However, this association may be confounded by unmeasured familial characteristics related to both SDP and offspring mental health. Consequently, we aim to investigate the effect of SDP by means of a sibling design that to some extent allows controlling for unknown environmental and genetic confounders. Using the Swedish Medical Birth Register (1987–1993), which was linked to the Swedish Prescribed Drugs Register (July 2005–December 2008), we investigated 579,543 children and among them 39, 007 were discordant for use of psychotropic medication and 4,021 siblings discordant for both use of psychotropic medication and for smoking exposure. Replicating the Finnish study using traditional logistic regression methods we found an association between exposure to ≥10 cigarettes per day during pregnancy and psychotropic drug use . Similar in size to the association reported from Finland . However, in the adjusted sibling analysis using conditional logistic regression, the association was considerably reduced . Preventing smoking is of major public health importance. However, SDP  Several studies have reported an association between maternal smoking during pregnancy (SDP) and offspring psychological disorders. These include mainly externalizing behavioral disorders, such as attention deficit hyperactivity disorder (ADHD), conduct disorder, and oppositional defiant disorder, but also internalizing psychopathology  However, almost simultaneously with Ekblad and coauthors Investigating causality through observational studies is problematic and the study of long-term causal effects of prenatal smoking exposure presents specific difficulties Recently, in an attempt to reduce residual confounding, several studies applied a design comparing siblings differently exposed to maternal SDP If the association between maternal SDP and psychiatric morbidity in the offspring was causal, this would further support the evidence that maternal smoking in this critical period of life puts the fetus at risk. If not, prevention should also be focused on improving those socioeconomic and psychosocial circumstances of the mother that are common causes of both SDP and offspring mental ill health.Therefore, applying the sibling design, we aimed to revisit the association between maternal SDP and increased psychotropic drug use in children and young adults recently reported by Ekblad et al For doing these sibling analyses we applied conditional logistic regression (CLR). CLR is suitable for matched case control studies. In our case, we can understand the sibling analysis as a matched case-control study where one of the siblings is a “case”  and the other sibling the “control” , and the matching variable is the mother. In the CLR analyses the estimations are obtained in siblings with discordant outcome  and exposure (smoking vs non-smoking). The association between SDP and psychotropic drugs is, by design, adjusted for the matching variable (mother). Therefore, the CLR accounts for the correlation of the information between the case and control siblings.However, the similarity between siblings and, thereby, the capacity of the sibling design for confounding adjustment should not be exaggerated On this background, we analyzed outpatient psychotropic drug use between 2005 and 2008 in children and adolescents born in Sweden between 1987 and 1993.The Swedish Medical Birth Register collects standardized information on the antenatal care, delivery, and medical examination of newborn babies. It includes about 98.6% of all pregnancies in Sweden that culminate in delivery The construction of the record linkage database used in our study was approved by The Regional Ethical Review Board in Southern Sweden, The National Board of Health and Welfare and Statistics Sweden. Lund Universidad signed a contract of confidentially with the Swedish Authorities. Active informed consent was waived as a requirement for the construction of the database.st, 1987, and December 31st, 1993, recorded in the Swedish Medical Birth Register. We excluded every non-singleton child . Measurement of psychotropic drug use using administrative registries reflects both access to healthcare and the presence of psychological disorder, which may originate information bias when studying the effect of smoking. Therefore, we also excluded every child with an immigrant parent  because children of immigrants have been reported to use less psychotropic medication in relation to their needs . To further increase the homogeneity of our study, we also excluded children with major congenital abnormalities . The final study population for performing traditional analyses consisted of 579,543 subjects. The sibling analyses were done on a sample of 39,007 siblings with discordant outcome (We furthermore excluded children whose mothers’ identification number was missing (n = 16), children who had died  or emigrated  before December 31 outcome . Out of The individuals were between 11 and 21 years of age when we gathered information about their use of psychotropic medication.st, 2005, to December 31st, 2008.The Swedish Prescribed Drug Register contains all dispensed medication prescribed in outpatient settings in Sweden since July 2005. It does not contain over the counter medication or medication given in hospitals and nursing homes Because we use psychotropic medication as a proxy of psychiatric disorders and the therapeutic profiles of the different medication groups overlap each other , we study psychotropic medication as a group.From the Swedish Medical Birth Register, we obtained information on self-reported SDP. This information was retrieved at the first antenatal care visit  From the Swedish Medical Birth Register, we collected information on parental relationship status, parity, birth order, Apgar score, the mother’s age at delivery, gestational age (GA) in weeks, birth weight, and birth weight adjusted for GA. Information on parents’ relationship status is reported by the mother at the first antenatal care visit. Apgar score is rated on a scale of 1–10 at 1, 5, and 10 minutes after birth. A score of 10 indicates a delivery without fetal distress. In the analyses, we used the 5-minute Apgar score. The variable “birth weight adjusted for GA” is categorized in the Swedish Medical Birth Register as small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Small for gestational age and LGA are defined as a birth weight below or above 2 standard deviations (SDs) from the average birth weight for those born at that GA in Sweden.th revisions, respectively, during the period 1973–2005. For most variables with continuous and ordinal data, we created categories, as shown in From the Income and Asset Register, we obtained information on whether the parents were receiving social welfare the year before the birth of the child. We also obtained information on the income of the parents the year before and after the birth of the child. We created a combined variable categorized into four groups using income tertiles and adding a fourth category for parents receiving social allowance. Using the National Inpatient Register, we collected data on maternal history of psychiatric diagnosis if the mother had at least one diagnosis coded 290–319 or F00-F99, according to the International Classification of Diseases and Related Health Problems (ICD), 9th and 10model a), we performed a traditional simple logistic regression analysis. Thereafter (model b), we replicated the study by Ekblad et al We analyzed the association between maternal SDP and use of psychotropic medication in a series of steps. Firstly  and socioeconomic variables  that could be considered as a common cause of both maternal SDP and later use of psychotropic medication by the children/adolescents. These models  were intentionally performed by applying the traditional logistic regression analysis, which do not take into consideration the dependence between siblings within mothers.Since we did not fully agree with the variables that Ekblad et al model d), we next analyzed siblings with discrepant use of psychotropic medication. We compared siblings using a conditional logistic regression analysis with the mother as the grouping variable. In the final model e, we expanded model d and included birth year of the children, birth order, maternal age, relationship status of the parents, and household income since these variables may change between pregnancies and can be related to both maternal SDP and later use of psychotropic medication by the children/adolescents. The conditional logistic regression is a suitable method to perform sibling analysis Applying a sibling design . We repeated the analyses in “R” version 2.15.1.The use of psychotropic medication increased with age. Smoking during pregnancy declined between 1987 and 1993, meaning that older children in this study population had also been more often exposed to SDP more often. Children born to women <20 years of age had the highest psychotropic drug use, and these young mothers were also the ones most often smoking during pregnancy. It seems that women who had delivered more than three children were more likely to smoke during pregnancy, and their children had higher use of psychotropic medication later on.Children of women with a psychiatric diagnosis in inpatient registers were at least twice as likely to be using psychotropic medication as children born to women without such diagnoses. Women with a psychiatric diagnosis also smoked during pregnancy almost twice as often as other women. Psychotropic drug use was higher among children whose parents were not living together and in children with low family income. The same factors were also associated with SDP.Compared to the full sample, the sibling sample was rather similar across all characteristics observed in When we adjusted for the same variables as used by Ekblad et al in their study In the third analysis (model c), we adjusted for a different set of variables than the ones used by Ekblad et al In the final part of our analysis  and, the second subsample, mothers who start smoking in the second offspring . The analyses show the order of the exposure has effect on the association between SDP and psychotropic use in adolescents. The adjusted model for mothers who quit smoking in the subsequent pregnancy shows an OR of 1.70  and 1.52  for 1–9 and >10 cigarettes, respectively, while the model for mothers who start smoking indicated smaller effects  and 1.30  for 1–9 and >10 cigarettes, respectively). These results are very imprecise but they suggest the existence of confounding rather than a causal effect of smoking. In fact, mothers might modify their tobacco habits  as consequence of health related issued that are a common causes of both changing smoking habits and early determinants of adolescent use of psychotropic drugs. This situation could explain the stronger association found in mother that quit smoking.The negative effect of smoking on reproductive health outcomes is unquestionable and preventing SDP is of major public health relevance. However, SDP in itself appears to have less impact on offspring psychotropic drug use than suggested by previous conventional analysis. We, therefore, conclude that the results obtained by Ekblad et al Our findings are relevant from a public health perspective, because they suggest that a preventive strategy that focuses on the smoking habits of mothers will have little influence on the mental health of children and young adults than previously believe. Rather, there seems to be a need for more complex strategies, with support for socioeconomically weak families and parents with psychiatric disease.We performed a sibling design, which is a better approach for analyzing causal associations than previous conventional analysis Our database contained information from registries covering the entire Swedish population. Moreover, the information in the Swedish Medical Birth Register, the National Patient Register, the National Cause of Death Register, and the Swedish Prescribed Drug Register is reported by law, and the quality of the registries is regularly evaluated by Statistics Sweden and the National Board of Health and Welfare.However, our study also has some limitations. Sibling comparisons are effective in accounting for unobserved familial characteristics but it cannot rule out any unmeasured confounding factor  that simultaneously varies between siblings Another possible source of bias could operate throughout a misclassification on maternal smoking information. Maternal smoking is self-reported by the mother at the first prenatal visit, therefore the information might not be reliable. In this line, a previous study concluded that about 6% of mothers who state they did not smoke during pregnancy were actually smoking A further difficulty is that matching cases to control siblings made it possible to reduce unknown and unaccounted confounding, but it also reduced the number of study subjects and, thereby, the uncertainty of the estimates.Our study was able to replicate almost exactly the association between maternal SDP and use of psychotropic medication in offspring, recently reported in Finland by Ekblad et al The harmful effect of SDP on reproductive health outcomes is indubitable and preventing SDP is of major public health importance. However, SDP per se appears to have less influence on offspring psychotropic drug use than previous conventional analyses suggest. Identifying the modifiable factors that are associated with both maternal SDP and offspring mental health, and launching public health interventions aimed at these factors seems more relevant than interventions exclusively targeted to maternal SDP in order to address psychiatric morbidity in children and young adults.


