There currently exists no data on birth defects from population-based studies in Vietnam. Our study's aim was to assess external birth defect (EBD) prevalence among live newborns in Binh Thuan Province in Vietnam with the help of health workers at all levels of the health system.A 2-month training session for 452 health professionals (HP) practicing delivery care in 127 Commune Health Stations (CHS) and in 12 provincial or district hospitals (DH) was setup in 2006. After a successful 6-month pilot study, a one-year registry of EBDs was established in 2008. All live newborns were screened for EBDs within 24 hours after birth in all DH obstetric departments and in all CHSs. Trained local HPs collected information by filling out a predesigned form and by photographing the affected newborn. EBDs were coded using the International Classification of Diseases system-10, Clinical Modification. The study was repeated in 2010.Throughout 2010, out of a total of 13,954 newborns, 84 cases with one or more EBDs were reported, representing an overall prevalence rate of 60.2 per 10,000 live births. The most common groups of EBDs were limbs , orofacial clefts  and the central nervous system .This first population-based study in Vietnam, which required coordination efforts at the local level, provides baseline prevalences of external birth defects. Data on EBDs from this study in southern Vietnam may be useful for setting up a regional population-based registry of birth defects in Vietnam. The toll of birth defects worldwide has been recognized as a severe public health problem. Birth defects, affecting 2-3% of all infants, are a major cause of perinatal mortality and childhood morbidity in both developed and developing countries –5]..5].Many studies have reported the prevalence of congenital anomalies in developed countries. Available data on this matter is very rare, however, in developing countries. Moreover, the few studies available are based on hospital births over a period of time rather than on a population ,6–8]..8].At the present time, there are only two organizations in cooperation with the WHOs Human Genetics Programme in order to establish a registry of birth defects. These organizations are: the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), which has 46 members representing 31 countries spread across the five continents , and theEUROCAT registries follow standardized guidelines and use multiple-source case ascertainment methods. They include all infants, including still births (from 20 weeks gestation), with anomalies diagnosed within the first year of life. Most major birth defect types are included. Termination of pregnancy for foetal anomaly (TOPFA) is also included. The criteria that must be met by registries participating in EUROCAT include a definition of the population, data collection and ascertainment, definition and coding of defects, calculation of prevalence rates, and confidentiality .There is currently no data on birth defects available at the population level in Vietnam. The country is lacking an organization that is responsible for the registry or surveillance of birth defects. However, Vietnam has strong policies that seek to provide equitable healthcare for its people, as well as a good primary healthcare structure. EBD surveillance is therefore possible.2, divided over 127 administrative communes. The population is over 90% Kinh ethnicity, which is the predominant ethnic group in Vietnam. As presented in Figure Binh Thuan is a rural province located along the south-eastern coast of Vietnam, with a population of approximately 1.1 million on an area of 7,992 kmAll CHSs provide obstetric and mother-and -child healthcare, and implement prevention programs such as immunization and health promotion. However, there is less than one physician per CHS and most deliveries are supervised by midwives. Binh Thuan does not have a program for prenatal diagnosis at any level of healthcare. The good structure of healthcare at all levels, good access to primary care and a stable population representing the country's major ethnic group were all suitable conditions for implementing a population-based program for a birth defect registry within a population from the grassroots level to the topmost level of health care in Binh Thuan province.Our study's aim was to assess EBD prevalence among live newborns in Binh Thuan Province in Vietnam with the help of health workers at all levels of the health system.A 2-month training session for 452 HP practicing delivery care in 127 Commune Health Stations (CHS) and in 12 provincial or district hospitals (DH) was setup in 2006. After a successful 6-months pilot study, a one-year registry of EBDs was established in 2008. After a few modifications in the setup, we conducted a whole registry in 2010.In order to be included in this study, (1) the mother had to reside in the province, (2) the mother had to sign a consent form for enrolment in the study, (3) gestational age had to be at least 22 weeks, and (4) the baby had to be alive at birth.All live births were physically examined to detect EBDs within 24 hours after birth in all DH obstetric departments and in all CHSs. When an EBD was suspected, a detailed clinical description of the EBD was collected and a photo of EBD was taken by a trained local health professional.Trained local HPs collected information by filling out a predesigned form and by photographing the affected newborn. An external birth defects atlas and a manual for detecting EBDs in newborns were provided to each HP during training.Data collection was performed by means of a structured form which contained three parts. The first part inquired on the mother's demographic profile, on medical and obstetric history, as well as on complications during the present pregnancy and labour. The second part pertained to neonatal characteristics, including sex, the Apgar score, gestational age, birth weight, head circumference, length, and history of birth defects in siblings. Finally, the third part was composed of a checklist for diagnosed congenital anomalies.Birth-weight measurements were obtained at delivery using a scale  that was accurate to 10 grams. Infants were fully unclothed and in the supine position. Recumbent length was measured with a baby board (UNICEF) and recorded to the nearest 0.1cm. A non-flexible plastic tape was used for measuring head circumference of the newborns and the result was also recorded to the nearest 0.1 cm. The two latter measurements were obtained within 24 hours after delivery. The methods of measurements used were based on the recommendation of the WHO . AbsolutEBDs were coded using the International Classification of Diseases system-10, Clinical Modification (ICD10-CM)  and commInstructions for photographing and describing EBDs are contained in the manual. The manual also describes the technique for screening for EBDs in newborns during the physical exam.All data (collection forms and photos of EBD cases) on live births were rechecked and entered into a Microsoft Excel sheet by a local trained data processor  before sending monthly data to a processing center at the Provincial Health Service.All photographs with a written description of an EBD were reviewed and classified by one of the authors (Y.G) who is a Belgian expert in clinical genetics. In case of disagreement between the expert’s diagnosis and the local coding, the photograph and the written description were reviewed and discussed with local paediatric physicians. The team decided the most likely diagnosis as a group.Statistical analyses were performed using the STATA statistical software.Total prevalence was calculated by dividing the numerator (EBDs) by the relevant denominator  for the same period of time at the same place.A newborn with multiple external defects was counted as one case unit for analysing birth defect case characteristics. When a newborn had more than one defect, each defect was counted as one unit when specific analyses for that particular defect or for system defect were performed. As a result, numerically adding up the number of defects could exceed the number of cases with defects.The birth defect registry project was approved by the Binh Thuan Provincial Health Service and the Pham Ngoc Thach University Ethical Review Committee, Hochiminh City, Vietnam. All mothers provided written informed consent for themselves and for their baby prior to enrolment in the study, and consent to photograph was obtained from the parents of an affected newborn.In 2010, a total of 13,954 newborns were registered, corresponding to a birth rate of 12.7 per one thousand people. The number of mothers was 13,877 because there were 71 pairs of twins  and 3 triple births . A caesarean section was performed for 17% of the deliveries.Mean maternal delivery age was 26.3 ± 5.5 years (mean ± SD) with a range of 13–50 years  were younger than 20 years, including 16 mothers who were 13 to 15 years.Regarding maternal gravidity, gravidity 2–3 accounted for about half of mothers. Primigravida accounted for about a third (33.8%) of mothers and gravidity was 4 or more in 13.0%.Figure Half of the mothers had a secondary school or higher education degree, and 3.4% of mothers were illiterate .There were 7,209 boys and 6,743 girls (sex ratio = 1.07). Two newborns had an indeterminate sex. The mean birth weight was 3,116 ± 432 g (mean ± SD) with a range of 400–5,300 g. Low birth weight accounted for 5% all live births. The mean gestational age for live births was 39.4 ± 1.6 weeks. About 8.2% of live births were premature. The mean birth length was 49.9 ± 2.3 cm (mean ± SD) with a range of 22–60 cm. The mean head circumference at birth was 32.6 ± 1.9 cm (mean ± SD) with a range of 16–60 cm for all live births. An Apgar score below 7 was observed in 6.4% of live births.There were 84 cases with one or more EBDs, representing an overall prevalence rate of 6.02 per 1,000 live births. In terms of sex distribution, 47.6% of the birth defect cases were boys (n=40), and 50.0% were girls (n=42).2.4% had ambiguous genitalia (n=2).For mothers giving birth to a baby with external birth defects, the mean maternal delivery age was 27.0 ± 6.2 years (mean ± SD), with a range of 17–40 years.The under 20 age group  and the 35–39 year age group  showed a 2.37 (95% CI: 1.09 - 4.95) and 2.91 (95% CI: 1.37 - 5.98) fold higher prevalence of overall external birth defects when compared to the 25–29 year age group , respectively  and 2.2 (95% CI: 1.17 - 4.08) times higher than in women with gravida 2 or 3, respectively.Regarding the maternal education level, the prevalence of EBDs was highest in the illiteracy group, and similar in other groups. Table The prevalence ratio (PR) of EBDs between literate mothers and illiterate mothers was 2.81 (95% CI: 1.02 - 5.76).The EBD prevalence was higher in mothers with a history of miscarriage , in mothers who had a caesarean section , in Kinh mothers , and in rural resident mothers . These differences, however, were not significant between groups  with a range of 1,000-4,300 g for babies presenting external birth defects. External birth defects