To examine the association between a woman's birth weight and her subsequent fecundability.In this prospective cohort study, we included 2,773 Danish pregnancy planners enrolled in the internet-based cohort study “Snart-Gravid”, conducted during 2007–2012. Participants were 18–40 years old at study entry, attempting to conceive, and were not receiving fertility treatment. Data on weight at birth were obtained from the Danish Medical Birth Registry and categorized as <2,500 grams, 2,500–2,999 grams, 3,000–3,999 grams, and ≥4,000 grams. In additional analyses, birth weight was categorized according to z-scores for each gestational week at birth. Time-to-pregnancy measured in cycles was used to compute fecundability ratios (FR) and 95% confidence intervals (CI), using a proportional probabilities regression model.Relative to women with a birth weight of 3,000–3,999 grams, FRs adjusted for gestational age, year of birth, and maternal socio-demographic and medical factors were 0.99 , 0.99 , and 1.08  for birth weight <2,500 grams, 2,500–2,999 grams, and ≥4,000 grams, respectively. Estimates remained unchanged after further adjustment for markers of the participant's mother's fecundability. We obtained similar results when we restricted to women who were born at term, and to women who had attempted to conceive for a maximum of 6 cycles before study entry. Results remained similar when we estimated FRs according to z-scores of birth weight.Our results indicate that birth weight appears not to be an important determinant of fecundability. Several studies have shown that individuals with a low weight at birth are at increased risk of developing morbidities in adulthood, possibly due to physiologic, metabolic, and hormonal changes during fetal life associated with insufficient growth A reduced probability of giving birth has been reported among women born before 32 full weeks Whether the association between weight at birth and subsequent health is attributable to direct effects of insufficient fetal growth or to underlying shared mechanisms, i.e., intergenerational factors with a potential influence on fetal growth and adult health, has been the subject of debate We examined the association between weight at birth and subsequent fecundability of women participating in a prospective cohort study of TTP, while controlling for potential confounding by reproductive characteristics of the women's mothers.In this study, we used data from the “Snart-Gravid” (“Soon Pregnant”) study, which is a Danish internet-based prospective cohort study of pregnancy planners, designed to examine the influence of lifestyle and behavioral factors on fecundability. The study design and data collection have been described in detail elsewhere By August 2012, 6,033 women had enrolled in the study by responding to the baseline questionnaire. We excluded 579 women who did not complete a follow-up questionnaire, 113 repeated entries, 294 women with implausible or missing information on date of last menstrual period, 538 women who had attempted to conceive for more than 11 cycles at enrollment, and 226 women who had been adopted, born after a non-singleton gestation, or had missing data on multiplicity of gestation. In order to obtain uniformly recorded data on gestational age at birth from the Danish Medical Birth Registry (DMBR), we also excluded 1,510 women who were born before January 1, 1978. The remaining 2,773 women were included in the analyses.We obtained data on the participants' weight at birth from the DMBR. This registry records over 99% of births in Denmark, reported prospectively by midwives attending the birth th cycle of attempted pregnancy to the analysis. Observed cycles at risk of pregnancy were defined as cycles contributed after study enrollment and were left-truncated. Thus, if a woman had already attempted to conceive for 8 cycles when she entered the study, she could contribute up to 4 more cycles after enrollment into the study, with her observed cycles starting at cycle 9 (delayed entry). The follow-up of women who started fertility treatment during follow-up was censored at the cycle in which they started the treatment.The event of interest was participants' report of any pregnancy regardless of outcome. More than 96% of participants used a home pregnancy test to confirm conception We obtained data on participants' gestational age at birth from the DMBR. Data on gestational age were based on the date of the pregnant woman's last menstrual period, corrected by ultrasound examination if performed, and registered in full weeks. Gestational ages of the participants were 28–44 completed weeks. We defined preterm to be a gestational age <37 weeks; full term to be 37–41 weeks; and post-term to be ≥42 weeks. From the DMBR, we also obtained information on participants' mothers' lifetime parity and participants' birth order by using the CPR number to identify mothers and siblings. Siblings born before establishment of the DMBR in 1973 were identified by the mothers' self-reported parity, which was also registered in the DMBR and has high validity From the DMBR we obtained data on mother's age and marital status at the time the participant was born. From the Danish National Registry of Patients (DNRP), which includes data on all admissions to Danish non-psychiatric hospitals since 1977, we obtained data on hospital diagnoses of hypertension or pre-eclampsia during the mother's pregnancy with the participant. These diagnoses were coded according to ICD-8 during the period of interest. We used ICD-8 codes 400–404 and 637.00  and 