The lipocalin apolipoprotein D (Apo D) is upregulated in peripheral nerves following injury and in regions of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, during aging and progression of certain neurological diseases. In contrast, few studies have examined Apo D expression in the brainstem, a region necessary for survival and generally less prone to age-related degeneration. We measured Apo D expression in whole human brainstem lysates by slot-blot and at higher spatial resolution by quantitative immunohistochemistry in eleven brainstem nuclei . In contrast to cortex, hippocampus, and cerebellum, apolipoprotein D was highly expressed in brainstem tissue from subjects  with no history of neurological disease, and expression showed little variation with age. Expression was significantly stronger in somatomotor nuclei  than visceromotor or sensory nuclei. Both neurons and glia expressed Apo D, particularly neurons with larger somata and glia in the periphery of these brainstem centers. Immunostaining was strongest in the neuronal perinuclear region and absent in the nucleus. We propose that strong brainstem expression of Apo D throughout adult life contributes to resistance against neurodegenerative disease and age-related degeneration, possibly by preventing oxidative stress and ensuing lipid peroxidation.  Apolipoprotein D is a glycoprotein first isolated from the plasma HDL fraction and also found in smaller amounts in VLDL and LDL. The amino acid sequence shows a high homology with the lipocalin family but not with other apolipoproteins. The main role of Apo D is still uncertain, but by analogy with other lipocalins it may serve as a transporter of small hydrophobic molecules between the circulation and tissue . The genThe Apo D protein has since been detected in many organs, tissues, and body fluids of both humans and other species , and is In the human peripheral nervous system (PNS), Apo D is synthesized and secreted by fibroblasts and Schwann cells under basal conditions and upregulated during regenerative processes that follow injury. Following sciatic nerve injury, Apo D mRNA and protein expression levels increase to levels much higher than all other apolipoproteins ,6. Like The human central nervous system (CNS) expresses a unique Apo D isoform with lower molecular weight (29 kD) than that founded in CSF or plasma (32 kD). In humans and other mammals, immunohistochemical and hybridohistochemical techniques have demonstrated Apo D on the surfaces of glial cells , pial cells, perivascular cells, and neurons ,8–13. Apolipoprotein D expression is more intense in white matter than grey matter due to particularly strong expression in oligodendrocytes, where it may be involved in myelination . On the Increased expression of Apo D in the CNS has been observed in neurodegenerative and neuropsychiatric disorders  samples were gathered retrospectively from pathology archives of necropsies performed for diagnostic purposes; 2) patient identities were anonymized and completely delinked from unique identifiers; and 3) there was no risk to the participants.All human brain tissue samples were provided by the Department of Pathologic Anatomy of the Central Hospital of Asturias and obtained from necropsies within 6 h of death. These samples were the same as those used in previous studies by our group -10,21. TApo D levels were quantified using a slot blot technique . SamplesThe blots of Apo D were dried and bands quantified as relative optical densities (arbitrary units) using a digital scanner  and ImageJ 1.37c  .After fixation, tissue blocks were washed in distilled water, dehydrated, cleared in butyl acetate, and embedded in paraffin. Sections were cut at 10 μm thickness and mounted on "SuperFrost Plus" (Mentzel-Glasse) slides, dried at 36 °C for 24 h, deparaffined in xylene, and partially rehydrated by incubation in a graded alcohol series (2 min per concentration). In each case, every 80th or 160th section was stained by the Nissl/Myelin technique  and exam2O2  to quench endogenous peroxidase activity, washed in distilled water, and treated with PBS. After blocking non-specific binding by incubation in BSA (30 min), sections were incubated with the antibody against human Apo D  overnight at 4 °C. Immunoreactivity was detected using the Extravidin biotin peroxidase staining kit (Sigma Extra 3), and peroxidase activity visualized by incubation with Sigma Fast DAB (Sigma D4168) at room temperature for 30 min. Finally, the sections were counterstained using a modified formaldehyde thionin method [For immunohistochemistry, fixed sections were permeablized with triton X , washed in distilled water, treated with Hn method , dehydraFor quantification of Apo D expression, the chromogenic signal was selected using Adobe Photoshop CS 8.0.1  and density measured by ImageJ 1.37c  according to a procedure developed by our group . BrieflyAll statistical calculations were conducted using SPSS 15.0 for Windows. Data sets were first tested for normality using the Kolmogorov-Smirnov test with Lilliefors correction. Expression levels of Apo D were compared among nuclei by the Mann-Whitney U test due to non-homogeneity of variance. A P value < 0.05 was considered statistically significant. The levels of Apo D expression were measured in 26 human brainstem samples from patients ranging in age from 32 to 96 years. Densitometric analysis of slot blots showed robust and relatively stable expression throughout adult life, particularly between the forth and eighth decades . RegressExpression of Apo D was also measured at the cellular level in 11 pontine and medullar nuclei of both sensorial and motor functional systems . All speAll somatomotor and branchimotor system nuclei studied showed robust Apo D immunoreactivity throughout life. The hypoglossal nucleus (XII), located in the middle and lower third of the medulla oblongata, is part of the somatic motor column of the brainstem. This somatomotor nucleus  exhibiteabducens nucleus (III) is also part of the somatic motor column of the brainstem and shares many characteristics with XII , a nucleus with well described topographic organization, contained many large Apo D-positive neurons and showed the highest Apo D expression of all nuclei studied . The denThe immunoreactivity of Roller’s nucleus  was alsoThe DX  and NST The general and special somatosensory nuclei of the brainstem are located in the pons and medulla oblongata. We also studied IO  due to iThe VNC consists of inferior (IVN), lateral (LVN), medial (MVN), and superior (SVN) components. The IVN contains neurons of a broad range of sizes, but medium-size neurons are predominant . The IVNUnlike forebrain regions and cerebellum, we found intense Apo D expression in many neurons and glial cells in young human brainstem nuclei. Immunostaining for Apo D was usually restricted to the neuronal cytoplasm, with highest intensity in the perinuclear region. When the signal was strong, it tended to fill the entire cell, even the neurites, but has been not observed in the cell nucleus. In general, larger neurons showed more intense staining for Apo D than smaller neurons. The number of Apo D-positive glial cells appeared highest at the periphery compared to the core of these nuclei . FinallyIn the present study, we found that expression of Apo D in medulla oblongata and pons is already high in young subjects, contrary to other areas of the brain previously studied ,9, and wIn human frontal cortex, expression is higher in white matter than grey matter due to higher synthesis by oligodendrocytes ,9,13,34.Increased expression of Apo D in the CNS has been associated with aging, neurodegenerative diseases, and neuropsychiatric disorders. However, the majority of studies on Apo D have focused on cerebral and cerebellar cortices and the hippocampus, areas particularly prone to pathological changes with age and during the progression of neurodegenerative diseases. In all these areas, Apo D expression in young subjects was lower in grey matter than white matter, and increased in both tissues with age and following injury. Apo D expression has also been linked to cellular senescence and growth arrest in cell culture ,35, and The underlying molecular mechanisms of CNS aging include instability of nuclear and mitochondrial genomes, neuroendocrine dysfunction, oxidative stress, altered calcium metabolism, and inflammation-mediated neuronal damage . A growiWe observed strong Apo D expression in all studied nuclei of the medulla oblongata and pons from both young and old subjects, and no statistically significant increase in Apo D expression with age. Thus, Apo D is not a marker of aging in the brainstem. Due to these high levels of Apo D, we speculate that human brainstem is not exposed to damaging OS during aging, that Apo D expression in this brain region is uniquely regulated, or that the predominant role for Apo D in this brain region is distinct from that in other regions. It has long been known that Apo D is critical for remyelination of rat sciatic nerve, as evidenced by the > 40-fold increase in expression in regenerating nerve compared to non-injured control nerve . ElevateFinally, Apo D may also regulate neuritogenesis and synaptogenesis. Co-cultures of adipocytes with peripheral neurons showed enhanced neurite and synapse formation. It has reported that apolipoproteins D and E3 exert neurotrophic and synaptogenic effects in dorsal root ganglion cell cultures . ConsideThe effects of aging on the CNS have been studied for more than a century, but only a few works have focused on effects to the brainstem. We previously reported that aging is not associated with neuronal loss in brainstem nuclei , only a Although the full spectrum of Apo D functions is unclear, the current study strongly suggests that this molecule is critical for resistance to age-related neural damage. Neurons that do not synthesize or import Apo D from surrounding glial cells are more vulnerable to age- and disease-related death. Diseases or injuries of the brainstem region are normally incompatible with life, requiring stable basal expression of Apo D (and possibly other neuroprotective factors). The results of this study support the hypothesis that Apo D is a critical neuroprotective molecule against neurodegenerative disease and the ravages of age.


