemispheres, and for bimanual motor coordination and function . The matThompson et al. found that very preterm infants had significantly reduced corpus callosum cross-sectional area, lower FA and higher MD values compared to term infants, thus suggesting that corpus callosum development is altered in preterm-born infants compared to term-born infants . A minorHowever, aside from these few studies, potential associations between corpus callosum structure and neuro-motor function in preterm-born neonates have not been reported. Outcomes from such investigations may prove clinically meaningful; for example, they may inform development of early prognostic indicators, interventions, and/or markers to inform instigation of such interventions. Hence the primary aim of this study was to investigate and explore potential associations between DTI measures of subregions of the corpus callosum and concomitant neurological measures in a small sample of preterm infants. We hypothesized that a positive relationship would exist between corpus callosum maturation and concomitant neurological measures. The participants were preterm infants born at gestational age between 28 and 32 weeks (GA) at the Royal Brisbane and Women's Hospital (RBWH) with no post-natal medical issues or complications. Inclusion criteria were: infants that were born at a gestational age between 28 and 32 weeks, with a birth weight and length between the 10th and 90th percentiles for gestational age and who were determined to be medically stable. Exclusion criteria were as follows: the presence of abnormalities on brain ultrasound  and the presence of major genetic disorders or malformations. These criteria were set to ensure that the study participants were at low risk for an adverse outcome and were medically stable. This study was approved by the RBWH Human Research Ethics Committee and Monash University Human Research Ethics Committee. Parents who agreed to their infant participation in the study signed a written consent form and were provided with a copy of the study protocol. On reaching term-equivalent age (42 weeks GA), the infants underwent the Hammersmith neonatal neurological examination (HNE)  at the RThe HNE evaluates a number of motor and behavioral functions including posture and tone, tone patterns, reflexes, abnormal signs and orientation, and behavior . When peb-value of 1000 s/mm2, along with one minimally diffusion weighted image (b = 0). The image resolution of the scans was 1.75 × 1.75 mm in-plane, with a slice thickness of 2 mm. Other imaging parameters were as follows: TR/TE 9300/130 ms, field of view 128 × 128, 47 slices. The acquisition time for the diffusion data was approximately five minutes. A field map was acquired to assist in the correction for susceptibility distortions. The MRI parameters for the field map acquired were TR/TE1/TE2 488/4.9/7.4 ms, matrix size 64 × 64, field of view 160 × 160 mm, slice thickness 2.6 mm with 0.65 mm slice gap, 29 slices, and flip angle 60 degrees. The infants underwent neuroimaging at approximately term-equivalent age refer to . The infb-matrix [Preprocessing was performed using ANTS, FSL, and Freesurfer. Preprocessing of the imaging data involved correction for any head movement using rigid-body registration with subsequent adjustment of the b-matrix , skull sb-matrix , as wellb-matrix  and corrb-matrix . Intensib-matrix . AdditioFractional anisotropy (FA), color FA, and MD maps of the brain were calculated for each infant, with FA representing the degree of anisotropic diffusion and MD representing the magnitude of diffusion. FA and MD were calculated using log-linear least squares with MRtrix . AlignmeThe infants ranged between 41 and 45 weeks GA at the time of DTI assessment. As it is known that FA values tend to increase rapidly with increasing GA , the FA Thirteen preterm infants were recruited into the study. Due to time constraints, MRI was not performed for two infants. Furthermore, due to technical issues and motion artifacts, DTI data from three infants was excluded from the analyses, leaving eight infants whose data was included in the correlation analyses. P = 0.001) and similarly between the motor-specific scores and the anterior midbody FA measures . A statistically significant negative correlation was found between the total HNE scores and the anterior midbody MD measures . Scatter plots illustrating these correlations are provided in Figures Using Spearman's rho, associations were explored between the clinical and DTI measures . It has been suggested that FA values in the corpus callosum are primarily a reflection of fiber density and organization, rather than myelination or axon diameter . Hence, This study appears to be one of the first studies to describe a strong correlation between the maturation of the anterior midbody and concomitant neurological function in preterm infants. In contrast, a number of studies (as described in In light of these findings, intervention programs and management strategies directed towards enhancing the development of white matter should be investigated further, as this may aid in enhancing motor function and possibly other neurobehavioral functions for preterm infants. An MRI study performed by Smith et al. demonstrated that stresses from the NICU environment correlated with decreased white matter maturation and interhemispheric communication in preterm infants, as assessed by DTI and functional MRI . This stThe observed relationship between anterior midbody integrity and neurological function, if replicated and extended in larger studies, may inform future development of prognostic tools for neonates. Future studies should investigate whether such DTI measures may demonstrate value in the prediction of neurodevelopmental, particularly motor outcomes at a later age. Conversely, in light of the strong correlation between HNE scores and DTI measures, it is possible that HNE assessment may also prove to be a valuable prognostic marker, with the added advantage of being easy to perform at the bedside. Such markers might also ultimately prove informative for future interventional trial programs, for example for selection of inclusion criteria, or predicting or assessing response to a given intervention.There are a number of limitations in the current study, particularly the small sample size and associated low statistical power . In addiA positive association was observed between DTI measures of structural maturation of the anterior midbody of the corpus callosum and neurological and motor function, in healthy preterm-born infants assessed at term-equivalent age. Future studies of larger samples may extend upon these preliminary findings and possibly investigate the value of corpus callosum DTI measures as early prognostic markers for neurodevelopmental and motor outcomes.