637.03, 637.04, 637.09, 637.19, and 637.99 . Prevalence of hospital admission due to maternal diabetes was below 1%, therefore maternal diabetes as measured by hospitalization was not a strong confounder in our analysis.2)). Further, data on participants' age, number of cycles of pregnancy attempt at study entry, intercourse frequency, mother's and father's educational level, and mother's smoking during pregnancy were reported in the baseline questionnaire.From the baseline questionnaire we obtained data on participants' own reproductive history, including age at menarche, cycle regularity, gravidity, parity, and history of unsuccessful pregnancy attempts ≥12 months. At baseline, participants also reported their weight (in kilograms) and height (in centimeters) and we calculated their body mass index (BMI) as (weight (kilograms)/height squared (mhttp://www.ssi.dk/Sundhedsdataotit.aspx). Data from the ”Snart-Gravid” study are hosted by the Department of Clinical Epidemiology, Aarhus University Hospital; as this study is still in progress, access to the data is not yet freely available. All data were anonymized after retrieval and no CPR numbers were included in the dataset that was the basis of our analyses.The “Snart-Gravid” study was approved by the Danish Data Protection Board  and the Institutional Review Board at Boston University. Consent was obtained from the participants before completion of the first questionnaire. Data from the DMBR and the DNRP were retrieved from Statens Serum Institut . We included 36 variables in the imputation, including all variables used in the substantive analyses, and imputed five data sets. Distributions of continuous variables were examined by histograms and box plots. Variables that diverged from the normal distribution were transformed to the log-scale before imputation.We calculated Kaplan-Meier estimates to assess the cumulative probability of conception within 3, 6, and 12 menstrual cycles, accounting for delayed entry using left-truncation, and losses to follow-up and other reasons for censoring . We described the distribution of participants' characteristics  according to weight at birth. Using a proportional probabilities model, we then estimated fecundability ratios (FR) and 95% confidence intervals (CI) for categories of birth weight , using TTP measured in cycles. The FR of any two groups was calculated as the ratio of their cycle-specific probabilities We examined potential interaction between weight and gestational age at birth by including product terms for gestational age as a continuous variable in the regression model, and found no evidence of interaction. Adjustments were made in three steps: first, we adjusted for year of birth and gestational age as a continuous variable with values 28–44 weeks only (model 1); second, we included parental socio-demographic and medical characteristics  (model 2); and third, we included markers of the participant's mother's fecundability in the regression model  (model 3). Variables included in the three models were chosen a priori because they have previously been associated with offspring weight at birth In addition to considering gestational age at birth by adjustment and restriction to term births, we also examined the association between weight at birth and fecundability by z-scores of birth weight, to compare infants of differing relative weights by using weight estimates that were adjusted for gestational age at birth Analyses were performed using Stata version 12.0  and SAS version 9.2 .Among the 2,773 women included in our analyses, 245 (8.8%) were lost to follow-up. Women lost to follow-up contributed cycles at risk for as many cycles as they were observed in the study, and were censored at the time of non-response. Among women lost to follow-up, mean birth weight overall was 3,281 grams , which was slightly lower than among women with complete follow-up. The distribution of gestational age at birth among women lost to follow-up was similar to that for women who completed the study (data not shown). Women with low birth weight that were lost to follow-up were more likely to have a mother who was divorced or widowed, and had a lifetime parity of ≥4 children, more likely to have a high birth order and irregular cycles, and more had only attempted to become pregnant for 0–1 cycles at study entry, compared with women with low birth weight who completed the study (data not shown).Mean birth weight overall among the 2,773 women in the study cohort was 3,315 grams , and mean birth weight among those born at term was 3,326 grams . There were 2,432 (87.7%) participants who had been born at term, 102 (3.7%) who had been born preterm, and 239 (8.6%) who had been born post-term.Kaplan-Meier estimates for the cumulative probability of conception among the 2,773 participants were 47% within 3 cycles, 67% within 6 cycles, and 83% within 12 cycles. Characteristics of participants according to their weight at birth are presented in Crude and adjusted FRs according to weight at birth are presented in In our study of 2,773 pregnancy planners, we found little evidence supporting a relation between weight at birth and fecundability. Results were similar when we restricted the cohort to women born at term, and when we considered relative measures of weight at birth using z-score transformation. Further, we found no indication that markers of maternal fecundability confounded the association between weight at birth and women's own fecundability.To our knowledge, this is the first prospective study to examine the association between