Low birth weight (LBW) continues to increase and is a major public health problem in Japan. In the present cross-sectional study, we examined the associations between LBW, preterm birth and small-for-gestational-age (SGA) and the prevalence of dental caries in young Japanese children.Study subjects were 2,055 children aged 3 years. Data on birth conditions were obtained through the transcription by parents or guardians of the information from their maternal and child health handbook, in which the data were recorded by staff at the birth hospital or clinic, to our self-administered questionnaire. Children were classified as having caries if one or more deciduous teeth were decayed, missing, or had been filled at the time of examination. Adjustments were made for sex, toothbrushing frequency, use of fluoride, regular dental check-ups, between-meal snack frequency, breastfeeding duration, paternal and maternal educational levels, maternal smoking during pregnancy, and secondhand smoke exposure at home.The prevalence of dental caries was 20.7%. The mean birth weight was 3018.3 g, and 8.3% were classified as LBW , 4.5% as preterm birth (<37 weeks), and 7.1% as SGA (<10th percentile). Preterm birth was associated with a 40% decreased prevalence of dental caries . There were no associations between LBW or SGA and the prevalence of dental caries.The results of the study failed to detect significant associations between LBW, preterm birth or SGA and the prevalence of dental caries in Japan. Further study is needed in other populations to confirm the generalizability of these findings. According to the Vital Statistics of Japan, the rate of low birth weight (LBW) <2,500 g) continues to increase, and in 2010, 9.7% of all live births in Japan were babies of LBW ,500 g co.Preterm birth also deleteriously affects the structure of dental enamel , which iThe FCHS is a cross-sectional study to investigate the association between various selected factors and child health problems, such as dental caries and allergic disorders. In Japan, when children reach 3 years of age, the local municipality performs a physical examination, which includes an oral examination, anthropometric measurements of height and weight, and an interview with parents or guardians about the child’s health. Eligible subjects for the present study were those children aged 3 years who received the physical examination that was offered at all seven public health centers in Fukuoka City, a metropolitan area on Kyushu Island in southern Japan, with a total population of almost 1,414,000. During the period from June 2006 to January 2007, out of the 8,269 eligible children, the parents or guardians of 8,064 were provided with a self-administered questionnaire, a brief self-administered diet history questionnaire, and a postage-paid, addressed return envelope. The parents or guardians of 205 children declined the receipt of these materials or were failed to be provided with them. Ultimately, the parents or guardians of a total of 2,109 children answered the questionnaires and mailed these materials to the data management center (participation rate = 25.5%). Our research technicians completed missing answers and/or illogical data by telephone interview. The current study was restricted to subjects who provided complete information on the variables under study, leaving data on 2,055 children available for analysis . Permission to perform this study was obtained from the ethics committee of the Faculty of Medicine, Fukuoka University.At the time of the physical examination, the presence of dental caries was assessed by a visual examination without radiographs. Data on the dental examination were recorded at the tooth level by a dentist in a maternal and child health handbook, which had been provided by the municipality during the pregnancy and which included information on prenatal checkups as well as postnatal health conditions of both the mother and baby, and the growth of the child. Data on birth weight and gestational age at birth are also recorded by staff at the birth hospital or clinic in the maternal and child health handbook. In this study, parents or guardians of the children were required to transcribe the data on the dental examination, birth weight, and gestational age at birth from the maternal and child health handbook to our self-administered questionnaire. We classified children as having dental caries if one or more primary teeth had decayed, were missing, or had been filled. We defined LBW as a birth weight of less than 2500 g. Preterm birth was defined as a birth occurring at a gestational age of less than 37 weeks. SGA was defined as a birth weight below the 10th percentile of the Japanese neonatal anthropometric norms for babies of the same gestational age, gender, and parity published by Itabashi et al. in 2010 .Information on sex, dental health behavior , between-meal snack habits, breastfeeding duration, paternal and maternal educational levels, maternal smoking during pregnancy, and secondhand smoke exposure at home were obtained from a structured self-administered questionnaire. Use of fluoride was defined as positive if children were reported to use fluoride agents, such as toothpaste and gel.Sex, toothbrushing frequency, use of fluoride, regular dental check-ups, between-meal snack frequency, breastfeeding duration, paternal and maternal educational levels, maternal smoking during pregnancy and secondhand smoke exposure at home were selected as a priori potential confounding factors. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated by binomial regression with the log link function . All staOf the 2,055 children, 426 (20.7%) had experienced dental caries and 1,629 (79.3%) were caries free. The mean number of teeth with dental caries for all subjects and for subjects who had experienced caries was 0.70 and 3.4, respectively.Characteristics of the study population are described in Table Table Maternal smoking during pregnancy is the leading cause of LBW and preterm birth. It also might increase the risk of dental caries in children. In the present study, when children were classified according to maternal smoking status during pregnancy, an inverse association of preterm birth with the prevalence of dental caries was more pronounced in children whose mothers had never smoked during pregnancy  than in those whose mothers had smoked during pregnancy . No difference was observed in the association of preterm birth with the prevalence of dental caries between children with or without maternal smoking during pregnancy (p for homogeneity of PR = 0.42).The present study found that preterm birth was associated with a 40% decreased prevalence of dental caries. Our findings are at variance with a previous cross-sectional study which showed that preterm birth was significantly positively associated with the prevalence of dental caries among US children aged 3 to 5 years . On the A longitudinal study among Australian children at 52 months of age showed that the prevalence of enamel defects, such as hypoplasia or opacity, was higher in preterm children than in full-term normal birth weight children . It is sNo previous studies have addressed an interaction between birth conditions and prenatal smoking with respect to dental caries. Maternal smoking during pregnancy is the leading cause of LBW and preterm birth. Our previous study showed that prenatal smoke exposure was associated with an increased prevalence of dental caries in children . MaternaThis research study had several methodological strengths. Study subjects were homogeneous in terms of age and geographic background. Information on birth weight and gestational age at birth was drawn from data recorded by hospital or clinic staff in the maternal and child health handbook. Data regarding dental caries were obtained from dental examinations by dentists. We were thus able to control for a variety of potential confounding factors.Several methodological limitations of the current study should also be clarified. Of 8,269 eligible children in Fukuoka City, only 2055 (24.9%) were included in this analysis, leading to a potential for selection bias. The study subjects were probably not a representative sample of Japanese toddlers in the general population. In fact, the educational levels of the subjects’ parents in the present study were higher than those of the general population. According to the 2000 population census of Japan, the proportions of men 35 to 39 years of age in Fukuoka City with < 13, 13 to 14, ≥15, and unknown years of education were 39.6%, 8.0%, 43.3%, and 9.1%, respectively . The corIn this study, because the data on dental examinations were transcribed by parents or guardians of the children from their maternal and child health handbook to our self-administered questionnaire, we cannot exclude the possibility that transcription errors occurred. However, misclassification of outcome is unlikely to differ across categories of birth conditions. The non-differential outcome misclassification might have biased the magnitude of the observed associations toward the null.To our knowledge, there has been no prior study in Japan on the relationship between birth conditions and dental caries. The results of this cross-sectional study revealed no associations between LBW, preterm birth, or SGA and the prevalence of caries in primary dentition in Japanese children; however, there was a suggestion of an inverse association between preterm birth and caries (p = 0.06). Although the present study did not find an association between birth conditions and dental caries in the primary dentition, it is possible that such an association may exist in the permanent dentition. Further studies, particularly prospective studies, are needed in other populations to confirm that there is indeed no association between birth conditions and dental caries in children.CI: Confidence interval; FCHS: Fukuoka Child Health Study; LBW: Low birth weight; PR: Prevalence ratio; SGA: Small-for-gestational-age.The authors declare that they have no competing interests.Both authors contributed to the study concept and design and the acquisition of data. KT was responsible for the analysis and interpretation of data and the drafting of the manuscript. Both authors participated in critically revising the manuscript and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/14/38/prepub