Fetal and neonatal mortality rates are essential indicators of population health, but variations in recording of births and deaths at the limits of viability compromises international comparisons. The World Health Organization recommends comparing rates after exclusion of births with a birth weight less than 1000 grams, but many analyses of perinatal outcomes are based on gestational age. We compared the effects of using a 1000-gram birth weight or a 28-week gestational age threshold on reported rates of fetal and neonatal mortality in Europe.Aggregated data from 2004 on births and deaths tabulated by birth weight and gestational age from 29 European countries/regions participating in the Euro-Peristat project were used to compute fetal and neonatal mortality rates using cut-offs of 1000-grams and 28-weeks . We measured differences in rates between and within countries using the Wilcoxon signed rank test and 95% confidence intervals, respectively.p<0.001), although these differences varied between countries. The use of a 1000-gram threshold included 8823 fetal deaths compared with 9535 using a 28-week threshold (difference of 712). In contrast, the choice of a cut-off made little difference for comparisons of neonatal deaths (difference of 16). Neonatal mortality rates differed minimally, by under 0.1 per 1000 in most countries (p = 0.370). Country rankings were comparable with both thresholds.For fetal mortality, rates based on gestational age were significantly higher than those based on birth weight (Neonatal mortality rates were not affected by the choice of a threshold. However, the use of a 1000-gram threshold underestimated the health burden of fetal deaths. This may in part reflect the exclusion of growth restricted fetuses. In high-income countries with a good measure of gestational age, using a 28-week threshold may provide additional valuable information about fetal deaths occurring in the third trimester. There is an ongoing debate about the value of international comparisons of fetal and neonatal mortality rates, given differences between countries in recording of births and deaths at borderline viability The World Health Organization (WHO) recommends the use of a 1000-gram threshold for international comparisons of perinatal mortality rates The aim in international comparisons is to maximise both comparability and scientific and policy relevance. The primary aim of using a birth weight threshold for international comparisons is to ensure comparability because birth weight measures are considered to be less prone to error than calculations of gestational age. When the date of the last menstrual period (LMP) is used alone to calculate gestational age, the results can be inaccurate Gestational age is generally considered to be a more relevant variable than birth weight for studying perinatal outcomes. Recent European cohorts have analysed the outcome for very preterm rather than very low birth weight babies, as gestational age has a better prognostic value th week of gestation or the beginning of the third trimester, this hypothesis has not been tested. The aim of this analysis was therefore to compare the use of a 1000-gram birth weight threshold with a 28-week gestational age threshold in terms of their impact on reporting of fetal and neonatal mortality rates within European countries and on comparisons between European countries.While the hypothesis underlying the current WHO recommendation is that the 1000-gram threshold provides a good approximation for the 28This study was embedded within Euro-Peristat, which developed a list of valid and reliable indicators for monitoring and evaluating perinatal health in the European Union (EU) The Euro-Peristat core indicator list includes fetal and neonatal mortality. The fetal mortality rate is defined as the number of deaths before or during birth in a given year per 1000 live and stillbirths in the same year. The neonatal mortality rate is defined as the number of deaths at 0 to 27 days after live birth in a given year per 1000 live births in the same year. Euro-Peristat collects data on births and deaths at or after 22 weeks of gestation, regardless of birth weight. Aggregated data on the number of live births, fetal and neonatal deaths by each week of gestation and by birth weight intervals of 500 grams were collected. These data were used to calculate fetal and neonatal mortality rates for births and deaths weighing 1000 grams and over and for those born at or after 28 completed weeks.Twenty-seven countries were able to provide data to calculate fetal mortality rates with birth weight and gestational age thresholds. Germany, Hungary, Ireland and Italy did not have data on neonatal deaths by birth weight or gestational age. Some countries could only provide data on some regions . Data from France came from a one-week national perinatal survey in October 2003, vital registration, and neonatal death certificates. Data on neonatal deaths from England and Wales related to 2005 and data from Italy were for 2003. Most countries had fewer than 5% of data missing for fetal and neonatal deaths by birth weight and gestational age, as presented in For neonatal deaths, fewer countries had high proportions of data missing. Over 5% of birth weights were missing for Denmark (14.8%), Luxembourg (9.1%), Sweden (7.1%), Scotland (6.8%), and Valencia (5.8%). Gestational ages were missing for over 5% in Luxembourg (9.1%), Denmark (7.0%), Portugal (6.8%), and