weight at birth and fecundability in a cohort of pregnancy planners. Our data allowed for a more accurate estimate of TTP, based on women with and without successful conceptions, in contrast to data retrospectively obtained from women who were already pregnant. A validation study of retrospective data on TTP, using prospective data as the gold standard, reported a mean difference in TTP of −1.4 months among women with a recall period of 3–20 months Data on birth weight were not recorded in a uniform manner in the DMBR during the birth years of the participants in our cohort In agreement with our results, a French prospective study of 403 women who had attempted to conceive found nearly no association between being born SGA and later TTP, relative to women whose size at birth was appropriate for gestational age Our findings differ from those of Nohr et al., who conducted a retrospective TTP study of 21,786 Danish women and reported an OR for a TTP of 6–12 months of 1.2  and OR for a TTP >12 months of 1.2  among women born at term with a birth weight ≤2,500 grams, compared with women born at term with a weight of 3,001–4,000 grams In conclusion, the present study indicates that infant weight at birth does not appear to have a meaningful influence on female fertility in adult life. If correct, this finding implies that even if gonadal development and function are compromised in adolescents with a small size at birth, such anomalies may not persist to influence fecundability in adult women attempting to conceive.The authors wish to thank Tina Christensen for her support with data collection and media contact, and Thomas Jensen for his assistance with website design.


Preterm infants are at increased risk of language-related problems later in life; however, few studies have examined the effects of preterm birth on cerebral responses to speech at very early developmental stages. This study examined cerebral activation and functional connectivity in response to infant-directed speech (IDS) and adult-directed speech (ADS) in full-term neonates and preterm infants at term-equivalent age using 94-channel near-infrared spectroscopy. The results showed that compared with ADS, IDS increased activity in larger brain areas such as the bilateral frontotemporal, temporal, and temporoparietal regions, both in full-term and preterm infants. Preterm infants exhibited decreased activity in response to speech stimuli in the right temporal region compared with full-term infants, although the significance was low. Moreover, preterm infants exhibited increased interhemispheric connectivity compared with full-term controls, especially in the temporal and temporoparietal regions. These differences suggest that preterm infants may follow different developmental trajectories from those born at term owing to differences in intrauterine and extrauterine development. The incidence of preterm birth before 37 weeks gestation has increased worldwide in recent years  during an orthographic–phonological reading task, Frye et al.  examinedRecent studies on brain functional connectivity have also demonstrated that preterm children and adolescents exhibit alternative neural networks for processing language compared with full-term controls  and adult-directed speech (ADS) by simultaneously measuring activations in the frontal, temporal, parietal, and occipital regions using multichannel NIRS. If development of neonate brain response to speech is determined by maturation, we would expect to find similar activation patterns in preterm and term infants with equal postmenstrual age (PMA). On the other hand, if neonate brain response to speech is affected by preterm birth, we would expect to find different activation patterns in preterm and full-term infants. We addressed these questions by examining not only cerebral activation in response to speech stimuli but also functional connectivity of the different brain regions involved in speech processing.Twenty-seven preterm infants and 29 full-term newborn infants participated in this study. Two preterm infants and four full-term infants were excluded from the final statistical analysis because of excessive motion artifacts (preterm = 2 and full-term = 1) or hair obstruction (full-term = 3). The final sample included 25 preterm infants (11 girls) and 25 full-term infants (10 girls). Demographic information for the preterm and full-term infant groups is summarized in Table Preterm infants born before 37 complete weeks of gestation and with a birth weight below 2500 g were included in the study. Among preterm infants, 11 were born with a birth weight below 1500 g (VLBW) and 7 below 1000 g . Children with severe neurologic complications such as brain lesions including periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH) and those with impaired hearing or vision were not included in the study.In preterm infants, the mean GA at birth was 218.3 days [standard deviation (SD) = 25.8] and the mean birth weight was 1488.9 g (SD = 567.8). The mean Apgar score 5 min after delivery was 8.1 (SD = 1.3). Preterm infants were measured using multichannel NIRS at term PMA. The mean PNA at NIRS measurement was 56.7 days (SD = 31.0) and mean PMA at NIRS measurement was 275.4 days (SD = 1.4). In addition, mean head circumference at NIRS measurement was 33.9 cm (SD = 1.7).In full-term control infants, the mean GA at birth was 270.6 days (SD = 9.0) and the mean birth weight was 2927.9 g (SD = 439.6). The mean Apgar score 5 min after delivery was 9.2 (SD = 0.4). The mean PNA at NIRS measurement was 4.7 days (SD = 2.0) and