Maternal educational attainment has been associated with birth outcomes among adult mothers. However, limited research explores whether academic performance and educational aspiration influence birth outcomes among adolescent mothers.Data from Waves I and IV of the National Longitudinal Study of Adolescent Health  were used. Adolescent girls whose first pregnancy occurred after Wave I, during their adolescence, and ended with a singleton live birth were included. Adolescents’ grade point average (GPA), experience of ever skipping a grade and ever repeating a grade, and their aspiration to attend college were examined as predictors of birth outcomes . Univariate statistics, bivariate analyses and multivariable models were run stratified on race using survey procedures.Among Black adolescents, those who ever skipped a grade had higher offspring’s birthweight. Among non-Black adolescents, ever skipping a grade and higher educational aspiration were associated with higher offspring’s birthweight; ever skipping a grade was also associated with higher gestational age. GPA was not statistically significantly associated with either birth outcome. The addition of smoking during pregnancy and prenatal care visit into the multivariable models did not change these associations.Some indicators of higher academic performance and aspiration are associated with better birth outcomes among adolescents. Investing in improving educational opportunities may improve birth outcomes among teenage mothers. In 2011, there were 333,771 live births to mothers age 10-19 in the U.S , stillbiAmong adult mothers, maternal educational attainment is positively linked with birth outcomes -14. LoweAlthough evidence of the association between maternal educational attainment and birth outcomes has been consistent, there remain uncertainties about the explanation for the association . Fuchs aThe Healthy People 2020 agenda includes goals related to improving adolescents’ academic success and achievement . AcademiHowever, while there has been growing literature on maternal educational attainment and birth outcomes among adult mothers, less research has been conducted exploring whether academic performance and educational aspiration influence birth outcomes among adolescent mothers. Teen mothers have been found to have poorer educational performance compared to other teens ,36. ThisThe purpose of the present study is to examine how maternal academic performance and educational aspiration during adolescence are related to birth outcomes among adolescent mothers. In addition, we examine whether these relationships, if any, can be explained by maternal smoking during pregnancy and utilization of prenatal care. We use data from a nationally-representative survey of school-attending youth who have completed their teenage years and thus have complete data on teenage pregnancies. Results will add to existing literature on the determinants of birth outcomes among adolescents.Data from waves I and IV of the National Longitudinal Study of Adolescent Health  contractual dataset were utilized . Add HeaWe applied a number of sample inclusion criteria. First, we limited to females who participated in Wave IV, as that was the Wave when all respondents had completed their teenage years and had complete teen pregnancy data. Second, we limited to female participants with valid sampling weights in order to make generalizations to the U.S. population. Third, we limited to females whose first pregnancies occurred during adolescence, after Wave I and ended with a singleton live birth to ensure the temporal ordering of predictors and outcomes (n = 978). Finally, we limited to females with complete information on all covariates. This left us with an analysis sample of 763 teen singleton live births.At Wave IV girls were asked about previous pregnancies and their outcomes. If they indicated they had given birth, they were asked “How much did the baby weigh at birth?”, “Was [baby’s name] born before or after [his/her] due date?” and then “How many weeks or days early/late was [baby’s name] born?” This was subtracted from 40 weeks to calculate gestational age. Birthweight was examined in kilograms and gestational age was examined in weeks.grade point average (GPA) based on their self-reported school performance in four subjects in Wave I in-home interview: English or language arts, mathematics, history or social studies, and science. Letter grades of A, B, C, and D were coded as 4, 3, 2, and 1, respectively and were averaged and dichotomized at the median (median = 2.5). In Wave I in-home interview adolescents were also asked whether they had ever skipped a grade [yes/no] and repeated a grade [yes/no].We measured adolescents’ educational aspiration scale by summing the items weighted by their factor loadings, with higher score indicating higher aspiration for college education. In bivariate and multivariable analyses, we standardized the score so that the regression coefficients represent change in outcome with a one-standard deviation change in the educational aspiration score.Adolescents’ educational aspiration was measured from three questions in Wave I in-home interview asking how much they wanted to go to college, how likely they were to go to college, and how disappointed the adolescent thought his/her mother would be if the adolescent did not graduate from college. Responses were provided in a 5-point Likert scale, with higher scores indicating higher expectation or likelihood of going to college. Because of the likely high correlation between these items, we conducted a polychoric principal factor analysis with varimax rotation among the three questions, and the results suggested a single-factor solution . We then created the We examined correlation among all predictor variables  and found low correlations, with polychoric correlation coefficients ranging from 0.01 to 0.34.smoking during pregnancy and timing of prenatal care visit as potential mediators of maternal education variables and birth outcomes. Smoking during pregnancy was assessed at Wave IV for each pregnancy reported. Respondents were asked to report on an ordinal scale how many cigarettes they smoked during their pregnancy (none/a few cigarettes but not every week/a few cigarettes a week but not every day/10 or fewer a day/11-20 a day/21-30 a day/31 or more a day). We dichotomized responses due to sparseness across smoker frequencies in the sample. The timing of prenatal care initiation was based on two questions asked about each pregnancy reported at Wave IV: “During this pregnancy with [partner] did you ever visit a doctor, nurse-midwife or other health care provider for prenatal care, that is, for one or more pregnancy check-ups?” and “How many weeks pregnant were you at the time of your first prenatal care visit?” Responses to these two questions were combined and categorized into three groups: initiated in the first trimester; initiated in the second trimester; and initiated in the third trimester or no prenatal care.Based on prior literature, we included measures of 2), normal weight (18.5 kg/m2 ≤ BMI < 25.0 kg/m2), overweight (25.0 kg/m2 ≤ BMI < 30.0 kg/m2), and obese (BMI ≥ 30.0 kg/m2) [We drew upon our previous analysis of predictors of birth outcomes in this cohort to determine confounders . This an0 kg/m2) .All analyses were conducted in SAS  using survey procedures, which apply population weights and adjust standard errors for non-independence between respondents due to school-based sampling. We began with descriptive statistics (means and percentages) for all analysis variables, then conducted bivariate analyses  to test the crude relationships between analysis variables and birth outcomes. Finally, we implemented multivariable linear regression models to examine the relationship between maternal academic performance and educational aspiration and birth outcomes after controlling for other individual and family characteristics. For each birth outcome , we examined two models: one without potential mediator variables and the other with potential mediators. Mediation was assessed based on change in effect estimates after inclusion of the mediating variables . AnalyseThe characteristics of the study population are presented in Table In bivariate analysis, none of the education variables was significantly associated with offspring’s birthweight among Black adolescents while higher educational aspiration and ever skipping a grade were related with higher birthweight in non-Black adolescents. Smoking during pregnancy was positively related with birth weight among Black adolescents Table . Ever skMultivariable analysis of birthweight is presented in Table For gestational age Table , none ofAs our study sample is a selected one including females whose first pregnancies occurred during adolescence and ended with a singleton live birth, we were concerned about potential sample selection biases that might have influenced our findings. We did a post-hoc analysis examining whether maternal academic performance and educational aspiration during adolescence predicted the likelihood of having teen pregnancy. Among 6,497 adolescent girls with valid sampling weight and non-missing values on all covariates, 1,406 (21.64%) ever had teen pregnancy. Among Black girls , below-average GPA was associated with a higher risk of teen pregnancy . Among non-Black girls , below-average GPA, ever skipping a grade, and ever repeating a grade were related with a higher likelihood of teen pregnancy ; higher educational aspiration was negatively associated with the risk of teen pregnancy.Educational goals and achievements are likely to be particularly important for adolescents, as school is their major social and occupational context . HoweverMultivariable analysis indicated that higher aspiration for college education was related to higher birthweight among non-Black adolescents. Higher educational aspiration could indicate a greater future orientation and greater social support  which woWe found that grade skipping was associated with higher birthweight and gestational age among non-Black girls, as well as higher birthweight among Black girls. Grade skipping is one way to accomplish the concept of appropriate developmental placement ,48. It aNo statistically significant relationship was found between adolescents’ GPA and either of the birth outcomes. However, we observed that among non-Black adolescents, those whose GPA was below average had higher birthweight and gestational age than those with GPA above average and the magnitude of the coefficients was larger than that for grade skipping. It is possible that this finding is (partly) due to the imperfect measurement of adolescents’ GPA; adolescents may have mis-reported their letter grades in Wave I in-home interview. Nonetheless, this was an unexpected finding. We tested the interaction between GPA and grade skipping, as well as interaction between GPA and grade repeating, to determine whether a low GPA represented more challenging courses relative to age, but neither was statistically significant (p > 0.05).Past studies suggested that the effect of maternal education on birth outcomes could be accounted for by the health-related risk behaviors, particularly maternal smoking and alcohol use during pregnancy and late entry into prenatal care ,14,15,19Surprisingly, we found that smoking during pregnancy was positively related to Black adolescent mothers’ birthweight and gestational age. This finding is inconsistent with extensive literature documenting increased risk of adverse birth outcomes with smoking during pregnancy . It is pIn the post-hoc analysis, we found that lower GPA was related with a higher risk of teen pregnancy in both Black and non-Black girls, and that higher educational aspiration was related with a lower risk of teen pregnancy in non-Black girls. Our findings were consistent with existing literature which suggests that better grades in school and/or higher educational aspirations are associated with postponed sexual activities -55. On tOur findings suggest that interventions that affect adolescents’ educational aspirations and grade acceleration might have positive effects on birth outcomes should the adolescent become pregnant. It has been found that both personal and social attributes are important factors that influence educational aspiration and grade acceleration in adolescent students ,60,61. AOur study used a large, nationally-representative dataset. Measurement of exposures was made prior to outcome data, which allows for the temporal inference between academic performance and educational expectation and the birth outcomes. Despite these strengths, our study has several limitations. First, we used adolescents’ self-reported letter grades rather than school transcript, which would have provided a more accurate and reliable measure of adolescents’ academic performance. The measurement of grade retention was also subject to reporting bias. Second, we reduced our sample size by requiring complete covariate data, which could bias our study results. Analyses comparing included (n = 763) versus excluded (n = 215) adolescents indicated no significant difference in birthweight (p = 0.71), gestational age p = 0.62), race (p = 0.10), age at pregnancy (p = 0.16), parental education (p = 0.10), GPA (p = 0.41), grade skipping (p = 0.20), adolescents’ educational aspiration (p = 0.15), smoking during pregnancy (p = 0.47), and prenatal care visit (p = 0.17). However, there were significant differences in baseline age , baseline BMI , and percent of grade repeating . Third, we relied on maternal self-reports of both birthweight and gestational age, which may be subject to recall biases. However, past studies comparing birth records to maternal self-report have found maternal reports of birth outcomes are largely a valid method of obtaining data [, race  after the inclusion of three potential mediators: smoking during pregnancy, initiation of prenatal care, and alcohol use during pregnancy.Click here for file