were 4.75 times (95% CI: 2.81 - 8.03) more frequent among live births with low birth weight than among live births who weighed more than 2,500 g.The mean gestational age for live births was 38.2 ± 3.5 weeks (mean ± SD) for babies with external birth defects. Babies born at less than 37 weeks of gestation were 2.09 times (95% CI: 1.17 - 3.27) more likely to have an external birth defect than babies born at 37 weeks or more.EBDs were 4.89 times (95% CI: 2.95 – 7.87) more frequent among newborns with an Apgar score under 7 points at five minutes than among newborns with an Apgar score of 7 or more.The mean birth length was 48.2 ± 4.2 cm (mean ± SD) with a range of 33–60 cm. The mean head circumference at birth was 31.4 ± 5.7 cm (mean ± SD) with a range of 16–60 cm for babies with external birth defects. There were no external birth defects in newborns from mothers in a consanguineous marriage  infants was born outside of a hospital Figure .The most commonly encountered group of anomalies were limbs, which accounted for 27.2/10,000 live births, followed by orofacial clefts  and the central nervous system . Prevalence at birth for selected external birth defects is shown in Table The prevalence of EBDs in Binh Thuan province was close to Taiwan data and not far from EUROCAT or Belgian data for most external birth defects. No cases of spinabifida were detected in our study.The prevalence of birth defects can be influenced by many factors including case definition, TOPFA, the time of observation after birth, population study methods, case ascertainment methods and reporting and statistical procedures used –16]..16].Termination of pregnancy is legal up to 22 weeks in Vietnam, but reporting of pregnancy termination is not required. However, prenatal diagnosis does not exist in our study's population. We therefore believe that the reason for termination of pregnancy in Binh Thuan is rarely an external birth defect. Consequently, TOPFA most likely does not have an influence the prevalence of the birth defects.We found that the prevalence of EBDs across the age distribution tended to be a U-shaped curve; prevalence dropped substantially for women over 40 years of age and only marginally for other age groups. For non-chromosomal defects, the U-shaped pattern of prevalence across maternal age has been documented by many authors ,15,17.In this study, the relationship between maternal education and an EBD did not necessarily mean that maternal education itself was a risk factor for EBDs. Educational qualification most probably determines socio-economic level and/or occupation and prenatal care behavior. It is therefore conceivable that education might affect the occurrence of EBDs indirectly .Most reported associations between occupational exposures and adverse reproductive outcomes in epidemiological studies are equivocal and often controversial . SignifiOur results show an increased prevalence of external birth defects occurring among mothers with either primigravida or gravida over 4.According to Swain et al., infants born to gravida 4 or more mothers have higher rate of birth defects when compared to mothers of lower gravidity . Tan et The relationship between the mother’s age at delivery and gravidity may be one possible explanation for the high rate of EBDs at both extremes of maternal gravidity in the present study.This study demonstrates that birth defects are significantly associated with preterm birth and low birth weight. Although preterm and low birth weight infants are more likely to have birth defects, the effect of birth defects on preterm birth and low birth weight has been difficult to study because of multiple confounding risk factors ,25.Many studies have documented male preponderance in birth defects ,27. HoweAs expected, the overall prevalence of EBDs in our study (6.02 per 1000 live births) was lower than the EUROCAT (25.53/1000) and Belgian 23.11/1000) registries /1000 reg.When considering the type of external birth defect, limb defects, nervous system defects, orofacial clefts and external genital system defects are by far among the most common birth defects worldwide –31]. In. In31]. In our study, the most common limb defects were clubfoot, polydactyly and limb reduction, respectively.Club foot is the common type of limb defect. Prevalence varies widely in among recent international reports. According to data from EUROCAT, the prevalence of clubfoot was reported to be 10.31/10,000 total births for all members, 11.21/10,000 in Belgium and varied from low  to high  in Ukraine and Saxony-Anhalt (Germany), respectively . Boo et Polydactyly is a major group. It is a defect that is easily detectable after birth and is an isolated finding in 85% - 88% of cases . Our polLimb reduction is one of the most common types of limb defects and accounts for 3.2 to 7.06 per 10,000 births in the literature ,27. ThisOrofacial clefts are among the most common of all major birth defects. Orofacial clefts are usually obviously visible immediately after birth.Cleft lip with or without palate involved 20 out of 13,954 live births , which is similar to the prevalence in Northern Ireland  ,35, loweAccording the international perinatal database report on typical oral clefts, the prevalence of cleft lip with or without cleft palate from 54 registries in 30 countries over at least 1 complete year during the period 2000 to 2005 was 9.92 per 10,000 births, which was lower than our finding .Isolated cleft palate is very difficult to detect prenatally due to shadowing artefacts from amniotic bands or other overlying structures.The prevalence of 5.37 per 10,000 live births for cleft palate in this study was comparable to those observed in the full member EUROCAT registry  . Our figNeural tube defects can be categorized as either anencephalus or similar (lack of closure in the head region) or spinabifida (lack of closure below the head). The two major categories of neural tube defects occur in approximately equal frequencies at birth ,42.Our data revealed that the prevalence for anencephalus or similar was 3.58 per 10,000 live births. This figure is comparable to that of the full member EUROCAT registry  and Belgium  [As expected, the prevalence of hydrocephaly in our study  was low compared to the full member EUROCAT registry , Belgium  and other registries ,27,29,39Hypospadias is considered the most common congenital malformation in the genitourinary system. Usually hypospadias is detected at birth by a detailed examination of the newborn or by abnormal flow of urine during urination. Experienced clinical personnel are required to detect hypospadias. In our study, newborns were examined within 24 hour after birth by a local health provider with limited expertise in hypospadias recognition. Thus the prevalence of hypospadias was low  compared to other registries ,29,39.The prevalence of external birth defects was not different between commune health stations and hospitals demonstrating health workers' abilities in detecting EBDs at commune health stations in Binh Thuan province.Internal organ defects are not visible during a physical exam or they are often asymptomatic, particularly during the first 24 hours of life. In this study, since the examinations were executed by simple measurements and observations of the newborn, birth defects of internal organs  were undetected.This first population-based study in Vietnam which required coordination efforts at the local level provides baseline prevalence of external birth defects. External birth defects can be diagnosed at birth; because our study was able to diagnose the majority of external birth defects occurring in Binh Thuan, the current data can be compared to the prevalence data of other registries.Data on EBDs from this study in southern Vietnam may be useful in setting up a regional population-based registry of birth defects in Vietnam.CHS: Commune health stations; DH: Provincial or District Hospitals; EBDs: External Birth Defects; EUROCAT: European Registration of Congenital Anomalies and Twins; HP: Health Professionals; ICD10-CM: International Classification of Diseases System-10, Clinical Modification; ICBDSR: International Clearinghouse for Birth Defects Surveillance and Research; TOPFA: Termination of Pregnancy For Foetal Anomaly.None of the authors of the above manuscripts has declared any conflict of interest statement.http://www.cud.be), which is a public funding from the Belgian government. The corresponding author has full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscript.TH participated in the design, carried out the study, performed the statistical analyses and drafted the manuscript. RR, TDA and YG provided advice in the design of the study and the analytical strategy and contributed to the manuscript revision. NNVP helped in the data analysis and report. AR and DNT are head of the project; they provided advice on the structure, the data analysis and presentation, and supervised the manuscript redaction. No author has any financial or private interest in this research project. There is no organization sponsoring this research which is granted by the Commission Universitaire pour le Développement (The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/13/67/prepub


Few studies have been conducted on the association between perinatal and early life factors with childhood depression and results are conflicting. Our aim was to estimate the prevalence and perinatal and early life factors associated with symptoms of depression in children aged 7 to 11 years from two Brazilian birth cohorts.The study was conducted on 1444 children whose data were collected at birth and at school age, in 1994 and 2004/2005 in Ribeirao Preto, where they were aged 10–11 years and in 1997/98 and 2005/06 in São Luís, where children were aged 7–9 years. Depressive symptoms were investigated with the Child Depression Inventory(CDI), categorized as yes (score ≥ 20) and no (score < 20). Adjusted and non-adjusted prevalence ratios (PR) were estimated by Poisson regression with robust estimation of the standard errors.The prevalence of depressive symptoms was 3.9% (95%CI = 2.5-5.4) in Ribeirão Preto and 13.7% (95%CI = 11.0-16.4) in São Luís. In the adjusted analysis, in Ribeirão Preto, low birth weight , skilled and semi-skilled manual occupation  and unskilled manual occupation and unemployment  of the household head were risk factors for depressive symptoms. In São Luís, maternal schooling of 0–4 years  and of 5 to 8 years , and paternal age <20 years , were independent risk factors for depressive symptoms.The prevalence of depressive symptoms was much higher in the less developed city, São Luís, than in the more developed city, Ribeirão Preto, and than those reported in several international studies. Low socioeconomic level was associated with depressive symptoms in both cohorts. Low paternal age was a risk factor for depressive symptoms in the less developed city, São Luís, whereas low birth weight was a risk factor for depressive symptoms in the more developed city, Ribeirão Preto. Even though there are no longer any doubts about its occurrence , many