Valencia (6.8%). As with fetal deaths, we excluded countries with highly divergent proportions of missing birth weights and gestational ages. We therefore excluded Denmark  and Sweden . Live birth data were missing for less than 5% with the exception of Brussels and Valencia where 6.3% and 5.5% of gestational ages were missing respectively.For countries included in the analyses, we excluded missing data from our primary analyses as this would reflect the reality if these cut-offs were used, but we also did a second set of analyses with missing data distributed according to observed birth weight and gestational age distributions for live births, and fetal and neonatal deaths separately.We calculated fetal and neonatal mortality rates with 95% confidential intervals, using both birth weight and gestational age thresholds. We also computed differences between rates with confidence intervals to test whether these were significant within countries. To test whether there was a systematic difference between countries in rates based on birth weight versus gestational age we used the non-parametric Wilcoxon signed rank test. In addition, we used the Wilcoxon rank sum test to assess whether rates based on a 28-week threshold minus a 1000-gram threshold differed significantly across countries. Finally, we tested the correlation between these two rates using the Spearman rank test to assess how these affected country rankings. These statistical tests were repeated on recalculated rates after imputation of missing observations, as described above, to ensure that the addition of these data would not change our results. Analyses were done with SPSS version 17.0 for Windows .p = 0.018) and England and Wales where the rate difference was 0.45 per 1000 with 95% confidence interval 0.23–0.66 (p<0.001).Except for the Czech Republic (0.16‰) and Estonia (0.21‰), where rates were 0.2 per 1000 higher with a birth weight cut-off, most countries had higher rates of fetal deaths when a gestational age cut-off was used, as illustrated in In contrast, differences between neonatal mortality rates were minimal, with 15 out of 21 countries/regions having differences between −0.1 and +0.1 per 1000 . Rates cp<0.001 for Wilcoxon signed rank test). The corresponding neonatal mortality rates did not differ significantly between countries (p = 0.370), however twelve countries had a positive difference while eight had a negative and there was one tie. In total, 8823 fetal deaths were included when a 1000-gram threshold was used compared with 9535 with a 28-week threshold, a difference of 712 fetal deaths . In contrast, the difference in neonatal deaths was minimal, 4710 using a 1000-gram threshold versus 4726 using a 28-week threshold (a difference of 16).Differences between countries in fetal mortality rates based on gestational age compared with those based on birth weight were significant (p = 0.002); while the choice of a cut-off made no difference for comparisons of neonatal mortality rates (p = 0.380).Results did not change when the observed birth weight and gestational age distributions for fetal and neonatal deaths and live births were used to include births and deaths with missing birth weights and gestational ages in the analyses. Fetal mortality rates based on gestational age were still significantly higher than those based on birth weight  for fetal mortality and ρ = 0.963  for neonatal mortality. Country rankings were therefore similar with a few exceptions such as Brussels which ranked sixth for birth weight and thirteenth for gestational age. Even for the Netherlands and England and Wales, where differences in fetal mortality rates calculated using the two definitions were significantly different, their ranks only differed by two places .Fetal and neonatal mortality rates computed using a birth weight threshold were highly correlated with rates computed using a gestational age threshold, with Spearman rank correlations of ρ = 0.952  While growth restriction is also a risk factor for neonatal death, the magnitude of the association may be less strong, especially in the gestational age and birth weight bands considered in this analysis. Recent studies in France and New Zealand found that 17% and 13% of all neonatal deaths were below the tenth percentiles of national standards In the European countries included in our analysis, fetal mortality rates calculated using a threshold of 28 weeks of gestation were higher than those based on birth weight cut-offs of 1000 grams, probably due in part to the role of intra-uterine growth restriction in antepartum fetal deaths. Assessing the health burden of third trimester fetal deaths using a cut-off based on gestational age provides valuable additional information. Comparisons based on this cut-off are possible in countries where a clinical estimate of gestational age is recorded in routine data sources and where women have access to early antenatal care and dating ultrasound as is the case in European and other high-income countries.Table S1Data sources used for data on live births, fetal and neonatal deaths in Europe in 2004.(DOCX)Click here for additional data file.Table S2Percentage of missing birth weights (BW) and gestational ages (GA). *Denmark , Italy  and Sweden  were excluded from analysis because of substantial difference in missing data by birth weight and gestational age. Proportions of 5% and over missing data are presented in bold.(DOCX)Click here for additional data file.