Studies throughout North America and Europe have documented adverse perinatal outcomes for racial/ethnic minorities. Nonetheless, the contrast in newborn characteristics between indigenous and non-indigenous populations in Latin America has been poorly characterized. This is due to many challenges, including a lack of vital registration information on ethnicity. The objective of this study was to analyze trends in anthropometric measures at birth in Chilean indigenous (Mapuche) and non-indigenous children over a 5-year period.We examined weight and length at birth using information available through a national data base of all birth records for the years 2000 through 2004 . Newborns were classified ethnically according to the origins of the parents' last names.The average birthweight was stable over the 5 year period with variations of less than 20 g in each group, and with mean values trivially higher in indigenous newborns. The proportion weighing less than 2500 g at birth increased modestly from 5.2% to 5.6% in non-indigenous newborns whereas the indigenous births remained constant at 5.2%. In multiple regression analyses, adjusting flexibly for gestational age and maternal characteristics, the occurrence of an indigenous surname added only 14 g to an average infant's birthweight while holding other factors constant. Results for length at birth were similar, and adjusted time trend variation in both outcomes was trivially small after adjustment. Anthropometric indexes at birth in Chile are quite favorable by international standards.There is only a trivial degree of ethnic disparity in these values, in contrast to conditions for ethnic minorities in other countries. Moreover, these values remained roughly constant over the 5 years of observation in this study. Characteristics of the newborn child reflect the complex web of intrauterine conditions and their interactions with the genetic potential of the individual. It is the multifaceted determination of these measures that makes them so useful not only as prognostic indicators for the child's health and development, but also as a robust index of social conditions and maternal health. Recently, an additional interest in these measures has centered around the possible association between a deficit in intrauterine growth and the elevation of risk for chronic diseases later in adult life ,2.Birthweight has long served as one of the most important indicators of maternal-child health, especially in the simple dichotomy of "low birth weight", often defined as birthweight less than 2500 g. The proportion of such births has been a mainstay of international comparisons for decades, and generally shows less favorable distribution in less developed countries. NonetheBirthweight has been considered in the public health and clinical literatures in many transformations, including the comparison of means or medians of the continuous measure, as well as the proportion below a cutpoint such as 2500 g. Tail proportions capture something of the spread of the distribution, while a mean only reveals where the distribution is centered, and thus the different indices reveal different aspects of population health. These considerations have been discussed in the work of Wilcox [In less developed nations, low birthweight may more commonly arise from intrauterine growth retardation (IUGR), whereas in developed nations it may arise more commonly because of shorter gestational ages (i.e. preterm birth) . Recent Chile is a country with an intermediate level of development and has experienced this last decade a rapid epidemiological transition, with major shifts in population into urban areas and into formal sector employment and supervised pregnancy. Overall, there has been rapid increase in standard of living for the population in aggregate. Furthermore, there has been a longstanding program of interventions targeted to mothers and children. These structural interventions have been characterized by an integrated vision of health and the life cycle with a priority for health care in ambulatory and community settings. The emphasis was placed on an interwoven concept of health and health service organizations and a continuing process of evaluation toward permanent improvement in the quality of the services . At the As in most of Latin American, one of the most highly disadvantaged groups in Chilean society has remained the indigenous inhabitants. The Mapuche, also called Araucanos, constitute the most important ethnic group in the nation in both population size and degree of cultural influence. Nevertheless, official statistics on health disparities between Mapuche and non indigenous populations are generally unavailable, due in part to the failure to collect health information categorized by ethnicity.In the Latin American context, Chile provides an ideal setting in which to examine birth outcomes given a modern and well-functioning system of vital registration that is essentially universal and is maintained electronically. Over 98% of labors are performed at specialized medical centers under the care of clinical nurse midwives  and an eThe universe of interest was defined as all live singleton births in Chile for the years 2000 through 2004. Data on all live births were collected, recorded by the National Institute of Statistics (INE) and the Civil Registration Office in the location where the delivery occurred. Numerous quantities are captured in the vital registration system, including weight in grams, length in centimeters, clinical estimate of gestational age at delivery and the reported level of education of the mother. Weight and length at birth are recorded by clinical nurse midwives trained to obtain these measures according to norms established and maintained by the Chilean Ministry of Health . These sEthnicity is not collected in Chilean vital statistics, and so in order to analyze the data by Mapuche or Non-Mapuche subgroups, it was necessary to develop an algorithm for making this distinction. This was accomplished by compiling an extensive data base of more than 7,000 Mapuche surnames . The eleThe mother's years of completed schooling were considered to form a socioeconomic status proxy. This information is provided by the mother when registering the baby at the Civil Registration Office. The variable was categorized in the descriptive analysis into the following groups: elementary education (up to 8 years of school), secondary school (those who had between 8 to 12 years) and those who reported having further university-level education (more than 12 years of instruction). In multiple regression analyses, the variable was used in continuous form (i.e. in units of completed years of education).In descriptive analyses, birthweight was divided into five categories: <1500 g, 1500 g to 2499 g, 2500 g to 2999 g, 3000 g to 3999 g and those who weighed over 4000 g at birth. To analyze the time trends for birthweight and length at birth in indigenous and non indigenous newborns, multiple linear regression models were fit, with birthweight (g) and length (cm) as the dependent variables and with socioeconomic and demographic factors  as control variables. A variable for calendar year from 2000 to 2004 was included to assess time variability. Linearity assumptions were relaxed for continuous variables  by adding quadratic terms to the model.This study was approved by the Ethics Committee of the Faculty of Medicine of the University of Chile and had the authorization of the Statistics Division of the Ministry of Health of Chile.A total of 1,166,513 live births were recorded, representing the universe of Chilean births occurring from January 1 2000 to December 31 2004. Of these, 1,145,752 were singleton newborns analyzed in this study. In the non-indigenous population there was a small but consistent decrease in the number of births that formed a decline of 2.7% over the study period. In the indigenous population, in contrast, the birth rate was approximately stable throughout the period of observation. The excess proportion of male births also remained relatively stable, fluctuating between 102.9 and 105.5% of the female births. The proportion of multiple births did not exceed 2% and was higher among the non-indigenous infants. The proportion of preterm births (born before 37 weeks of gestation) increased slightly over the interval, especially in non-indigenous children, reaching figures of 6.0% in the year 2000 and 6.9% the year 2004. In relation to the mother's years of schooling, the pattern was different between ethnic groups; in the indigenous the proportion of mothers with university education did not exceed 10% but with a modest increase over time, whereas among the non-indigenous this proportion was close to 20%, also with an upward trend (Table The percentage of newborns with low birth weight <2500 g) was similarly stable over the 5 year interval, increasing modestly from 5.25% to 5.63% in non-indigenous newborns and remaining roughly constant in the indigenous group with slightly lower values. The indigenous newborns showed the highest proportion with birthweight over 4000 g, one percent higher than non-indigenous newborns in all the years studied . Being indigenous decreased the length at birth by 0.17 mm after multivariable adjustment, a smaller effect than living in a rural area (0.11 mm). The R2 for the model is 0.46.Another approach to analyzing the disparities between ethnic groups and over time is through multiple regression, as this allows for conditional estimates (i.e. the effect of one covariate while holding another variable constant). In fully adjusted models, having an indigenous surname increased birthweight by 12 g holding all other factors constant Table . The secAn analysis of over a million births in a middle-income nation reveals a favorable distribution of anthropometric measures at birth, independently of ethnic origin. This is reflected in the modest prevalence of children with low weight at birth, for which indigenous children have an even lower proportion . The time trends in these anthropometric variables during the 5 year period of observation in this study is roughly stable, with a modest but detectable increase of weight at birth observed after adjustment for gestational age and other variables.The absence of an ethnic disparity in these outcomes is surprising because Chileans with Mapuche identity have substantial socioeconomic disadvantages, and notable health disparities for many other outcomes ,15. NoneThese results suggest that with respect to the usual indicators of reproductive health, Chile behaves much more like a developed country. Birth outcome statistics in this study are very good in comparison with the rest of the region, and approach patterns typical of North America and Europe ,18, resuBetter conditions of pregnancy in Chile may be explained through the rapid overall improvement of socioeconomic conditions represented, for instance, in a rapidly increased gross national product (GNP) and a similarly precipitous decrease in levels of poverty. Chile's GNP grew by a remarkable 7% per year in the 1990s, although economic growth has moderated in the last few years, as in most of the world economy. ConcomiThe somewhat surprising result that the indigenous population does not suffer from adverse anthropometric conditions at birth suggests that by the first decade of the 21st Century, the kind of deprivation that affects so much of the indigenous population of Latin American is conquered in Chile, at least to the extent that pregnant women appear to have sufficient resources and pregnancies that are on average as healthy as those in the majority population. While vast inequalities in access to health and resources still exist in Chile, it seems that these are not evident in pregnancy, and that public health attention can be shifted to later life conditions. This situation may be peculiar to the Chilean indigenous