mean PMA at NIRS measurement was 275.3 days (SD = 9.0). In addition, mean head circumference at NIRS measurement was 34.1 cm (SD = 2.0). None of the full-term infants exhibited signs of neurological disorders or hearing or visual impairment.t(48) = −9.58, p < 10−9], lower birth weight , lower Apgar score 5 min after delivery , and higher PNA  at the time of measurement. On the other hand, there was no significant difference between preterm and full-term infants in PMA  and head circumference at NIRS measurement .The preterm infant group had significantly lower GA at birth . Previous studies have shown that IDS utterances are slower than ADS utterances, even when speaking the same sentences  for the ADS samples and 2.3 s (SD = 0.1 s) for the IDS samples. In addition, the mean intersentence pause duration was 0.7 s (SD = 0.1 s) for the ADS samples and 1.2 s (SD = 0.4 s) for the IDS samples. The mean sentence duration and intersentence pause duration were significantly longer for the IDS samples than for the ADS samples . The mean pitch range, which was calculated by subtracting the minimum pitch from the maximum pitch, was significantly greater for IDS stimuli than ADS stimuli .The mean pitch of the six sentences was significantly higher in IDS stimuli than in ADS stimuli [paired f)]. The mean intensities of the IDS, ADS, and pink noise samples had equal root mean square (RMS) amplitudes.The non-speech control stimulus (20 s duration) was constructed using pink noise . Within the measurement groups (full-term and preterm), individual z (r) values were examined using one-sample t-test against zero in a measurement channel. The calculated t values were then converted to z statistics according to the formula For each infant, pairwise correlation coefficients (z (r) values were subjected to a two-way mixed ANOVA with repeated measures for the two measurement groups (full-term and preterm) as a between-subjects factor and the two stimuli conditions (IDS and ADS) as a within-subject factor for the channels that exhibited significant functional connectivity for each ROI.To compare functional connectivity between the two groups (full-term and preterm) under two speech conditions (IDS and ADS), the Hemodynamic responses in preterm and full-term infants to ADS and IDS compared with those to the control stimuli (pink noise) are shown in Figure p < 0.05 level  in the right frontotemporal area .To examine the effect of preterm birth on cerebral activation in response to speech stimuli, we performed two-way mixed ANOVA for the two measurement groups (full-term and preterm) and two stimuli conditions (IDS and ADS) for each channel. We found that the magnitude of changes in the oxy-Hb response indicated a significant main effect of stimuli condition in large brain areas, including the bilateral frontotemporal, temporal, and temporoparietal regions, at the FDR-corrected el Table , and infp < 0.05 level. Using the uncorrected p < 0.01, there was a statistically significant interaction effect of stimuli and group in the left temporal region . The post hoc Bonferroni test showed that LBW infants exhibited significantly greater responses than ELBW infants, but only in the IDS condition (p = 0.010). In addition, preterm infants were divided into three groups on the basis of GA: extremely preterm infants (GA < 28 weeks); very preterm (GA between 28 and <32 weeks); moderate to late preterm (GA between 32 and <37 weeks). To investigate the effect of GA on these responses, we compared the activation patterns of 5 extremely preterm infants, 9 very preterm infants, and 11 moderate to late preterm infants. This analysis revealed no significant main effect of GA at birth or on the interaction between GA and stimulus condition at the FDR-corrected p < 0.05 and uncorrected p < 0.01 levels. Analyses of deoxy-Hb revealed no statistically significant differences in any comparisons at the uncorrected p < 0.01 level.In the preterm group, we compared the activation patterns of seven ELBW infants (birth weight < 1000 g), 4 VLBW infants (birth weight of 1000 to <1500 g), and 14 infants with low birth weight . The analysis detected no significant main effect of birth weight or interaction on birth weight and stimulus condition at the FDR-corrected We evaluated the spatial distribution of functional connectivity in the selected ROIs located in the prefrontal (Fp1 and Fp2), frontotemporal (F7 and F8), temporal T3 and T4), and temporoparietal (P3 and P4) regions  values for the two measurement groups (full-term and preterm) and two stimuli conditions (IDS and ADS) revealed a significant main effect of group at the FDR-corrected p < 0.05 level  values in measurement channels that exhibited significant functional connectivity with each ROI and PNA at NIRS measurement. Oxy-Hb changes in response to IDS were inversely correlated with PNA in Ch62 and Ch72 in the right temporal region of the preterm group .To examine the effect of PNA on cerebral activation and functional connectivity in response to speech, Pearson’s correlations were employed to examine the relationships between oxy-Hb changes or r = −0.62, p = 0.0010). There were no significant correlations between PNA and activation or functional connectivity in the full-term group.With respect to functional connectivity during IDS and ADS presentation, functional connectivity during ADS presentation was inversely correlated with PNA between ROIs located in the left frontotemporal region  and Ch89 in the right temporal region in the preterm group , preterm infants had fewer intrauterine sensory