The etiology of birth defects has been widely studied but is not yet fully clarified, previously published data had suggested that maternal age or parity maybe involved, but without consistent conclusions.A population-based, case-control study was nested in a cohort of perinatal infants born from 2010 to 2012 in Baoan District, Shenzhen. Four categories of isolated birth defects were defined as cases: congenital heart defects , polydactyly (n = 352), cleft lip with or without palate  and equinovarus (n = 119). Controls were non-malformed infants  randomly selected from the same area and period. Odds ratios (ORs) and the 95% confidence intervals (CIs) were computed by multivariable unconditional logistic regression analysis.Young maternal age (<25 years old) was associated with a reduced risk of CHD , while with an elevated risk of polydactyly . Increased risk of CL/P-affected pregnancy was observed in mothers older than 35 years old . Compared to primipara, those having their second, and third or more delivery were less likely to have infants with equinovarus, with significant adjusted ORs of 0.59 (0.40–0.89) and 0.42 (0.19–0.93), respectively.Maternal age was significantly associated with CHD, polydactyly and CL/P relevant pregnancy. Mothers with higher parity might have lower risk of equinovarus occurrence in offsprings. The etiology of non-chromosomal birth defects has been widely discussed but is not yet fully clarified, though numerous studies have confirmed that environmental and behaviors components are involved Baoan district is accounted for the second largest area among the six functional districts in Shenzhen City, and accounted for the largest proportion (38.8%) of Shenzhen's total population (10.36 million) at the end of 2010 As is generally accepted, population characteristics differ considerably across geographical location, therefore public health decision making should be based on the specific regional researches. However, etiologic studies regarding congenital defects in Chinese southern area have rarely been reported in recent years.In the light of the above, we conducted a case-control study to investigate the relationship between maternal age, parity and selected isolated birth defects through a large cohort from Baoan district, Shenzhen, China.st, 2010 to December 31st, 2012. Data utilized in this study were derived from Shenzhen Maternal and Child Health Management System (available on http://218.18.233.230:8888/), a continuously updated health care electronic database with an approximate 99.5% geographic coverage of the total area of Shenzhen. Anonymity and confidentiality were guaranteed, and written consents were given from the expectant parents, or their next of kin on the behalf of the newborn participants, for their information to be stored in the System at the time of the expectant mothers were awaiting delivery in the hospital. The study protocol was approved by the institutional review board of Baoan Maternal and Child Health Hospital.This study is a multi-center, population-based case-control study within a cohort of perinatal infants born in Baoan district from January 1Perinatal infants (from 28 weeks' gestation to one week after birth) with congenital malformations were identified by Birth Defects Monitoring System (BDMS), a branch of Shenzhen Maternal and Child Health Management System.In the present study, cases were defined as perinatal infants confirmed with isolated congenital heart defects (CHD), polydactyly, cleft lip with or without palate (CL/P) or equinovarus, which represented the top four phenotypes of birth defects in Baoan district. Those with multiple congenital defects, syndromic diseases or chromosomal aberrations were excluded as high genetic components were concerned The control pool was composed of all non-malformed perinatal infants born in the area from which the cases were recruited during the same period (2010–2012). Out of 203,154 records that met the primary criteria, 189,378 (93.2%) with complete information. The Power and Sample Size Calculations program  was used to assess the minimum sample size of controls to guarantee a power of at least 79.6%  to detect an OR of 2.0 or greater. Eventually a number of 11,305 records were randomly selected and constituted a share control group.Data on maternal and child records were prospectively entered into the Shenzhen Maternal and Child Health Management System. Once the cases and controls were ascertained, their basic characteristics were retrospectively reviewed and the selected covariates were extracted independently by two authors (Luo and Gao): general information of mothers  and prenatal infants , the key exposure variables  as well as other covariates that were chosen to included in the analysis. Once the data extraction was completed, the outliers were rechecked by looking through the original medical records.th weeks of gestation and more than five times be counted through the whole gestation.With rapid industrialization and urbanization, millions of Chinese peasants left their hometowns and headed to Shenzhen for job, making this city a famous modern industrial zone and worker-gathered area. For better management, Shenzhen government has classified the inhabitants' household registry into three types: 1) local resident for those who achieved permanent residence permit, 2) temporary population for those who lived in Shenzhen for more than one year without permanent residency and 3) migrant population for those who lived in Shenzhen for less than one year without permanent residency. The frequency of antenatal checkup was defined as the total numbers that had been taken through the whole gestation and treated as a categorical variable with four levels: 0, 