population, although there is some published evidence to suggest that in other places on the continent also, malnutrition initiates after weaning ,25.The fact that more than 10% of the country's population weighs more than 4000 g at birth and that this proportion is actually higher in indigenous newborns may be considered a public health alert, since various studies are now reporting high prevalence of excess weight in school children. The trajectories of weight gain connecting birthweight to adult weight are not yet clear, but this could be quite an important fact in a country like Chile that is experiencing such an explosive growth in excess weight in almost all age groups .Length at birth has been described as a predictor of "stunting" at subsequent ages  but for Many hypotheses are available to make sense of these patterns. For example, the proportion of multiple births has been stable, while the duration of pregnancy has decreased slightly, which may reflect the situation that newborns from more advantaged social classes, in which non-indigenous parents predominate, have shorter pregnancies. This confounding by social class would serve to balance out the averages of weight and length to erase a true disparity that exists within strata, although control for mother's education did not have a profound influence on these results. Of particular note when considering socioeconomic confounding is the fact that Chile currently has one of the highest percentages of caesareans in the region, approaching up to 40% of births, which is almost the double that seen in many other Latin American countries. This procedure now occurs in one out of 3 labors in public hospitals and in 60% in private ones, which can also introduce important confounding due to the truncation of the gestational period .The continuing modest trend toward heavier births in Chile is potentially related to the disappearance of gaps between social groups, and is a phenomenon that has not been well described in Latin America. Other changes have occurred in relation to pregnancy and childbirth in Latin America which affect anthropometric measures in newborns, and are surely part of the complex mix in the Chilean situation as well. These include not only changes in social conditions such as income, poverty, nutrition and mothers' employment, but also an increase in the average intergestational interval, increases in prevalence of gestational diabetes, and decreases in the prevalence of smoking among pregnant women ,31. AddiOne of the limitations of this study is the use of the gestational age variable, information that was obtained from the birth certificate, which is an amalgam of different pieces of information . The algorithm for combining these pieces of information varies from one place to another, and it is quite likely that health units that assist rural populations do not have the same availability of equipment as those located in areas of higher demand or centers attended by higher income urban women. Although there exists no "gold standard" for assessment of gestational age, the use of several pieces of data in combination is supposed to be a better approximation. Nonetheless, this is a source of some uncertainty in our data set, and a possible target for sensitivity analysis or other corrections.This study was conducted on the universe of those born alive in the country, and data have gone through quality control. The fact that there was no sampling suggests that there is no need to rely on inferential statistics such as p-values or confidence intervals. The latter are provided to demonstrate the great precision of the estimates, but in fact they do not have any formal interpretation because the entire population was included in the study . This adAlthough we have great precision to detect small variations in the measures obtained, this does not imply that such small differences necessarily have a clinical relevance. Nonetheless, our work is engaged from a population perspective. While there is variability in every population group, the mean birthweight for the Chilean indigenous population of newborns differs only trivially from the mean birthweight for the non-indigenous population. In this respect, disparities in this outcome, one of the most universally acknowledged markers of population health, have largely disappeared.This study has reported the absence of any important differences in anthropometric measures at birth between ethnic groups for a 5-year period among singleton live births in Chile. The data also reveal a low prevalence of children with low weight at birth. The time trends in these anthropometric variables is relatively stable, with a modest but detectable increase of weight at birth, conditional on gestational age and other covariates. The absence of an ethnic disparity in these outcomes is surprising because Chileans with indigenous background have documented socioeconomic disadvantages along with resulting health disparities for other outcomes.The authors declare that they have no competing interests.HA and PB were in charge of the planning, collection of the data, analysis and writing the paper. JK was also responsible by the analysis, statistic advice, and writing, editing and approving the final version of the submitted manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/392/prepub


We developed a method based on Information Theory  to the aCPG motor neurons 5] in th in th5] via artificial fish, both in real time and previously recorded sequences. Analysis using Information Theory tools revealed that the stimuli sequences play a significant role in the fish response.Weakly electric fish provide a wonderful opportunity to study and interact with a living intact nervous systems. Their electrical organ discharges (EODs) are not only complex signals that belong to the processing of environmental sensory information by the nervous system but they are also easy-to-detect. Each EOD generates an electric field that reaches a myriad of electroreceptors disposed to detect small changes in the cutaneous electric field. With this apparatus the weakly electric fishes are able to detect objects as well as social electrocommunication. Using n


To determine the rates of birth registration over a five-year period in New South Wales (NSW) and explore the factors associated with the rate of registration.This is a cross-sectional study using linked population databases. The study population included all births of NSW residents in NSW between 2001 and 2005.Birth registration rates in NSW were 82.66% in the year of birth, 93.19% in the first year, 94.02% in the second, 94.56% in the third and 95.08% in the fourth year after birth. The non-registration of births was mainly associated with such factors as neonatal and postneonatal death ; being Indigenous ; maternal age <25 or >39 years ; low birthweight  ; living in remote areas ; being born after the first quarter of year ; mother having more pregnancies . Mothers who were born overseas were more likely to register their births than those born in Australia . Multiple births were more likely to be registered than singleton births . About one-third of the non-registrations of births in NSW were explained by the risk factors. The reasons for the remaining non-registrations need to be investigated.Of birth in NSW, 4.92% were not registered by the fourth year after birth. Australia’s mothers and babies[In Australia, information on births is published annually by two organisations: the Australian Bureau of Statistics (ABS) and the Australian Institute of Health and Welfare (AIHW) National Perinatal Statistics Unit (NPSU) ,2. The AThe MDC consistently reports more live births than the RBDM by year of birth. In 2004, the MDC reported 255,286 live births which was 4.8% higher than the 243,680 live births in the birth registration report [In New South Wales (NSW), the percentage difference between the MDC and RBDM was 2.4% in 2000, 3.9% in 2001, 4.3% in 2002, 5.5% in 2003 and 6.7% in 2004. There is also variation in the size of the gap among other states and territories in Australia. In 2004, the differences were 6.7% in NSW, 6.3% in Queensland, 4.8% in South Australia, 3.9% in Western Australia, 2.5% in Victoria, 0.9% in ACT, 0.8% in North Territory and 1.2% in Tasmania [In order to determine the reasons for the discrepancies between the numbers of births collected by the NSW MDC and the NSW RBDM, birth registration rates were followed up for four years after birth using linked data. The birth registration rates and factors associated with the rates are described in this paper.The study population included all live births of NSW residents recorded in the NSW MDC between January 2001 and December 2005. The birth records of the residents of other states and territories were excluded from the analysis.Data is recorded in the MDC by either the midwife or medical staff. It includes all births in NSW of at least 20 weeks gestation or more than 400 grams birthweight, and includes maternal demographic factors, obstetric information and pregnancy outcomes. The NSW RBDM is recorded by the parents of the child and the forms are lodged with the Registrar of Births, Deaths and Marriages. It covers all births registered in NSW and includes demographic factors and some pregnancy outcomes. Study data were obtained from the NSW MDC and linked with the NSW RBDM. The births in the MDC were followed up until registration by the RBDM. The babies born from 2001 to 2005 were followed up until 2005. The births in 2001 had the longest follow-up period of four years.For babies born in NSW from 1 January 2001 to 31 December 2005, there were 434,513 birth records, including 46 duplicate records, in the MDC and 405,366 birth records including 623 duplicate records in the RBDM. If the duplicate records are excluded, there were 434,467 birth records in the MDC and 404,743 birth records in the RBDM. The analysis is based only on NSW residents. In the MDC, 4,614 records included 4,521 residents of other states and territories; 93 records that did not state place of residence were excluded from the analysis. In the RBDM, 4,963 records included 4,338 residents of other states and territories; 625 records that did not state place of residence were excluded from the analysis. The missing rate in value of living place in RBDM (0.15%) was significantly higher than MDC (0.02%) p < 0.01.The study was approved by the NSW Population & Health Services Research Ethics Committee, the Human Research Ethics Committees of University of Sydney and University of New South Wales, and the Aboriginal Health and Medical Research Council. Identifying information such as name, address, date of birth and gender obtained from the MDC baby and RBDM birth datasets is included in the Master Linkage Key which is constructed by the Centre for Health Record Linkage (CHeReL).http://www.cherel.org.au). At the completion of the process each record in the Master Linkage Key was assigned a record identification number and a Master Linkage Key person ID (Project Person Number (PPN)) to allow linked records for the same individual to be identified and extracted. Linkage quality was assessed with the use of a random sample of 1,000 PPNs in which the false positive rate of the linkage was 0.4% and false negative less than 0.1%.CHeReL performed the data linkage using probabilistic record linkage methods and ChoiceMaker software (refer Descriptive statistics and cross-tabulations were generated for registration rates and proportions. Logistic regression model (enter) was used to explore the factors associated with registration rates. The factors entered into the model included being Indigenous, maternal age, mother’s country of birth, remoteness of living area, birthweight, the quarter of the year in which the baby was born, parity, plurality and neonatal and postneonatal death. The odds ratios (ORs) for the explanatory variables are presented. Some babies had more than one record in the data collections. The duplicate records were identified and excluded before merging the databases.Maternal Indigenous status: women who have