gaThe prevalence of depression detected in Brazilian and international studies can vary considerably depending on the age range evaluated , the instrument for evaluation, cut-off points and the sample selected ,5-8. A hSome studies have investigated the association between low birth weight/preterm birth and health problems in later life . There iChildren are a part of the population whose mental health problems are less studied than those of adults. Knowing the risk factors for depression during childhood is essential for a better understanding of the etiology of this disorder and for planning prevention strategies.The objective of the present study was to estimate the prevalence of depressive symptoms and to assess the association of perinatal and early life risk factors with depressive symptoms in children aged 7 to 11 years belonging to two Brazilian birth cohorts. We hypothesized that low birth weight, preterm birth, low socioeconomic status, low parental age and female sex are associated with a higher risk of depressive symptoms in childhood.The study was based on two birth cohorts, one started in Ribeirão Preto in 1994, and the other in São Luís in 1997/98, and on follow-up studies conducted at school age when the children were 10 to 11 years old in Ribeirão Preto, in 2004/05, and 7 to 9 years old in São Luís, in 2005/06.Ribeirão Preto is a city located in the Southeast of the country, a wealthy and industrialized region, with a population of 461,427 inhabitants in 1994. Its Municipal-Human Development Index (M-HDI) was 0.855 in 2000,26. São A total of 2923 liveborn infants delivered at 10 city hospitals over a period of 4 months (April to August 1994) were included in the first stage of the Ribeirão Preto study, representing 99% of all live births during the period. Stillbirths were not included. Fewer than 5% of births were not interviewed due to early discharge or refusal. Excluding multiple births, the final sample consisted of 2858 births [The first stage of the São Luís study was conducted from March 1997 to February 1998. Systematic sampling was used, stratified according to the number of births in each of the 10 public and private maternities of the city. At each hospital, one in 7 children was systematically selected from a total of 2,542 hospital live births, stillborns and singleton or multiple births of mothers residing in São Luís. The sample was representative of city births since hospital deliveries corresponded to 96.3% of the total. After the exclusion of multiple births (n = 50) and stillborns (n = 48), the final sample consisted of 2,443 births. Losses due to refusals or to the impossibility of locating the mother occurred in 5.8% of the cases .Five groups of birth weight were considered for the follow-up study: <1500 g, 1500 to 2499 g, 2500 to < 3000 g, 3000 to <4.250 g, and infants whose birth weight was at least two standard deviations above the mean for the study population, ≥ 4250 g. Infants in the weight range with the lowest number of newborns  were oversampled in order to increase the study power. Because in the groups <1500 g and ≥4250 g achieved sample size was small for a meaningful analysis, birth weight was then reclassified into low birth weight (LBW <2500 g) and non-low birth weight (NLBW ≥2500g).A search for the children of the cohort was carried out in the schools of both cities. All parents or persons responsible for the children in the <1500 g, 1500 to 2499 g and ≥4250 g groups and a fraction of one to three of those responsible for children in the groups of normal birth weight were invited by telephone or by mail to participate in the study. In Ribeirão Preto, after the exclusion of deaths during the first year of life (n = 47), 1150 children were eligible for follow-up. The follow-up rate was 68.7% (169 LBW and 621 NLBW children), with 790 children aged 10–11 years participating in the study.In São Luís, after the exclusion of deaths during the first year of life, 2378 children were alive at one year of life and 926 were eligible for follow-up. Thus, 673 children aged 7–9 years were followed up , 81 of them being LBW and 592 NLBW.Losses occurred due to the impossibility of locating the children, to migration, to the fact that the children were not enrolled in school, to refusal on the part of the parents or because two schools in São Luís did not allow the research team to contact the children.A sample of 673 children in São Luís and a sample of 790 children in Ribeirão Preto have an 80% power to detect a minimum 5% absolute difference in the prevalence of depressive symptoms, estimated at about 10%, with a 5% probability of type I error.et al..[The Childhood Depression Inventory (CDI) was used to investigate the presence of depressive symptoms. The CDI is a screening test that evaluates the presence and severity of specific depressive symptoms and is based on a self-report inventory elaborated by Kovacs in 1981, consisting of 27 items with 3 reply options, with the child checking the one that best describes how he/she feels. A version with 20 items was adapted and standardized by Gouveia et al.. for BrazThe CDI was applied to subsamples of 774 children in Ribeirão Preto and of 670 children in São Luís, evaluated at school age. In the present study we used the original 27-item version of the CDI because the original version of the inventory showed a higher degree of internal consistency when compared to the reduced version of the instrument . The chiExplanatory variables were collected at the time of the child’s birth by applying a standardized questionnaire to the mother. They were chosen based on having been previously reported to be associated with depression in some studies. The following variables were considered: sex, number of household members , maternal and paternal age in completed years at the time of the child’s birth , maternal schooling , paternal schooling , occupation of the family head , mother’s job outside the home, maternal smoking during pregnancy , marital status , parity , low birth weight (<2500 g) and preterm birth  . Birth wThe response variable was depressive symptoms, categorized into yes (CDI ≥ 20) and no (CDI < 20). Uni- and multivariable analyses were used and the prevalence ratios (PR) and their respective 95% confidence intervals were estimated. Statistical analysis was performed using Poisson regression, with robust adjustment of variance . Multivasvy commands of the Stata software. The different probabilities of selection of each birth weight group and preterm birth group were taken into consideration in the weighting procedure. Sample stratification according to birth weight was also taken into consideration.Due to the complex sampling design, the sample was not equiprobabilistic, i.e., low birth weight (<2500 g) and high birth weight (≥ 4250 g) children were over-represented in the sample. For this reason, the estimates of prevalence and their respective standard errors were weighted using the set of o 2165/2004) and by the Research Ethics Committee of the University Hospital, Federal University of Maranhão, UFMA (No 060/2005).The reasons for the study and the methodological procedures involved were explained to the parents and/or persons responsible who, after accepting the participation of their children in the study, signed an informed consent form at birth and at follow-up according to the directives and the regulatory norms of research involving human beings of the Brazilian National Health Council, resolution 196/1996 and complementary ones. The right to interrupt the study at any time, access to the results and confidentiality about them were guaranteed to the participants. The project was approved by the Research Ethics Committee of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo  and with higher family income (45.5% earned ≥4 minimum wages) whereas children from the São Luís cohort were younger (7–9 years of age) and presented a lower family income (only 7.3% earned ≥4 mininum wages). White children represented 56.3 of the sample in Ribeirão Preto and 23.5% in São Luís. Birth weight was lower in the Ribeirão Preto  than in the São Luís cohort . Gestational age was also lower in the Ribeirão Preto  than in the São Luís cohort .The prevalence of depressive symptoms using the cut-off point of 20 was 3.9% (95%CI = 2.5-5.4) in Ribeirão Preto and 13.7% (95%CI = 11.0-16.4) in São Luís. Using 17 as the cut-off point, the prevalence of depressive symptoms was 5.8% (95%CI = 4.0-7.4) in Ribeirão Preto and 21.9% (95%CI = 18.6-25.2) in São Luís. These differences between cities were statistically significant (P < 0.001).In univariable analysis, in São Luís, maternal schooling ≤4 years (PR = 2.05) and from 5 to 8 years PR = 1.74) were risk factors for the presence of depressive symptoms. Sex, low birth weight, preterm birth, number of household members, parity, maternal smoking during pregnancy, maternal and paternal age, mother’s job, occupation of household head, marital status and intrauterine growth restriction were not associated with the presence of depressive symptoms  and marriage (PR = 0.37) were protective factors against depressive symptoms. Conversely, maternal schooling ≤4 years (PR = 4.60), low birth weight PR = 2.72), skilled and semi-skilled manual occupation (PR = 8.67), unskilled manual occupation and unemployment of the family head (PR = 12.57) were risk factors for the presence of depressive symptoms. Sex, preterm birth, parity, maternal smoking during pregnancy, maternal and paternal age, and mother’s job were not associated with depressive symptoms  and of 5 to 8 years (PR = 1.80) continued to be risk factors for the presence of depressive symptoms. Paternal age <20 years, which was not associated with depressive symptoms in the unadjusted analysis, was an independent risk factor after adjustment (PR = 1.92). Even after adjusting for paternal schooling the association remained significant (data not shown). In Ribeirão Preto, low birth weight (PR = 3.98), manual skilled and semi-skilled occupation (PR = 5.30), manual unskilled occupation and unemployment (PR = 6.65) of the family head continued to be risk factors for the presence of depressive symptoms  and its quadratic term (p = 0.037) were associated with depressive symptoms in Ribeirão Preto but not in São Luís. Gestational age and its quadratic term were not associated with symptoms of depression in both cities . In Ribeirão Preto predicted prevalences of depressive symptoms were higher for lower birth weights, decreased from 500 g to 3500 g and increased thereafter  were risk factors for presence of depressive symptoms.According to the American Academy of Child and Adolescent Psychiatry, the prevalence of depression among children and adolescents aged 9 to 17 years has been estimated at 5% . Using tet al. in 1995 [Several investigations have demonstrated a wide variation in the prevalence of depression in children and differences according to the criteria of diagnostic classification adopted, mainly due to the diverse mode of presentation of depression and the association of this disorder with other psychopathologies. In