experiences and more extrauterine sensory experiences than full-term controls. The auditory system of the human fetus is functionally developed during the last trimester of pregnancy , which exceed recommended levels (Lasky and Williams, Previous structural and functional studies have suggested that intrauterine rather than extrauterine development appears to have an adequate impact on brain maturation in preterm infants and that brain maturation appears to constrain the effects of postnatal experience on speech discrimination during the early stages of language acquisition in preterm infants. (Peña et al., In conclusion, the present study demonstrated that preterm infants at term exhibited decreased activation in the right temporal region and increased connectivity between the bilateral temporal and bilateral temporoparietal regions during speech presentation when compared with full-term neonates. This difference might suggest that preterm infants and full-term neonates follow different developmental trajectories during the postnatal period. It is also possible that early neural alternations in the development of speech perception may be related to later difficulties with language development in preterm children and adolescents. Further studies are required to explore the relationship between hemodynamic responses to speech at term and later development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Birth order has been suggested to be linked to several cardiovascular disease (CVD) risk factors, but the evidence is still inconsistent. We aim to determine the associations of birth order with body mass index (BMI), muscle strength and blood pressure. Further we will analyse whether these relationships are affected by family characteristics.BMI, elbow flexion, hand grip and knee extension strength and systolic and diastolic blood pressure were measured at conscription examination in 1 065 710 Swedish young men born between 1951 and 1975. The data were analysed using linear multivariate and fixed effects regression models; the latter compare siblings and account for genetic and social factors shared by brothers.Fixed effect regression analysis showed that birth order was inversely associated with BMI: second and third born had 0.8% and 1.1% (p<0.001) lower BMI than first-born, respectively. The association pattern differed among muscle strengths. After adjustment for BMI, first-born presented lower elbow flexion and hand grip strength than second-born . Knee extension strength was inversely related to birth order though not always significantly. The association between birth order and blood pressure was not significant.Birth order is negatively associated with BMI and knee extension strength, positively with elbow flexion and hand grip strength, and is not associated with blood pressure among young men. Although the effects are small, the link between birth order and some CVD risk factors is already detectable in young adulthood. Cardiovascular diseases (CVD) are the leading cause of mortality worldwide and thus a major public health problem Birth order has been shown to be associated with several CVD risk factors in childhood, adolescence and young adulthood The decline of fertility rate during the recent decades is decreasing the family size and consequently increasing the proportion of first born status in many countries This study has been approved by the Ethical Review Board, Stockholm, Sweden. According to the current regulations, the Ethical Review Board waived the need for informed consent from the participants because this is a large register-based study without need to contact the participants.This longitudinal dataset was created by a record-linkage between the nationwide Swedish Military Service Conscription Register (MSCR), the Swedish Multi-Generation Register (MGR) and the Swedish Population and Housing Censuses (PHCs) using personal identification numbers. Conscription examination, which predates active military service, was mandatory in Sweden by law for all young male Swedish citizens in our study cohorts. Only males with severe handicap or a chronic disease were exempted from the conscription examination. In this study, we analysed cohorts born from 1951 to 1975 (conscription year 1969–1993). In the entire data set, we had conscription data available for 1 133 812 men. We excluded all multiple births (1.7% of the data). In addition, to keep the sample age-homogenous, men aged less than 17 or more than 20 years at conscription were excluded (18 027 men) since they represented only a small fraction of the whole study population (1.6%).2). These values may have been true values or may represent measurement or data entry errors. To minimize errors of misclassification, we excluded these men from further analyses. In addition, we had missing values for muscle strength in 841 men. For blood pressure, the limits for accepted values were 40 to 100 mmHg for DBP and 100 to 180 mm Hg for SBP, with missing or invalid cases in 13641 men. In the final dataset, we had valid measures from all anthropometric and blood pressure traits on 1 065 710 men. Since BMI was not normally distributed, logarithmic transformation was applied. Information about conscription age and conscription centre was obtained from the MSCR. Based on continuous data in the MGR we created categorical variables for birth order , maternal age at birth (5-year groups from 15–19 to 45–49 years) and number of children in the family . Biological sisters were also taken into account for the calculation of birth order and family size. Information