given birth who identify themselves to be of Aboriginal and/or Torres Strait Islander origin.Live birth: the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of the pregnancy, which, after such separation, breathes or shows any other evidence of life, such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles, whether or not the umbilical cord has been cut or the placenta is attached. Each product of such births is considered to be live born (WHO definition) .Neonatal death: death of a liveborn baby within 28 days of birth .Postneonatal death: death of liveborn baby after 28 days and within one year of birth [The risk group included births with one or more of the following conditions: gestational age <37 or >41 weeks, birth weight <2,500 grams, neonatal or postneonatal death, Indigenous ethnicity, maternal age <25 or >39 years and not living in major cities.The non-risk group included all remaining births with gestational age 37–41 weeks or birth weight ≥2,500 grams or no neonatal or postneonatal death or baby’s mother being non-Indigenous or aged 25–39 years or lived in major cities.For NSW residents, there were 427,134 live born babies between 1 January 2001 and 31 December 2005. There were 61 records excluded from the analysis because they were incomplete. The results are based on the eligible 427,073 births.The overall registration rate between 2001 and 2005 was 91.80% by the end of 2005. There were 35,017 babies (8.20%) who had not been registered by 31 December 2005. The registration rates are described in detail in Table The majority of births (82.66%) were registered in the same year of birth, and 93.19% of births were registered by the end of the first year after birth. Babies from the risk groups accounted for 46.54%  of all live births, but accounted for 63.09%  of the non-registered births.The births in 2001 had the longest follow-up time. The cumulative birth registration rates of babies born in 2001 are shown in Figures The registration rates in the non-risk group were higher than in the risk group. The differences in the 2001 births were 5.81% in the year of birth, 5.07% in the first, 4.79% in the second, 4.41% in the third and 4.06% in the fourth year after birth.For the births in 2001, there were 4,674 births that were not registered. The non-registration rate in the risk group was 4.06% higher than in the non-risk group (7.66% − 3.60%). The difference was attributed to risk factors and accounted for 53.00%  of the non-registered births in the risk group. The risk factors can explain 35.00%  of non-registered births in 2001. The rest of the non-registrations , accounting for 65.00% of the non-registered births, cannot be explained by this data.Table Table Birth data are an essential source of information for governments, researchers and the community. The accuracy and ascertainment of births and registration data are important for planning and research. Birth registration, a state administration’s official record of a baby’s birth, is also important for individuals who use a birth certificate to prove age, parentage and citizenship.Population and development review published by UNICEF in 1998 reported that the registration rates were 99.8% in Europe, 98.9% in the Americas, 98.8% in Central Asia, 98.1% in the Middle East and North Africa, 90.4% in Sub-Saharan Africa and 76.5% in East/South Asia and the Pacific [Registration rates differ by country and area. The Australia’s mothers and babies 2005 and the current study may be attributed to reporting biases, delayed registration and different data collection methods.Few studies report Australian birth registration rates and very few countries have attempted to assess the coverage level of registration objectively and thoroughly . Many coAustralia’s mothers and babies over the years was similar to the current study, except that the registration rate in the year of birth was relatively higher than in the current study (87.3% versus 82.7%) [Australia’s mothers and babies 2005 included summary data, and the registration rates were calculated by dividing the number of registrations in the RBDM by the number of MDC births in the same year. The births which occurred outside of Australia but were registered should but not be excluded from the summary data. The linked data of the current study show that 5,741 (1.3%) of NSW residents’ births registered between 2001 and 2005 could not be linked to the birth records in the MDC and were excluded from the analysis. Data linkage can overcome this shortcoming in the summary data by excluding the births registered, but cannot be linked to the midwife’s birth records and accurately distinguish between registered and non-registered records. Consequently, the results from the linked population data are more accurate. However, the unlinked 1.3% of births in RBDM could not fully explain the difference of 4.6% (87.3% − 82.7%). This study implies that the registration rates in NSW were lower than the national registration rate.The trend of registration rates in This study found that the non-registration rate in NSW was 5.53% and associated with neonatal or postneonatal death, being Indigenous, maternal age <25 or >39, gestational age <37 or >41 weeks, low birthweight  and not living in major cities. UNICEF’s report (1998) showed that ethnic minorities, babies born at home and mobile populations have lower rates of registration than the general population [The cohort study in Korea showed that the registration rate within the legal due date was lower in mothers under 20 years of age and above 35 years, and in mothers who had only primary education . The stuBirths, Australia, shows the percentage of birth years when births were registered [The ABS publication, gistered . Of the gistered . The resBirths, Deaths and Marriages Registration Act 1995 all births in NSW are to be registered within 60 days of a child’s birth [Reasons suggested for the interval between the occurrence and the registration of a birth included delays by the parents in submitting a completed form to the registry or delays by the registry in processing the birth. Hospitals and birth clinics notify state registries of recent births on a regular basis. For those births known to a registry that have not been registered within a prescribed time period, a reminder letter is sent to the parents of the child as a follow-up. Under the ’s birth -10. The The Baby Bonus is a non-income tested lump sum payment for each child born (including stillborn) or adopted by Australian families. Parents were not required to formally register the birth of their child as a condition of receiving the Baby Bonus for births prior to 1 July 2007 . This miIndigenous births were less likely to be registered. The average interval between the occurrence and registration of the birth was longer in Indigenous births (6.4 months in 2006) than in the general population (2.2 months in 2005) ,12. The The fee charged for registration and birth certificates are economic barriers for birth registration and UNICEF recommends free birth registration and birth certificates . In NSW,Approximately 3.60% of babies in the non-risk group were non-registered; this cannot be explained by delayed registration or the risk factors mentioned above. A further study, in which parents of non-registered babies are interviewed, is necessary to identify other barriers to registration.Public Health Act 1991. It received notifications of all births which occurred in NSW [Births, Deaths and Marriages Registration Act 1995, all babies in NSW must be registered within 60 days of birth. The hospitals in which the birth occurs, or the child and mother are taken to within 24 hours of the birth, supply a birth registration statement (BRS) to parents and a notification to the RBDM. If the birth occurs at home or in a location other than a hospital with a registered doctor or registered midwife in attendance, the registered doctor or midwife advises the RBDM of the birth and also provides the mother with a BRS. If the birth occurs in a location other than a hospital without a registered doctor or midwife in attendance, and the child is not taken to a hospital within 24 hours of the birth, the mother should call the RBDM and provide her name and home address, and names and addresses of two independent witnesses who saw the birth. Statutory declarations are then posted to the witnesses. Once they are signed and returned to the RBDM, a BRS is posted to mothers [The Midwives Data Collection (MDC) is a population-based surveillance system covering all births including live births and stillbirths in NSW public and private hospitals, as well as homebirths. In 1992, the MDC became a statutory data collection under the NSW d in NSW . The att mothers . If 100%There were several limitations in this study which may have impacted its results. The analysis of factors was limited to the variables available in the linked data. Birth place, marital status and socio-economic level should be included in future studies. On the other hand, the interval from birth to registration cannot be calculated because the month of registration is not available in this study. However, the birth registration rates in this study imply that the median was less than one year. In some underdeveloped areas or countries, many children are registered later in life, for example when they enrol in school . If the The majority of births (82.66%) were registered in the same year of birth and 93.19% of births were registered in the first year after birth. There were 4.92% of NSW births that were not registered by the fourth year. Around one-third of birth non-registrations in NSW could be explained by the following factors: neonatal or postneonatal death, Indigenous status, maternal age <25 or >39, gestational age <37 or >41 weeks, low birthweight (<2500 grams) and not living in major cities. Meanwhile, the remainder (65%) of non-registrations could not be explained.The authors declare that they have no competing interests.FX participated in the study design, data analysis and paper writing. LH participated in the study design. MPA participated in diagnoses grouping. EAS participated in the study design and coordinated and supervised the study. All authors read, revised and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/12/147/prepub