addition, there still is no single instrument for the evaluation of depression . Among t in 1995 .Other factors that impair comparison of the results are the different age ranges of the populations studied and the time and location of the studies. More recent studies  have repThe prevalence of depressive symptoms detected in São Luís is similar to that observed by Barbosa and Gaião  in ParaíIn Ribeirão Preto, the prevalence of depressive symptoms was higher among low birth weight (<2500 g) children compared to normal birth weight children. This result agrees with other studies that showed that LBW, including VLBW (500–1499 g), may influence the development of depression in later life ,17,18,24In São Luís, there was no association between LBW and the presence of depressive symptoms, in agreement with other international studies -23. MortIt is known that when children approach adolescence their depressive symptoms tend to resemble those of adults . This maIn Ribeirão Preto, in a model including birth weight, treated as a continuous variable, and a quadratic term for birth weight, association between birth weight and depressive symptoms was non-linear, being higher in the lower birthweights, decreasing from 500 g to 3500 g and increasing thereafter, suggesting that risks of depressive symptoms are higher for both low and high birth weight groups.Few studies have been published on the association between LBW and depression at school age ,20,24. MA worse socioeconomic situation assessed on the basis of maternal schooling and occupation of family head was an important predictor of the presence of depressive symptoms in both cities, in agreement with other studies ,11,18. MIn our study young paternal age (<20 years) was independently associated with increased depressive symptoms in the less developed city, São Luis . Some yoSex was not associated with the presence of depressive symptoms, in contrast to some international studies, which reported that depression was more prevalent among adolescent or adult females ,9. This This was one of the few cohort studies carried out to assess the prevalence of risk factors for depressive symptoms in children in a middle-income country, by comparing a more developed city to a less developed one. The over-representation of the groups of high and low birth weight was a strategy used to increase the statistical power of the study.The high rates of loss due to mortality, migration and failure to locate many children was a limitation of the study. Participation rates were lower in Ribeirão Preto for mothers who were less than 20 years of age (p = 0.005), who cohabited (p < 0.001) or had ≤ 4 years of full time education (p < 0.001) in comparison to eligible children who did not participate. In São Luís, a lower proportion of children were born to mothers with ≥ 12 years of full time education (p < 0.001), who were primiparous (p = 0.049) or gave birth to males (p = 0.001) among those who participated in the study in comparison to the eligible group who did not participate . These dThe CDI is a screening test. Although it can serve as an aid in the diagnostic process, it cannot yield a diagnosis by itself . It coulThe age difference of two years may have contributed to explaining part of the differences in depressive symptoms between the two cohorts. Children from São Luís were a little younger than those from Ribeirão Preto and may have had difficulties in describing and evaluating their feelings in the last fortnight, as asked by the CDI. A study has shown that the reliability of the child's report of the Diagnostic Interview Schedule for Children (DISC) increased with age and was lower for children aged 6–9 than for those aged 10–13 and 14–18 . HoweverThe prevalence of depressive symptoms was much higher in the less developed city, São Luís, than in the more developed one, Ribeirão Preto, and than the values reported in various international studies. Low socioeconomic level was associated with the presence of depressive symptoms in both cohorts. Low birth weight was a risk factor for the presence of depressive symptoms in the more developed city, Ribeirão Preto, only. Young paternal age was associated with a higher report of symptoms of depression in the less developed city, São Luís, only. Improvement of the socioeconomic situation, increasing paternal age at childbirth and the prevention of LBW are measures that could reduce the prevalence of depressive symptoms. However, most of the variation in the prevalence of depressive symptoms was not explained by the variables present in the model.The authors declare that they have no competing interests.AAS, MAB and HB conceived the study. AAS and TSP performed the statistical analysis. RFB, MTA, AAS, TSP, VMS, FLF, FPF, JDR, MAB and HB contributed to data analysis and interpretation of results. AAS and TSP wrote the paper. All authors read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/605/prepub


Preterm birth is a global problem in Perinatal and infant Health. Currently is gaining a growing attention. Rates of preterm birth have increased in most countries, producing a dramatic impact on public health. Factors of diverse nature have been associated to these trends.In Chile, preterm birth has increased since 90. Simultaneously, the advanced demographic transition has modified the characteristics of woman population related to maternity.The principal objective of this study is to analyze some sociodemographic characteristics of the maternal population over time, and their possible association to rates of preterm birth. The second aim is to identify groups of mothers at high risk of having a preterm child.This population-based study examined all liveborn singletons in Chile from 1991 to 2008; divided in three periods. Preterm birth rates were measured as % births <37 weeks of gestation.Logistic regression assessed the risk of preterm birth associated with mother’s age, parity, and marital status, expressed as crude and adjusted odds ratios.Over time, rates of preterm birth increased in overall population, especially during the third period (2001–2008). In the same time, characteristics of maternal population changed: significant increase of extreme reproductive ages, significant decrease in parity and increase in mothers living without a partner.Risk of preterm birth remained higher in groups of mothers: <18 and >38 years of age; without a partner; primiparas and grandmultiparas. However, global increase in preterm birth was not explained by the modification of socio demographics characteristics of maternal population.Some socio demographic characteristics remained associated with preterm birth over time. These associations allowed identifying five groups of mothers at higher risk to have a preterm child in the population.Increase in overall preterm birth affected all women, even those considered at “low sociodemographic risk” and the contribution of more recent period (2001–2008) to this increase is greater.Then, studied factors couldn’t explain the increase in preterm birth. Further research will have to consider other factors affecting maternal population that could explain the observed trend of preterm birth. Preterm birth (PTB) is gaining increasing attention. During the four last years, several call for action and for research has been made throughout the systematic revue of worldwide incidence/prevalence and also throughout the series of Global Reports -4.The seven Global Reports on preterm birth and stillbirth, issues of Conference on Preterm birth and Stillbirth on may 2009 (USA), estimated that 13 million babies are born before 37 completed weeks of gestation annually. Later, in the Global Action Report on Preterm Birth: Born Too Soon (WHO 2012), the number of preterm birth increased to 15 million annually.Rates (% births <37 weeks of gestation), are generally higher in low- and middle income countries than high income countries. In these countries is born 92% of all preterm birth and 99% of them die. Rates are also increasing in most of these countries .Multiple factors may be associated with increase in PTB, among them, socio demographics changes in maternal population such as increased maternal age and delayed primiparity ,7. NeverGlobally, few countries have been assessed the maternal sociodemographic factors over time as Finland and Sweden who have monitored the maternal population through studies in birth cohorts ,16. ThosChile is a middle income country where the PTB rates have significantly increased . This inIn Chile, maternal and perinatal health constitute a major focus of public health policies and PTB is a health priority . HoweverThe objective of present study is firstly: to examine sociodemographics characteristics of maternal population in the past two decades, then, to analyze their association with the risk of PTB, and finally to identify groups at higher risk of giving birth to a premature child.This population-based observational study of singletons liveborn in Chile 1991–2008) examined 4 475 444 births recorded in the National Livebirth Database in Chile. The Chilean database is the official source of health statistics about live births in the country; it undergoes systematic verification from hospital sources. It does not impute any data. Data are available under demand of the researcher  and data are not linked with medical or clinical files. Since the individual identification of women is not available, patient’s consent is not possible.Primarily, the aim of this research is in compliance with the Helsinki Declaration with a reasonable likelihood of benefit to the population studied.In all, 83 017 observations (1.85%) were removed from the initial set. Table From the final set for analyses, N = 4 392 427), we can observe a highly significant increase (p <0.001) in the rates of PTB by period . Despite a weak diminution of OR during the third period, this group remained high both risks: the absolute and relative risk of having a premature child.• Mothers younger than 18 years (compared with those aged 18–38 years). They keep the same statistical relative risk over the time.• The mothers living without partner (compared with those living with a partner). Adjusted OR of PTB declined during the second period but then rose again from 2001 onward.– Group whose number was falling in the population:• Grand multiparas, (compared to multiparas). Their relative risk remained unchanged over the time.