on parental education and occupational socioeconomic position (SEP) was derived from the PHCs conducted in 1960, 1970, 1980 and 1990 as described in detail elsewhere During the conscription examination, height, weight, elbow flexion, hand grip and knee extension strength, and diastolic (DBP) and systolic blood pressure (SBP) were measured according to a standardized protocol described elsewhere To study the association between birth order and CVD risk factors, linear regression analyses adjusted for different covariates were performed. Since BMI was log-transformed, the estimated regression coefficients for this variable can be interpreted as percentage changes (logBMI*100 =  % change). Model 1 adjusted for birth year, conscription age and centre. Model 2 added controls for maternal age and parental SEP and education. We continued to analyse within family associations by using fixed effects regression models (Model 3 and 4). These models compare brothers born to the same mother and remove the confounding influences of all fixed observed and unobserved genetic and social characteristics shared by the brothers st born) to 36.6 years (6th+born). Higher birth order was associated with older cohorts, larger families and lower proportion of high parental SEP  and education (more than 13 years). Regarding anthropometric and blood pressure traits, from birth order 1 to 6+ height and weight showed an average decrease of 1.7 cm and 1.4 kg respectively, whereas BMI remained stable. For all three muscle strength measures, second born presented the greatest mean values. For elbow flexion and hand grip strength, no defined pattern was observed. For knee extension strength, average value decreased monotonically with birth order . The trends for SBP and DBP differed: whereas SBP showed the greatest mean values for birth order 1 and 6+, DBP increased monotonically from the second born.The characteristics of the sample are reported separately by birth order in Comparisons between fixed effects regression estimates in Second and third born young men had 0.8% and 1.1% (p<0.001) lower BMI compared with first-born men (Model 4 and 5), but differences became weaker with higher birth order. Elbow flexion strength showed a significant association only after adjustment for height  or BMI , that is, once the effect of body size and mass were taken into account. The second born presented 2.20 N and 3.83 N more elbow flexion strength  than the first-born. For hand grip strength, second-born men were approximately 6 N stronger than first-born men  and the greatest difference from first-born men, 8.94 N, was observed for birth order 5 (when adjusted for height). Considering all three adjustments , knee extension strength showed the most robust association for birth order 6+, with 15.36 N/13.61 N (adjusted for height/BMI) less than the birth order 1. Finally, birth order showed non-significant association with SBP, and only a weak association with DBP (for birth order 5 and 6), which disappeared after adjustment for BMI.As a sensitivity check, we re-estimated the results after excluding families with only one children from the analyses; the associations changed only little from those presented here . The onlDuring the last decades, major changes in population demography and family structure have occurred as consequence of the social and economic transition The negative relationship detected between birth order and BMI in this population is in agreement with other studies carried out in young men of southern Brazil Muscle strength is an indicator of physical fitness, which is considered as one of the most important health markers nowadays Concerning the birth order effect on blood pressure, although the most common finding across studies indicate a negative association This study has several strengths. The main advantage is the large sample size, which together with the analytical approach, allowed us to detect the within families variation with adequate power. In addition, this is the first study to investigate the long-term consequences of birth order on muscle strength. Since military conscription was mandatory during the study period, participation bias due to selection does not exist. But our study also has some limitations. First, our sample included only men and thus our results cannot be directly generalized to women. Second, the analysed sample was collected in young adulthood. This fact could be one of the reasons for the relatively small or non-significant birth order effect observed in this population, because more disadvantageous CVD risk factors levels tend to be observed in later life. Third, although military conscription was mandatory during the study period, disability or a severe chronic disease was a valid reason to be exempted, thus our cohort represents mainly healthy Swedish men at baseline. And finally, it should be mentioned that in the present study the association are significant because of a very large sample size, that is, in smaller samples some of the differences would not become statistically significant.To summarize, the birth order effect on the analysed CVD risk factors in young adulthood is in general small and dependent on family characteristics. Birth order influence may vary in strength over time and place, but due to the unprecedentedly large population based dataset and that observed and unobserved characteristics shared by brothers were accounted for by fixed effect regression models, it is unlikely that birth order can have a substantially greater influence, at least in similar populations. Our findings indicate that birth order is inversely associated with BMI and knee extension, positively with elbow flexion and hand grip strength, and not associated with blood pressure. Since these associations may increase through adulthood, the birth order impact on CVD risk factors has public health implications because it can be used to target prevention and treatment strategies toward individuals at high risk. Finally, linking CVD risk factors with birth order suggests that part of the disadvantageous conditions observed in the populations could be attributed to the worldwide trend to smaller families and higher proportion of first-borns.Table S1Fixed effects regression coefficients for the effect of birth order on CVD risk factors – families with only one child excluded.(DOCX)Click here for additional data file.


Fertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures.All patients in South Australia receiving assisted conception between Jan 1986–Dec 2002 were linked to the state-wide perinatal collection . We examined stillbirth, mean birth weight, low birth weight , small size for gestational age , large size for gestational age (>90th percentile), preterm birth , postterm birth (≥41 weeks gestation), Apgar <7 at 5 minutes and neonatal death.Relative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn  1.34–2.48), while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight , very low birth weight , very preterm birth  and neonatal death . Outcomes varied by type of assisted conception. Very low and low birth weight, very preterm and preterm birth, and neonatal death were markedly more common in singleton births from IVF and to a lesser degree, in births from ICSI. Using frozen-embryos eliminated all significant adverse outcomes associated with ICSI but not with IVF. However, frozen-embryo cycles were also associated with increased risk of macrosomia for IVF and ICSI singletons . Infertility status without treatment was also associated with adverse outcomes.Births after assisted conception show an extensive range of compromised outcomes that vary by treatment modality, that are substantially reduced after embryo freezing, but which co-occur with an increased risk of macrosomia. While birth outcomes after assisted conception have been studied, particularly descriptively, and subject to meta-analysis We have recently demonstrated that treatment modality, subfertility and embryo freezing each contribute to the risk of major birth defects As previously described There were 20,383 exclusions. The majority  were pregnancies among mothers under 20 years of age as only 2 of these pregnancies were conceived with infertility treatment. Births of higher-order multiplicity (triplet and quadruplet) were also excluded because appropriate size references do not exist. As all analyses were adjusted for infant sex of the baby, 311 births and terminations of indeterminate sex and where the sex was unknown were also excluded (n = 304 (0.1%) conceived spontaneously and n = 7 (0.1%) conceived with infertility treatment).Births after any assisted conception  were compared to those after spontaneous conception . The spontaneous conception group was further classified into births to women with no history of infertility in their records and no infertility treatment , births to women who had a recorded diagnosis of infertility but no associated assisted conception treatment from a specialist clinic , and births as a result of spontaneous conception in women with a previous birth from assisted conception .Types of assisted conception considered were: donor oocyte procedures, gamete intrafallopian transfer (GIFT), intrauterine insemination (IUI), in vitro fertilization (IVF) with fresh-embryo cycles, IVF with frozen-embryo cycles, intracytoplasmic sperm injection (ICSI) with fresh-embryo cycles, ICSI with frozen-embryo cycles, minimal medical intervention and ovulation induction (OI) only. Conceptions with donor oocytes were grouped together irrespective of mode of assisted conception. Conceptions resulting from IUI only (n = 702) and IUI after cancellation of IVF (n = 11) or ICSI (n = 2) were grouped.The IVF with fresh-embryo transfer group (n = 1519) included pregnancies arising from zygote intrafallopian transfer (ZIFT) or tubal embryo transfer (TET) (n = 9) (as such treatments have medication and culture regimens similar to those of IVF), and all natural-cycle (n = 12) and OI  IVF pregnancies not specifying embryo transfer. All pregnancies involving donor embryos (n = 9), imported embryos (n = 10), and IVF specifying “embryo transfer” with or without mentioning freezing  were included in the IVF with frozen-embryo transfer group (n = 604).The minimal medical intervention group (n = 710) included conceptions in women who were tracking their ovulatory cycles in anticipation of starting treatment or who were being monitored for other reasons (n = 167), to women who received donor insemination (n = 466), to a woman whose primary treatment was weight loss, to a woman whose husband was treated with human chorionic gonadotrophin (hCG); conservatively, these women were counted among this group because it is possible that some received hormonal medication to adjust ovulation timing, even though this was not recorded in their medical records . As well, conceptions during ovarian suppression regimens (n = 69) and after tubal or ovarian surgery (n = 6) were counted in this group.The OI only group (n = 406) included pregnancies among those who received only an OI regimen (clomiphene citrate +/− bromocryptine) (n = 386), those