1–5, 6–10 and >10. We also further grouped the checkup into “regular” and “irregular”. Regular checkup was defined as the first examination be taken from the 12In this study, maternal age was categorized into four groups: <25, 25–29, 30–34 and ≥35 years old. The second group was chosen as a reference because generally women of 25–29 years old has the lowest overall prevalence and represents the largest proportion. Parity was defined as the numbers of live birth a female has borne prior to the index pregnancy 2χ test or Fisher's exact test were performed to compare the status of case and control groups. Multivariable unconditional logistic regression analysis was used to compute the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for the effects of maternal age and parity on the selected malformations. Two regression models were used: one crude model without any adjustments and another adjusted model that included adjustments for covariates that were deemed to be plausible confounders . Specially, liner regression analysis using a stepwise procedure was carried out to test co-linearity problems  prior to multivariable logistic analysis. Variance inflation factor (VIF) ≥10 indicated strong co-linearity and then only one significant covariate was selected into the adjusted model. All statistical analyses were conducted by the SPSS, version 13.0 . P value <0.05 was considered statistical significance.For the enumeration data, independent sample A number of 693 CHD, 352 polydactyly, 159 CL/P and 119 equinovarus cases and 11,307 unaffected healthy controls were enrolled in the final analysis. The selected information of study subjects were summarized in P<0.05). Infants with CHD and CL/P in general had a lower birth weight and were more often prematurely born than those without malformation (P<0.01). The frequencies of still birth were also statistically higher in the CHD (8.2%), CL/P (15.1%) and equinovarus (2.5%) groups than those in the control group (0.3%). As the liner regression results had obviated the possibility of strong co-linearity (VIF = 1.439) between gestational age and birth weight, the above and other significantly incomparable covariates were considered to be biologically potential confounders and were entered into the adjusted model.In many instances, there were statistically significant differences between case and control groups. A male predominance was noted among the polydactyly (64.8%) and CL/P (64.2%) cases as compared with controls , indicating that the impacts of parity were independent by maternal age.–P = 0.11).–As outlined in In the current case-control study, we found that maternal age was significantly associated with CHD, polydactyly and CL/P relevant pregnancy, and those with higher parity were less likely to have equinovarus-affected offsprings.The impacts of maternal age on birth defects have been long investigated, with inconsistent findings. An earlier study Meanwhile, Reefhuis and Honein Unlike the widely explorations of CHD and CL/P, relatively little was reported about the impacts of maternal age on polydactyly and equinovarus. Our finding of a modest but significant association between young maternal age and a higher risk of polydactyly was in accordance with one previous study Similarly, it had not been verified whether maternal parity could contribute to the occurrence of certain birth defects. Recently Duong et al. We deemed that nonstandard criteria for the age and parity grouping might be partially responsible for the inconsistent findings. Generally, the risk estimates for maternal age were calculated using 5-year categories with 25–29 years as the reference, while some studies introduced different classifications. For instance, Parker et al. Our study had several notable methodological advantages, namely: 1) the sample size of the present study was comparatively large and substantial to decrease the rate of false-positive or false-negative of the results, the 95% CIs for risk estimates were relatively narrow and suggested sound statistical precision; 2) for the widely coverage and objectively data collection from the population-based register, both cases and controls could be considered as representative of the general population in Baoan district. Moreover, the selection and information bias was rendered to minimum; 3) multivariable adjusted analyses were conducted to reduce the errors introduced by confounders, just as the liner regression analysis for the co-linearity problems.However, certain limitations were also needed to be acknowledged. Environmental conditions  or maternal certain personal behaviors , as mentioned before, also had influence on the whole pregnancy outcome. Nevertheless, these information were not available for analysis, and it was difficult to derive such specific data because of the nature flaw of the Shenzhen Maternal and Child Health Management System, as the routine data collections were primarily used for administrative or governmental reports, most of the environmental and behaviors exposures were recorded as texts without uniform standard. Given the complexity of embryonic developments and the modest effect from single factor, it was possible that our findings were attributable to interactions among various components. Thus we stressed that the aforementioned results merited further comprehensive investigations.In summary, our findings indicated that maternal age and parity might play an important role in the development of certain isolated birth defects. Given the prevalence of these defects in Baoan district, our findings might help other researchers to conduct more etiological studies and plan more comprehensive strategies to reduce the occurrence of birth defects in further generation.