– Group whose number was relatively stable through the observed time:• The primiparas (compared to multiparas). Adjusted OR for PTB did not vary after 1996, although it remained higher than during the first period.Over an 18-year period, the rate of PTB has increased significantly in this population database. At the same time, the sociodemographic profile of mother’s population has changed substantially: parity has decreased and the percentage of younger, older and mothers not living with a partner rose.Mothers following these trends had a considerable high risk of give birth to preterm child over time. Moreover, the number of women belonging to such groups at risk has also increased markedly (except for grand multiparas).All and every of the studied factors are not enough to explain the increase of PTB because increase in the rates of PTB affected the entire population including those mothers without sociodemographic risk. Also, the more recent period contributed significantly to this increase independently of these factors.Probably the last period reveals the effect of other possible factors, not available in this data base, such as life style changes, new patterns of sexual behavior or family structure. Some of this factors have already been observed by other studies in Chile .Furthermore, another factors reported in the literature, but not available in data base, should be determined in this population, such as the status and conditions of working mothers, exposure to environmental and occupational contaminants, consumption habits, and most generally, the health issues of women.Moreover, these trends could be related, as well, to the increase in obstetric interventions (cesarean deliveries and induction of labor) established by public and private policy in order to reduce maternal and fetal risk. In fact, the rates of both cesarean deliveries and induction of labor have been increasing in Chile for three decades and are among the highest in South America ,31. UnfoThe observed trends over the past two decades may also be related to an increase number of birth of extremely preterm infants. This could in part be associated to obstetrical and perinatal interventions aimed at diminishing fetal mortality among them, the progressive use of systematic fetal USN of first trimester.The results suggest that in Chile, early, accessible prenatal monitoring ensures the collection of good quality data for estimating gestational age. It has reported a steady level of agreement between ultrasounds performed during the first trimester and gestational dates estimated by last menstrual period (61.9% in 1994 and 65.6% in 2001).The quality of GA might be expressed in this study by the low proportion of error of classification of GA throughout the observation period. These errors decreased over time, this is probably the principal effect of systematic fetal USN of first trimester since the second period. In this context, the contribution of USN to increase of PTB seems to be modest. In addition, the trend to increase of PTB is sustained and it remains beyond the systematization of USN.In all, only 1.85% of births were excluded of the initial set. This proportion is lower than other studies in population data base ,33. But The Tukey’s rule, was also used by Arbuckle in Canada , this meComparing with previous studies, the trends observed in the groups at highest risk are similar to those observed in studies of parity, marital status and older mothers in France  and EnglSimilar results have been observed In Belgium , whit a In the same direction of these results, Haas in USA  has repoIn Chile access to medical care during pregnancy is universal. Beyond this, the high — and still rising — proportion of adolescents mothers is the continuation of an unsolved public health problem in Chile .Countries such as France  and FinlAmong the groups at highest risk, the observed increase in maternal age is a new public health challenge in terms of maternal and perinatal results, as it requires a greater focus regarding the need for medical interventions during pregnancy and delivery, for assisted reproductive technologies, and for other highly specialized services .Chile reached in 2003 its lowest rate of maternal mortality 12.2/100.000 live births after years of successfully reducing its prevalence, nevertheless the prevalence has risen over the past five years to 19.8/100.000 live births in 2005. The authors claim that maternal age over 35 years is the principal explanatory factor of this result, due to concomitant chronic diseases affecting such group of mothers .Unfortunately, one of the principal limitations of the study is our inability to assess other important factors like clinical maternal and fetal condition. Moreover the absence of information available about the mode of delivery prevents us from being able to distinguish between spontaneous and medically indicated PTB .Concerning rates of multiple gestations in Chile, they are increasing; this trend is showed in a recent study made over the same period (1991–2008) . This inConcerning assisted reproductive technologies (ARTs), they are rising and it is related to the increase of maternal age and late primiparity. However, this group of births has not significantly contributed to the rate of prematurity. Indeed, the report including twenty years of ARTs in Chile shows that between 1991 and 2008 only 3910 children were born through ARTs. The contribution of this group to preterm birth in those twenty years is poor: 353 single preterm birth, 585 doubles preterm and 210 preterm births in triples .The principal reason is that these techniques are not yet a large coverage because they are very high cost.Another challenge is the group of mothers living without partner. This is the only group for which the risk is probably due to sociodemographic context; nonetheless this group is still largely unknown. Countries that have succeeded in reducing this risk have implemented measures to support these mothers and to reduce their psychosocial and economic vulnerability ,44; ChilFurther studies may be suitable using the others available variables in data base, such as: socio demographics characteristics of father, maternal education level. This group of variables could guide the hypotheses about the socio economic condition as important contributor au PTB.In this direction, the study of K Joseph gave an important orientation about the distribution of sociodemographics factor by socioeconomics levels.At the same way, the evaluation of the risk associated with interaction between these factors appears useful in view of the multifactorial etiology of PTB and LBW. For the moment; little research exists in this domain, but Schempf, in the United States, observed an important increase in risk of PTB in both groups: primipara teenager and primipara older in Hispanic mothers .The main strength of this research is having allowed identify some sociodemographic factors of risk of preterm birth over time, as well as, allowed identifying the trends of mothers with such characteristics.The results indicate the need to redirect resources toward specific primary and secondary prevention but also toward the research; otherwise the trends reported here might unfortunately continue over time. Measures for prenatal care appropriate to this “new profile of mother’s population” should be considered and implemented through education, organization of care and professional resources. Resources also should be intended to the whole population of the women.The implication of this findings, both, from a clinical and public health perspective is particularly interesting to other middle-income country similar to Chile, or countries which are beginning the process of demographic transition. The results might aid in the analysis of challenges to be expected in the domain of preterm birth.Unfortunately, this study does not provide a clear explanation for the sustained increase of these births over nearly two decades in Chile. This limitation is principally due to lack of available data. Then this study revealed the enormous need for information about obstetric care, the lifestyle of women, their work context and their reproductive choice between other factors not considered here.These factors may affect all women and they could help explain the growing trend of the premature birth as epidemiological phenomenon currently affecting most countries in the world. The results support the necessity of use of research and action, formulated by the last global report Born Too Soon.The first, in order to understand thoroughly the causes of increase of PTB, there is a need to strengthen existing data by collecting detailed information about events and clinical history during pregnancy and delivery.Further progress in explaining the determinants beyond that were analyzed here will require an interdisciplinary approach that will take into account their diversity, their complexity and their probable interactions. Such approach could shed light on the role of qualitative factors, such as women’s lifestyles or family structure.Preterm birth has increased over the past two decades in Chile. Some sociodemographic characteristics of mothers are steadily associated with the risk of preterm birth over time. Such association has allowed identifying five groups of mothers at higher risk of PTB. The epidemiologic importance of these groups is changing over time through an increase in the number of women belonging to groups at higher risk of preterm delivery.Despite of these specifics results, sociodemographics factors, by themselves, are not enough to explain the marked trends to increase in rates of PTB affecting the overall population.Further research could be define the role of others underlying factors over time, that are probably widely affecting the population of mothers, especially during the most recent period.The authors declare that they have no conflicts of interest in regard to this research.PL Designed the study, made possible the acquisition of data, analyzed and interpreted the data. GB Made substantial contributions to conception and design of this study, has been involved in drafting the manuscript and revised it, providing critical and important intellectual content. It has revised and approved the final version submitted for publication. Both authors read and approved the final manuscript.