Thyroid hormones are essential for brain development, and maternal thyroid disease may affect child neurocognitive development. Some types of seizures may also depend upon early exposure of the developing central nervous system, and we hypothesized that maternal thyroid dysfunction could increase the risk of seizure in the child. In a Danish population-based study we included 1,699,693 liveborn singletons, and from the Danish National Hospital Register we obtained information on maternal diagnosis of hyper- or hypothyroidism and neonatal seizure, febrile seizure, and epilepsy in the child. Maternal diagnosis of thyroid dysfunction before or after birth of the child was registered in two percent of the singleton births. In adjusted analyses, maternal hyperthyroidism and hypothyroidism first time diagnosed after birth of the child were associated with a significant increased risk of epilepsy in the child. Moreover, hypothyroidism diagnosed after birth of the child was associated with a significant increased risk of neonatal and febrile seizures. No significant association was seen for maternal diagnosis prior to birth of the child. We speculate if some degree of maternal thyroid dysfunction was already present during the pregnancy in mothers diagnosed after birth of the child and if this untreated condition may present a neurodevelopmental risk. Thyroid hormones are essential for fetal brain development , 2 and rThyroid diseases are common in women of reproductive age either as overt or subclinical disease , 8, and Fetal Programming. Abnormal thyroid hormone levels or treatment of a thyroid disease before/during pregnancy could affect the fetal brain and increase susceptibility to seizure in the child. An association with maternal thyroid disease diagnosed before birth of the child might then be expected. (2) Genetics. A genetic component passed on to the child from the parent suffering from thyroid disease could increase susceptibility to seizure in the child. If genetic factors play a role, an association with paternal thyroid disease or with maternal thyroid disease diagnosed after birth of the child might then also be expected. (3) Subclinical Thyroid Disease. The impact of maternal thyroid dysfunction present before and/or during pregnancy but clinically diagnosed and treated after birth of the child could increase susceptibility to seizure in the child. An association with maternal thyroid disease diagnosed after birth of the child might then be expected.We hypothesized that maternal thyroid dysfunction, hyper- and hypothyroidism, would increase the risk of seizure in the child via subtle changes in brain structure. We examined the impact of maternal thyroid dysfunction diagnosed before, during, and after the pregnancy on the risk of neonatal seizure, febrile seizure, and epilepsy in the child. More specifically we hypothesized that an association between maternal thyroid dysfunction and the risk of seizure in the child could be caused by one or more of the following mechanisms. (1) We conducted a population-based cohort study using Danish nationwide registers. A unique ten-digit personal identification number is used in all national registers in Denmark, and in the Danish Civil Registration System  we identThe Danish National Hospital Register (DNHR)  holds daDiagnoses of maternal thyroid dysfunction were obtained from DNHR. Hyperthyroidism was defined as ICD-8: 242.00–242.29 and ICD-10: E05–E05.9 (excluding thyrotoxicosis factitia (E05.4), overproduction of thyroid-stimulating hormone (E05.8A), and thyrotoxic heart disease (E05.9A)). Hypothyroidism was defined as ICD-8: 243.99, 244.00–244.09 (excluding secondary hypothyroidism 244.02) and ICD-10: E03–E03.9 and E89.0  and atrophy of the thyroid ).Diagnoses of seizure were obtained from DNHR using the following ICD codes: febrile seizure ICD-8: 780.21 and ICD-10: R56.0 and R56.0A, epilepsy ICD-8: 345.09–345.99 and ICD-10: G40.0–G41.9, and unspecified seizure ICD-8: 780.29 and ICD-10: R56.8. Diagnoses of breath-holding spells (ICD-8 780.20 and ICD-10 R56.8C) were not included. Neonatal seizure was defined as ICD-10: P90.9 or any of the seizure diagnoses listed above obtained in the neonatal period (first 28 days of life). Febrile seizure was defined as a diagnosis of febrile seizure after the neonatal period and before the age of 5 years with no previous diagnosis of neonatal seizure or epilepsy. Finally, epilepsy was defined as a diagnosis of epilepsy after the neonatal period . From the Medical Birth Registry , which hFrom Statistics Denmark we obtained information on maternal cohabitation, income, origin, and geographical residence at birth of child. Information was only available from 1980, and data from 1980 were used to substitute missing values in 1978 and 1979. For maternal cohabitation and origin we replaced additional missing values by available information in the preceding or following five (origin) or three (cohabitation) years, whichever came first. Maternal residence at birth of child was used as an indicator variable for iodine intake. Iodine is required for thyroid hormone synthesis, and Denmark was previously iodine deficient with regional differences: moderate iodine deficiency in West Denmark and mild iodine deficiency in East Denmark (divided by the Great Belt). The mandatory iodine fortification of salt was introduced in the year 2000 and had increased urinary iodine to lower recommended level in 2004-2005 .From DNHR we obtained information on parental diagnosis of epilepsy and febrile seizure, maternal diagnosis of preeclampsia/eclampsia (ICD-8: 637.03–637.19 and ICD-10: O14-O15.0) and diabetes (ICD-8: 249.00–250.09 and ICD-10: E10.0–E14.9 and O24–O24.9) and child diagnosis of cerebral palsy (ICD-8: 343.99 and 344.99 and ICD-10: G80–80.9) and congenital malformations (ICD-8: 740.99–759.99 and ICD-10: Q00–Q99). n = 13 or maternal covariates: parity n = 169, origin n = 5,015, cohabitation n = 1,257, and income n = 1,335, thus leaving 1,699,693 singletons in the final cohort for followup. Singletons not alive after the neonatal period (n = 838) or who had emigrated (n = 109) during the neonatal period were not included in the followup study on the risk of febrile seizure and epilepsy.We excluded children with missing information on maternal identification number Children were followed up from birth  or from day 29 after birth (febrile seizure and epilepsy) and until the date of admission for the first in- or outpatient visit with a diagnosis of seizure, emigration, or death or until day 28 after birth , age of 5 years (febrile seizure), or December 31, 2006 (epilepsy).The Cox proportional hazards model was used to estimate hazard ratio (HR) with 95% confidence interval (95% CI) for risk of neonatal seizure, febrile seizure, and epilepsy in children exposed to maternal hyper- or hypothyroidism diagnosed before and/or after birth of the child compared to children unexposed. The proportional hazards assumption was tested in plots of log cumulative hazards. Robust standard errors were used to adjust for dependence between maternal multiple pregnancies. Univariate and multivariate analyses were performed, and in the multivariate analyses we adjusted for potential confounders including gender of the child (boy/girl), birth year , and the following maternal variables obtained at the time of the child's birth: age , parity including index pregnancy , cohabitation (married/not married), income , origin (born in Denmark/not born in Denmark), residence (East/West Denmark), and maternal diagnosis of febrile seizure and/or epilepsy registered in the Danish National Hospital Register (DNHR) before January 1, 2007 (yes/no). In parallel analyses, HR with 95% CI for risk of seizure in children exposed to paternal thyroid dysfunction was estimated. n = 173,440), (b) children born to mothers with a diagnosis of preeclampsia/eclampsia and/or diabetes , (c) children with gestational age at birth <37 or >41 weeks or birth weight not appropriate for gestational age  , and (d) children with a diagnosis of thyroid disease . Apgar score, birth weight, and gestational age were a priori considered possible intermediates and hence not included in the main model. Analyses were repeated after the exclusion of (a) children with a diagnosis of cerebral palsy, congenital malformations, and/or 5-minute Apgar score below 7  and a 5% level of significance was chosen. The study was approved by the Danish Data Protection Agency.Among 1,699,693 liveborn singletons in Denmark between January 1, 1978, and November 30, 2006, we identified 34,582 singletons (2.0%), whose mother had a diagnosis of hyperthyroidism (1.3%) or hypothyroidism (0.7%) registered in DNHR before January 1, 2007. The majority of exposed singletons were born to mothers diagnosed with hyper- or hypothyroidism after birth of the child (74.3%) with a median time from birth of the child to maternal diagnosis of 10.7 years (range 0.003–28.9 years). For maternal diagnosis before or at birth of the child, median time from diagnosis to birth of the child was 3.0 years (0–27.5 years) for hyperthyroidism and 1.7 years (0–29.8 years) for hypothyroidism. In the group of singletons born to mothers with a diagnosis of thyroid dysfunction before birth of the child and valid information on gestational age, 2,498 singleton births followed a maternal first time diagnosis of thyroid disease during the pregnancy. Figures P < 0.001. Median age at diagnosis was 1.4 years for febrile seizure and 5.3 years for epilepsy, and in 18.2% of the cases a diagnosis of epilepsy occurred during the first year of life. Children were followed up for up to 28.9 years, and The crude and adjusted HR for risk of seizure in the child differed according to seizure type and maternal thyroid dysfunction . The adjWe subsequently evaluated if the increased risk of epilepsy in children born to mothers with a diagnosis of hyper- or hypothyroidism differed according to time of maternal diagnosis in relation to birth of the child . MaternaMaternal hypothyroidism was associated with an increased risk of febrile seizure and neonatal seizure in the child. n = 8, febrile n = 83, and epilepsy n = 26), and the adjusted HR for risk of seizure in the child did not indicate that maternal diagnosis during pregnancy revealed a high risk: neonatal seizure HR 1.64 (95% CI 0.82–3.28), febrile seizure 1.10 (0.88–1.36), and epilepsy 1.25 (0.85–1.84). However, numbers were small and did not permit stratification by maternal type of thyroid dysfunction.Among the 2,498 children whose mother had hyper- or hypothyroidism diagnosed during the pregnancy, a total of 111 children developed seizure during followup  or hypothyroidism  registered in DNHR before January 1, 2007, and among these children, 288 (5%) had a diagnosis of seizure . No significant increased risk of seizure in children exposed to paternal thyroid disease was observed , febrile seizure 0.99 (0.86–1.15)). The adjusted HR for risk of epilepsy in the child was on the borderline of statistical significance 1.20 (95% CI 0.99–1.46). We identified 5,742 singletons (0.3%) whose father had a diagnosis of hyperthyroidism ). Restricting the cohort to children born at term with a birth weight appropriate for gestational age did not change results for maternal hyperthyroidism, but for hypothyroidism the risk of neonatal seizure (adjusted HR 1.42 (0.87–2.32)) and epilepsy (1.18 (0.98–1.43)) were no longer statistically significant.n = 960, hypothyroidism n = 1,431) with a median age at diagnosis of 14.6 years. The frequency of seizure was higher in this group (8.4%), but the associations were similar after the exclusion of these children. Restricting analyses to firstborn child did not change results, neither did the exclusion of children born to foreign-born mothers. We identified 627,100 singletons with available information on maternal smoking during the pregnancy. Applying the same main model to this restricted cohort revealed similar associations regardless of the inclusion of maternal smoking in the model (data not shown).The exclusion of children born to mothers with a diagnosis of preeclampsia and/or diabetes did not change results. A small group of children had a diagnosis of thyroid disease  when analysing the association with maternal thyroid disease diagnosed after birth of the child. The time from birth of child to maternal diagnosis becomes “immortal”, which may cause bias . HoweverThe quality of the diagnoses in DNHR has been evaluated, and the positive predictive value of a diagnosis of febrile seizure and epilepsy was 93 and 81%, respectively , 36. A dMisclassification of exposure and outcome does exist in our study population; however, we believe this misclassification is nondifferential. Maternal onset of disease was defined as the day of first admission to hospital. We only included women with a hospital diagnosis of thyroid disease, and we did not have results of thyroid function tests, thyroid autoantibodies, scintigraphy, and/or treatment modality. We believe that pregnant women are in general referred to hospital for diagnosis and therapy , but theAlthough we adjusted for a number of potential confounders, unmeasured confounding might still exist. Information on maternal infections and use of antibiotic during pregnancy  was not The potential benefits and harms of screening pregnant women for thyroid dysfunction in early pregnancy have been an ongoing discussion in recent years, as discussed in detail in . The preMaternal hyper- and hypothyroidism diagnosed after birth of the child may increase the risk of epilepsy in the child. In addition, maternal hypothyroidism diagnosed after birth of child was associated with increased risk of neonatal seizure and febrile seizure. The findings lead to speculations whether undetected maternal thyroid hormone aberrations were already present during the pregnancy in mothers diagnosed after birth of the child.