Background: Preterm birth (PTB) is responsible for 70% of neonatal mortalities. Various factors influence the risk of neonatal mortality in different populations.Objective: Our objective was to evaluate neonatal survival rate of preterm infants, and to define its predictors in Iranian population.Materials and Methods: This retrospective cohort study included all preterm (26-37 weeks) infants (n=1612) born alive in Shahid Akbar-abadi university hospital, during one year period (April 2010-2011). These infants were evaluated for fetal-neonatal, maternal, and pregnancy data. Survival analysis was performed and viability threshold and risk factors of neonatal mortality were evaluated.Results: Total overall mortality rate was 9.1%. Survival rate were 11.11% for extremely low birth weights (LBW) and 45.12% for very early PTBs. The smallest surviving infant was a 750 gr female with gestational age (GA) of 30 weeks and the youngest infants was a 970 gram female with GA of 25weeks plus 2 days. History of previous dead neonate, need to cardio-pulmonary resuscitation (CPR), need to neonatal intensive care unit (NICU) admission, postnatal administration of surfactant, presence of anomalies, Apgar score <7, multiple pregnancy, non-cephalic presentation, early PTB, very early PTB, LBW, very low birth weight (VLBW) and extremely low birth weight (ELBW), were risk factors for mortality in preterm neonates.Conclusion: Our study revealed that neonatal survival rate is dramatically influenced by birth weight especially under 1000grams, GA especially below 30 weeks, neonatal anomalies, history of previous dead fetus, multiple pregnancy, non- cephalic presentation, and need for NICU admission, resuscitation and respiratory support with surfactant  Infants born before 37 weeks of gestation are at greater risk for morbidity and mortality compared with term newborns . PretermAlthough extremely low birth weight (ELBW) (≤1000 g) infants comprise less than 1% of all live births, they account for approximately half of the perinatal mortality rate . During et al in our population, with larger sample size and considering the risk factors of neonatal mortality  infants (n=1612) born alive in Shahid Akbar-abadi University Hospital, during one year period (April 2010-April 2011). This hospital is the largest maternity hospital in the capital city of Iran, Tehran, with a level III NICU. It covers more than 80% of all deliveries in the south and south west, with approximately 20,000 deliveries in a year. Data CollectionData was collected using questionnaires from patient medical records. The questionnaire comprised of fetal-neonatal, maternal, and pregnancy data; antenatal medications; root of delivery; management in the neonatal period; postnatal outcomes (described below) and delivery to discharge duration. Questionnaire was completed for each preterm baby during the study period, (N=1800). Inclusion criteria was all live born preterm (before 37 weeks of gestation) babies delivered during the study period, with at least one examination in first 20 week (for accurate estimation of GA). Infants born from diabetic and hypertensive mothers, who had lethal congenital anomalies, who did not receive prenatal steroid  at the time of admission and who received antenatal magnesium sulfate were excluded from the analysis. Outcome MeasuresPrimary outcome was delivery to discharge survival rate among preterm infants. Predictive variables for survival were: GA, presentation, order, delivery root, Apgar score, birth weight, neonatal sex, congenital non-fatal anomalies , need for NICU admission (defined as admitting in NICU for more than 12 hr), need for resuscitation , duration of NICU admission, postnatal surfactant (administered in cases of respiratory distress syndrome), time of neonatal death and time to discharge. Secondary outcomes were delivery to discharge survival for each predictor variable separately, the most important of them were: GA, neonatal birth weight, sex and Apgar score. GA was determined on the basis of the last menstrual period and sonography in the first half of pregnancy. According to current guidelines developed by the American Academy of Pediatrics, we did not initiate resuscitation for infants younger than 23 weeks or those whose birth weight was less than 400 g . Survival was defined as the proportion of live births surviving up to the time of discharge. Early and late neonatal mortality rates were defined as proportion of dead neonates in first 7 and 28 days respectively. LBW, VLBW and ELBW were defined as birth weight under 2500, 1500 and 100, respectively. Late PTB, early PTB and very early PTB were defined as delivery at 37-34, 34-30 and under 30 weeks of gestation.Statistical analysisNumerical variables were reported as mean±SD when normally distributed, otherwise as median and range. We used independent sample t-test and analysis of variance to compare the difference of numerical variable across demographic groups. The Chi-square was used for analysis of the qualitative variables. The Kaplan-Meier method was calculated to estimate mortality rate of preterm infants. The effect of GA, birth weight, neonatal sex, Apgar score on survival were studied by Kaplan-Meier survival estimators for each category using log rank test. P≤0.05 was considered to be statistically significant. All analyses were performed using SPSS for Windows version 16 . Questionnaire was completed for 1800 preterm baby during the study period, among which 178 were excluded. Analysis was performed on the complete data of 1612 preterm neonates. Characteristics of the study group are summarized in Among dead neonates, 39% and 63.7% were died during the first 24 hours and the first 48 hours, respectively, 84.3% in early neonatal period (the first week), 12.24% in late neonatal period (7-28 days) and 3.4% died thereafter. Survival rate at first 24 hours, 48 hours, one week, 2 weeks and 4 weeks were 95%, 93%, 87%, 83%, and 79% respectively. Total cumulative survival of preterm neonates is demonstrated in All neonates with GA ≤25 weeks or birth weight ≤700 grams died before 48 hours, where, 11.11% (n=5 out of 45) of extremely LBW and 45.12% (n=74 out of 162) of very early PTBs were survived. The smallest surviving neonate was a 750 gr female with GA of 30 weeks and the youngest neonate was a 970 gr female with GA of 25 weeks plus 2 days. Survival was higher in late PTBs comparing early and very early PTBS (p=0.0001) and also higher in normal birth weights comparing LBW, VLBW and ELBW babies (p=0.0001). Survival for very early PTB and ELBW infants were dramatically low. Preterm neonates’ survival specified for GA and birth weight estimation using Kaplan-Meier method and Log-Rank test are shown in We could not find a significant difference among male and female sex for mortality rate, however, neonates with ambiguous genitalia showed very high mortality rate (66.66%). Six neonates had ambiguous genitalia, 4 cases were among dead (2.7%) and 2 among alive neonates (0.1%). This difference was statistically significant (p=0.0001). There was also no difference in root of delivery and mother’s education among dead and alive neonates.The present study revealed that LBW, VLBW, ELBW, early PTB, very early PTB, ambiguous gender, presence of anomalies, history of previous dead fetus, multiple pregnancy, non-cephalic presentation, need for NICU admission, need for resuscitation and respiratory support with surfactant, were associated with neonatal mortality in preterm births. It suggests that neonatal short term survival was dramatically influenced by birth weight especially ELBWs and GA especially below 30 weeks. It is generally accepted that births before 26 weeks, especially those weighting less than 750 gr, are at the current threshold of viability and that these preterm infants pose a variety of complex medical, social, and ethical considerations . The biret al. in Iran, in a study with a small sample size, which showed that the expected survival rate of neonates was greatly influenced by a gestational age of higher than 32 weeks and a birth weight of more than 1250 grams  are 2-3 fold greater than the risk among appropriate for gestational age infants , 16, 23.In a recent study on neonatal outcomes in early PTBs by delivery root, there was no difference in neonatal mortality for vertex presentation; however, neonatal mortality was increased for breech presentation in vaginal delivery . It alsoWe showed that the survival of neonates with cephalic presentation, either delivered vaginal or abdominal, were better than other presentations. It is clearly due to the more prevalence of non-cephalic presentation in smaller age and weight neonates, and more prevalence of anomalies in non-cephalic infants. In our study singletons had better survival compared to multiple pregnancies, while multiple births showed to have no detectable effect on the adjusted composite neonatal outcome of mortality and morbidities . Our stuThe significant reduction in neonatal mortality during recent years, results from technological and pharmacological advances over the last 30 years. Considering the limitation of available resources, the important question is: where and how should we invest in neonatal care. Having knowledge about outcome of preterm infants and the risk factor of their mortality and morbidities influence the way professionals take care of mothers and their infants, and help to use the resources properly. The strength of this study was its large size and its novelty in our population. However, our data lacks the evaluation of neonata morbidities and long term outcome of survived babies as we could not follow neonates after discharge. The results also may not be generalizable to other populations. Preterm newborns from other populations may have different survival rates and mortality risk factors.The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.


P = .29 at rest; r = −.18, P = .04 following stress). This finding was strengthened if the children had a relatively low birth weight for their placental weight . Our findings suggest that lateralization of cerebral activity is influenced persistently by early developmental experiences, with possible consequences for long-term neurocognitive function.Adverse fetal environments are associated with depression, reduced cognitive ability and increased stress responsiveness in later life, but underlying mechanisms are unknown. Environmental pressures on the fetus, resulting from variations in placental function and maternal nutrition, health and stress might alter neurodevelopment, promoting the development of some brain regions over others. As asymmetry of cerebral activity, with greater right hemisphere activity, has been associated with psychopathology, we hypothesized that regional specialization during fetal life might be reflected persistently in the relative activity of the cerebral hemispheres. We tested this hypothesis in 140 healthy 8–9 year-old children, using tympanic membrane temperature to assess relative blood flow to the cerebral hemispheres at rest and following psychosocial stress . Their birth weight and placental weight had already been measured when their mothers took part in a previous study of pregnancy outcomes. We found that children who had a smaller weight at birth had evidence of greater blood flow to the right hemisphere than to the left hemisphere (r = −.09,  Adverse fetal environments are associated with impaired neurocognitive function in later life, including depression It is well established that asymmetrical activation of the cerebral hemispheres is associated with altered affective states, including depression Technologies such as fMRI and positron emission tomography (PET) allow detailed study of cerebral activity but they have limitations that constrain their use in large epidemiological studies, particularly in studies of children. These include expense, limited access, noise or radiation exposure, motion intolerance, an environment that limits interaction with participants and that may stress them, and the requirement for time-consuming, technically challenging data analysis procedures. We sought out a technology that might give useful insights in such studies, enabling investigation of developmental effects on cerebral activity in cohort studies.Tympanic membrane (TM) thermometry has emerged as a simple, inexpensive and non-invasive means to assess cerebral blood flow to the two hemispheres. Brain temperature and TM temperature (TMT) are usually higher than the temperature of incoming blood from the body. Thus, increased blood flow cools these tissues, leading to an inverse relationship between temperature and perfusion. Brain temperatures, estimated by MR thermometry, are related inversely to regional blood flow In this study, we evaluated cerebral activity and its laterality at rest and in response to a psychosocial stressor using TMT measurements to examine the hypothesis that regional specialization of the brain is affected persistently by differences in the fetal environment.We recruited 140 healthy children aged 8–9 years for a cross-sectional study. They had been followed since 12 weeks of gestation when their mothers took part in a study of children born in Southampton, United Kingdom The children attended a clinical research facility for the TSST-C. The children were asked to stand in front of a video camera and microphone and perform an exciting story of their own invention, followed by a serial subtraction task for an audience of three adult strangers. They had 5 minutes to prepare before the stress test, which had a median duration of 11.1 (IQR 10.8–11.3) minutes. The original TSST-C protocol Simultaneous bilateral TMT was measured using a pair of infrared tympanic thermometers  on three occasions. After participants had acclimatized to their novel environment for one hour approximately, a baseline measure was taken, which preceded the TSST-C by 2 hours approximately. Further measures were taken at median delays of 4.5 (IQR 4–5.3) and 33 (IQR 32.4–33.9) minutes after completion of the TSST-C.Each pair of measurements (left and right TMT) was taken twice, with the measurers and their thermometers swapping ears to allow correction for small differences in thermometer calibration and measurement technique. Side of first measurement and choice of thermometer for each user on each occasion were randomized by computer. Room temperature at the time of each measurement was recorded using a calibrated digital thermometer . Thermometer calibration was regularly assessed using a Diatek 9600 blackbody device  and no drift in measurement accuracy was found in the thermometers.t-tests were used to compare temperatures between the sexes. Partial correlation was used to assess relationships between temperature measures and other variables. Because TMT was found to vary by sex and TMTL was found to relate to hand preference, adjustment was made for these factors in all analyses. Measures of fetal size were adjusted by linear regression with first and second order terms for gestational age to fit their slightly curvilinear relationship, yielding a small improvement in fit over linear adjustment. This ensured that our findings were not the result of variations in gestational length. Fetal growth in relation to growth of the placenta was assessed by considering the residual birth weight variation after that predicted by placental weight was removed by linear regression. This measure is uncorrelated with placental weight and might be preferred to the ratio of placental weight to birth weight because the ratio is correlated to both variables and is, therefore, more difficult to interpret. Analyses were repeated with current weight as a covariate to test the possibility that birth weight was acting as a proxy for current weight. Analyses were further repeated with maternal socioeconomic status and smoking included as covariates as these factors are known to influence birth weight and placental weight and could impact upon childhood neurodevelopment. For all statistical tests, P-values below .05 were taken to be significant.Mean left and mean right TMTs were calculated after swapping thermometers and their users to the opposite ears to minimize errors introduced by thermometer bias or measurement technique. TMT laterality (TMTL) was calculated by subtracting TMT on the right from that on the left. The polarity of this measure was chosen arbitrarily. Thus, TMTL should be greater if the RH is relatively more active than the LH, given the inverse relationship between TMT and activity. Average temperature of the two ears was used to assess overall cerebral activation, with lower temperatures indicating greater activity. Two-tailed student P = .001) in girls  than boys . TMTL was distributed normally with a mean of 0.01°C . There were no significant differences in TMTL according to sex. There was no significant relationship at any time of room temperature with either average TMT temperature or TMTL.Complete TMT measures were obtained in 136 of the participants (67 boys and 69 girls) with a median age of 8.9 (range 7.6–9.7) years . Their mP = .018) at baseline, but not significantly so following stress . There was no significant difference, according to hand preference, in mean left or right TMT, considered in isolation, suggesting that neither hemisphere was more important in determining the relationship of hand preference with TMTL at baseline.Mean TMTL was 0.2°C lower in left-handers than right-handers (P = .06) towards such an association 33 minutes after stress. The findings did not differ significantly by sex and after adjustment for current weight, the findings were unaltered apart from the association of birth weight with TMTL 4.5 minutes after stress, which strengthened  and the associations of birth weight adjusted for placental weight with TMTL at baseline, which strengthened  and at 4.5 minutes after stress, which also strengthened . Thus, the findings with prenatal growth were independent of attained childhood weight.To establish which hemisphere was most responsible for the associations between size at birth and TMTL shown in All fetal growth analyses were robust to further adjustment for maternal socioeconomic status and smoking during pregnancy.To our knowledge, this study provides the first evidence that regional differences in cerebral activity may be influenced persistently by early developmental experiences. We found inverse linear associations between markers of fetal growth and RH activity 8–9 years later, which strengthened when fetal growth was considered in relation to placental growth. The associations seen at rest were markedly stronger in the period immediately following the TSST-C, suggesting that stress unmasks inherent differences in cerebral laterality. Thus, the activity of brain regions involved in the processing and response to stressful stimuli may be particularly susceptible to altered lateralization in fetal life. The associations were continuous across the normal ranges of birth weight and placental weight and not dependent on a threshold effect such as might be seen if they resulted only from medically significant intrauterine growth retardation. As the children were born at or near to term and birth size measures were adjusted for gestational age, the findings are not the result of prematurity.We studied young children who are unlikely to have been affected by the psychological disorders or neurodegenerative processes that usually appear in later life. Our findings were robust to adjustment for current weight and maternal socioeconomic status and smoking, increasing the likelihood that they represent the direct effect of altered neurodevelopment.We found that hand preference was related to TMT differences indicative of greater baseline activity in the hemisphere that was not dominant for motor functions. While this finding may seem counter-intuitive, it agrees with long-established evidence that overall hemispheric activity is usually greater in the hemisphere that is not dominant for motor activities We used birth weight as a summary measure of fetal growth. As the heritable component of birth weight is small In healthy pregnancies, fetal and placental weights generally increase proportionately. In childhood, we found that birth weight adjusted for placental weight was a stronger determinant of increased RH activation following stress than birth weight alone. This suggests that disproportionate growth of the fetus and placenta is more important than fetal growth restriction alone in determining cerebral laterality. In our data, a relatively small baby with a relatively large placenta was associated with a neurodevelopmental outcome that might be associated with impaired neurocognitive function in later life. This is not the first time that such disproportion has been linked to later pathology. For example, increased placenta to fetus weight ratio has been linked to risk of hypertension in adulthood In our study, a relatively small fetus with a relatively large placenta might be considered detrimental. Although a precise pathogenesis cannot be determined, existing data allows for some speculation on the type of placental adaptation that may have occurred. Maternal undernutrition during pregnancy may stimulate placental overgrowth as an adaptation to poor nutrient supply in an effort to improve fetal nutrition in later gestation Recently, maternal nutritional status has been implicated as a moderating factor that might determine the polarity of feto-placental growth disproportion There is evidence that prenatal influences other than maternal nutrition may play an important role. In a recent large-scale study of the influence of maternal stress on human pregnancy outcomes In vertebrates, neuroanatomical asymmetries appear very early in gestation as the result of complex expression of genetic signaling pathways Our study has a number of limitations. Our markers of fetal developmental experiences are non-specific and further studies should address specific influences on neurodevelopment in both early and late gestation. Our measure of cerebral activation is indirect, is likely to have limited sensitivity and cannot specify which regions of the brain are involved. Future work with fMRI or PET has the potential to address these issues in selected groups of subjects. Finally, due to the disruptive nature of our measurement technique, we were unable to measure TMT during the TSST-C. Thus, our first measure was several minutes after the termination of stress. It is unknown how rapidly changes in cerebral activation are reflected in TMT changes and it is therefore possible that our findings represent a reduced ability to return RH activation to baseline following acute stress rather than differences in acute RH response to stress. However, the presence of similar albeit weaker associations at rest argues against this. Further work with TMT measurement could explore continuous measures to fully assess the response to stress.We have provided evidence that early development of the fetus influences the lateralization of cerebral activity, particularly following stress, in early childhood. Risk of depression and enhanced stress responsivity, with their consequent risks for ill health including cardiovascular disease, is increased in people who were small at birth. Our findings suggest that persistent differences in cerebral lateralization determined during gestation offer a potential explanation for this. Brain regions involved in the processing and response to stressful stimuli may be particularly susceptible to these effects.


Exposure to air pollution has been demonstrated to increase the risk of preterm birth and low birth weight (LBW). Although evidence has accumulated on characteristics associated with increased risk of air pollution-related health effects, most studies have been conducted in the adult population and evidence on reproductive outcomes is limited. We examined whether socio-economic position (SEP) and parental characteristics  modified the relationship between air pollution and adverse birth outcomes.Data were extracted from a perinatal hospital database based in Shizuoka, Japan. We restricted the analysis to mothers who delivered live-born single births from January 1997 to December 2010 . Each birth was assigned proximity to major roads. Multivariate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated for the outcomes of preterm birth and term LBW. We stratified subjects by individual/area-level SEP and parental characteristics. We then measured interactions on the additive scale between the respective factors and exposure.Lower SEP at both individual and area levels was associated with the increased occurrence of adverse birth outcomes. Living within 200 m from a major road increased the risk of preterm birth by 1.5 times (95% CI: 1.3-1.9) and LBW by 1.2 times (95% CI: 0.9-1.6). Mothers with lower individual SEP defined by household occupation experienced higher ORs for term LBW  compared with those with higher individual SEP. In contrast, mothers who lived in the highest area-level SEP region  showed slightly higher point estimates compared with those who lived in middle or poor areas. In addition, maternal diabetic and hypertensive status modified the association between proximity and preterm birth, while maternal smoking status modified the association between proximity and term LBW.The present study demonstrated that air pollution is an independent risk factor for adverse birth outcomes. Mothers with lower individual SEP and mothers living in higher SEP region may be susceptible to the adverse effect of air pollution. Maternal diabetic, hypertensive, and smoking status may also increase susceptibility to this air pollution-related health effect. Evidence has accumulated on the association between air pollution and adverse birth outcomes, such as preterm birth or low birth weight (LBW) -4. IndeeRecently, several studies have attempted to identify characteristics associated with increased risk of air pollution-related health effects, e.g. age, preexisting cardiovascular disease, diabetes, and low socio-economic position (SEP) ,10. HoweBecause SEP is a robust predictor of health outcomes, it has been questioned whether SEP is a confounder or an effect modifier of the association between air pollution and adverse health outcomes . A growi10) as the exposure index, found a higher effect estimate for preterm birth in low SEP regions [In the field of air pollution and reproductive epidemiology, four studies have examined how SEP potentially modified the relationships between air pollution and adverse birth outcomes -25. ThreMoreover, few studies have evaluated how parental characteristics (except SEP characteristics) modify the association between air pollution and reproductive outcomes, although the findings may provide important insights for possible mechanisms . One stuIn the present study, we therefore used a hospital-based perinatal database to evaluate how SEP at both individual and group/area levels and parental characteristics potentially modify the relationship between air pollution and adverse birth outcomes (preterm birth and term LBW).Data were extracted from the perinatal database maintained at the Seirei Hamamatsu General Hospital, Shizuoka, Japan since January 1997. The hospital is the main perinatal medical center in the western part of Shizuoka prefecture (west of Tokyo). The hospital reported 1582 new live births in 2010, and approximately one-eighth of the babies born in the western part of Shizuoka were born in this hospital .The availability of residential information at delivery was a prerequisite for inclusion in the study because we used proximity to major roads as an index for air pollution exposure; as a result of this criterion we excluded 206 births. Furthermore, since the hospital is located in the western part of Shizuoka prefecture, we restricted births to those whose mothers lived in the western part of Shizuoka prefecture, because mothers who lived in central or eastern parts were likely to have returned to their parents’ home during pregnancy to give birth (a Japanese tradition). However, we could not obtain information regarding maternal movement. When we adopted term LBW as a health outcome, we further restricted the analysis to mothers who delivered term births (born at 37 or more weeks of gestation). Our final set of participants included 16,615 births for preterm birth and 14,836 births for term LBW analyses  based on previous epidemiological studies ,27-29 anMajor roads were defined as those having total vehicle counts greater than 50,000 per 24 hours on a weekday ,33. RoadWe examined two adverse birth outcomes: preterm birth and term LBW. Preterm births were defined as births less than 37 weeks gestational age. Gestational ages were measured based on the last menstrual period, and mostly confirmed or corrected by ultrasound measurements at approximately 10 weeks gestational age. Term LBW was defined as birth weight <2500 g among term newborns.We retrieved information about individual characteristics from the perinatal database. Individual information was obtained from mothers by trained obstetricians or midwives at the time of prenatal checkup when the expected delivery date was confirmed, and added or corrected during admission. Occupation of the mother or father (whichever was higher) was used as our measure of individual SEP. Although occupation was available in five categories , we combined the last three categories because of limited numbers in the last two categories.2).We also extracted the following personal characteristics: maternal age, maternal smoking , maternal alcohol consumption , paternal smoking , maternal obesity (before pregnancy), maternal past history of diabetes, and maternal past history of hypertension. Maternal obesity (before pregnancy) was defined as mothers whose body mass index (BMI) was more than 25. BMI was calculated as body weight before pregnancy (kg) divided by height squared (mArea-level SEP (at the district level) was measured as the proportion of professional workers and the proportion of production or transportation workers over 15 years of age in the corresponding census region where the mothers lived. Data were obtained from the 2000 national census. The study area included 1872 census regions. In the analyses examining effect modification by area-level SEP, the SEP level was tertiled as previous studies used trichotomized categories of regional SEP ,25.First, we calculated the proportions of preterm births and term LBW according to air pollution exposure category , personal characteristics, and individual/area-level SEP. We then examined the distribution of individual/area-level SEP and personal characteristics separated by proximity to major roads.We next estimated the multivariate adjusted odds ratios (ORs) for preterm birth or term LBW according to major roads using a logistic regression model. We first obtained crude ORs (Model 1) and then adjusted for maternal age, newborn’s sex, and personal characteristics that could be considered as potential confounders (Model 2) as follows: household occupation , maternal smoking , maternal alcohol consumption , paternal smoking , and maternal BMI. We further adjusted for individual SEP (Model 3). Finally, we additionally adjusted for area-level SEP (Model 4), i.e. the proportion of professional workers in the corresponding census. Gestational age was also included in all models in the analyses for LBW. Maternal BMI, the proportion of professional workers, and gestational age were treated as continuous variables. Maternal age was entered as a linear and quadratic term into the models because a U-shaped association was expected between maternal age and adverse birth outcomes.We also employed the alternative trichotomized exposure indictor  instead of the simple dichotomization  and repeated the analyses.To examine effect modification by individual/area-level SEP and parental characteristics, we stratified the subjects by individual/area-level SEP and parental characteristics and applied the final fully-adjusted logistic models . Each variable was excluded when the subjects were stratified by the corresponding variable. We then measured interactions on the additive scale between the respective factors and exposure. We used Excel  spreadsheets provided by Knol and VanderWeele  and calcAll confidence intervals (CIs) were estimated at the 95% level. The PASW software package  was used for statistical analyses. Approval for this study was obtained from the Institutional Review Board of Seirei Hamamatsu General Hospital and Okayama University (No 498).Proportions of preterm births and term LBW according to demographic characteristics are shown in Table In Table Table Although none of the additive interaction terms between air pollution and individual/area-level SEP were statistically significant, some tendencies were observed in the stratified analyses by individual/area-level SEP Table . MothersRegarding stratified analyses by parental characteristics, mothers who reported a past history of diabetes and hypertension experienced a higher OR for the association between proximity and preterm birth Table : e.g., OIn this study, we evaluated how SEP at both individual and group/area-levels and parental characteristics modified the relationship between air pollution and adverse birth outcomes (preterm birth and term LBW), using proximity to major roads as an exposure indicator. We observed that mothers from lower individual SEP, defined by household occupation, had higher effect estimates for term LBW compared with mothers with higher individual SEP. In contrast, mothers from higher area-level SEP regions tended to have higher effect estimates for both preterm birth and term LBW compared with mothers from lower area-level SEP regions. In addition, maternal diabetic, hypertensive, and smoking status modified the association between proximity and birth outcomes.There is a lack of studies on this topic from Asian countries. Extrapolation from studies conducted in different areas may be inappropriate because of differences in pollution characteristics, health care systems, meaning of SEP indicators, study designs, and demographics of the population.The findings of this study are consistent with recent studies suggesting that air pollution exposure increases the risk of preterm birth and term LBW ,7. Our sIn the analyses stratified by SEP, although not statistically significant, mothers with lower individual SEP showed susceptibility to air pollution as expected, especially in the “Self-employed/Part-time workers/Unemployed” occupational category. This finding is consistent with previous air pollution studies examining cardiopulmonary outcomes among the adult population. These studies showed susceptibility associated with lower education or income at the individual level -21. In cMoreover, we found that maternal diabetic and hypertensive status modified the relationship between air pollution and preterm birth. This finding is consistent with previous air pollution studies in adult settings, which showed that air pollution-related health effects were stronger among diabetic or hypertensive patients ,10,39. IAlthough most air pollution studies used register-based participants -24,42,43In the present study, we used mothers’ proximity to major roads as an index for air pollution exposure, since air-monitoring stations are limited in their coverage and spatial resolution. However, there is a possibility that proximity to major roads is limited in temporal resolution. Traffic information in this study was obtained from the Road Traffic Census conducted in 2005, and traffic volume data were recorded for only 1 day, during the period from September to November in 2005. Thus, our exposure indicator does not reflect year-to-year or seasonal variations in traffic exposure. Because major roads did not change, the traffic volume would not have varied substantially in the year-to-year comparison. The average changes (increase) in daily traffic volume over a 12-hour time period for the whole Shizuoka prefecture were 135 vehicles from 1999 to 2005 and 200 vehicles from 2005 to 2010, respectively . HoweverExposure misclassification could have occurred because of mothers’ movement during pregnancy, as we used maternal residential information at delivery. Therefore, we restricted subjects to those who lived in the western part of Shizuoka prefecture to reduce the possibility of misclassification. Although we could not obtain information about maternal movement, such possible non-differential exposure misclassification between the two categories  would likely have moved effect estimates toward the null .In the present study, we used household occupation as our measure of individual SEP. However, the category was relatively crude. Moreover, we had to combine three categories  because of limited numbers. Furthermore, we did not have other individual SEP information such as education, income, or wealth . These iThe present study demonstrated that air pollution is an independent risk factor for adverse birth outcomes, and lower SEP at both individual and area-levels was associated with the increased occurrence of adverse birth outcomes. Although the interaction was not statistically significant, mothers with lower individual SEP and mothers living in higher SEP regions tended to be susceptible to the adverse effect of air pollution. Moreover, maternal diabetic, hypertensive, and smoking status increased susceptibility to the effect. Further studies are needed to identify mothers vulnerable to air pollution to reduce reproductive adverse outcomes of newborns.According to the ethical guidelines for epidemiological research in Japan, no informed consent from participants was needed because data were existing materials and analyzed anonymously.AP: Proportion attributable to the interaction; BMI: Body mass index; CI: Confidence interval; GIS: Geographic Information System; LBW: Low birth weight; OR: Odds ratio; SEP: Socio-economic position.The authors declare that they have no competing interests.Study concept and design: TY, SK, ST, HD, IK; Data collection: HN, TM; Data handling: TY, SK; Analysis: TY; Interpretation of data: TY, SK, ST, HD, IK; Drafting of the manuscript: TY, IK; Critical revision of the manuscript: HN, SK, ST, TM, HD; Study supervision: IK. All authors read and approved the final manuscript.