who were tracking their cycles and receiving OI regimens (n = 7), and those whose IUIs were cancelled for ovarian hyperstimulation (n = 4). The group also included pregnancies arising during IUI control cycles (n = 6), and from donor insemination after IVF cancellation (n = 3), as it was likely that such women had begun OI or that ovarian hyperstimulation was the reason for cancellation.Birth outcomes considered were stillbirth, birth weight, very low birth weight , low birth weight , very preterm birth , preterm birth , postterm birth (>41 weeks gestation), very small size for gestational age , small size for gestational age , large size for gestational age , Apgar score <7 at 5 minutes, and neonatal death. Analyses of birth outcomes other than stillbirth were restricted to liveborn singletons  and twins . Australian national standards for sex-specific birth weight centiles by gestational age were used to define VSGA, SGA, and LGA separately for singletons Analyses were stratified by plurality. Generalized estimating equations were used to produce odds ratios accounting for clustering of births within women. All analyses were adjusted for maternal age, parity, and infant sex; those for twin analyses were further adjusted for same-sex twinship to reduce the role of fetal zygosity. Within some assisted conception groups, certain outcomes were too rare for stratification. In these circumstances, groups were combined within type of conception first (i.e. singletons and twins were grouped together) and then if necessary, assisted conception groups were combined according to similarity of treatment. Where singletons and twins were grouped, models were fitted to force the estimates for modality to be the same for both groups, with multiplicity-specific comparators  All statistical analyses were performed using SAS 9.2 .Approval for the study was obtained from the ethics committees of the South Australian Department of Health, the University of Adelaide, and Flinders University. Individual level consent was not required.Compared to spontaneous conceptions in women with no recorded infertility history or infertility treatment , spontaneous conceptions to women with a recorded infertility diagnosis but no treatment , and conceptions achieved with GIFT, with IVF with fresh-embryo cycles, and with ICSI with fresh-embryo cycles were more likely to end in stillbirth. Conceptions resulting from IVF with frozen-embryo cycles were more likely to be stillborn than the fertile group, but the difference did not reach statistical significance. There were no differences in stillbirth risk among twins by mode of conception.Relative to the spontaneous conception, fertile group, infants of women with a recorded infertility diagnosis but no treatment were significantly lighter, more likely to be born VLBW or LBW, very preterm or preterm, and VSGA, were more likely to have a an Apgar score <7 at 5 minutes, and were more likely to die in the neonatal period. Infants of women with a previous assisted conception birth  were less likely to be born postterm, VSGA or SGA than the spontaneous conception, fertile group. However there were no other differences in outcomes between these groups.Compared to the spontaneous conception, fertile group, infants as a result of donor oocytes did not differ significantly in mean birth weight, but were at increased risk of being born VLBW, LBW or very preterm. Infants resulting from GIFT were lighter, and were more likely to be born VLBW, LBW, very preterm, VSGA, and SGA, and less likely to be postterm. IUI infants were lighter at birth and more likely to be VLBW, LBW, preterm, or VSGA, and less likely to be postterm.Infants from IVF with fresh-embryo cycles were lighter at birth and more likely to be born VLBW, LBW, very preterm or preterm, SGA, and were more likely to die in the neonatal period. They were also less likely to be postterm or LGA than those in the spontaneous conception, fertile group. Among infants from IVF with frozen-embryo cycles, there was no increased risk of neonatal death, VLBW or VPTB, however the associations with LBW, PTB, and SGA remained, and there was an increased risk of LGA. Infants from ICSI with fresh-embryo cycles were lighter, had increased risks of LBW, VSGA, SGA and a decreased risk of being postterm or LGA. However, the associations between ICSI and adverse perinatal outcomes were no longer present for ICSI with frozen-embryo cycles. In fact, these infants were significantly heavier and more likely to be LGA than those in the spontaneous conception, fertile group.Infants of women in the minimal medical intervention group were less likely to be postterm and did not otherwise differ from the spontaneous conception, fertile group infants. Use of ovulation induction alone was associated with an increased risk of LBW and PTB.Compared to twin births in the spontaneous conception, fertile group, twins from GIFT were less likely to be LGA, twins from IUI were more likely to be VLBW, those from IVF with fresh-embryo cycles were born lighter, those born after ICSI with fresh-embryo cycles were less likely to be SGA and those born after ICSI with frozen-embryo cycles were more likely to be LGA.In this large, population-based dataset, singleton births resulting from any assisted conception had almost double the risk of stillbirth of those conceived spontaneously. Liveborn infants from assisted conception were significantly more likely to be born preterm, be compromised on a range of indicators of birth size, and die in the neonatal period compared to their spontaneously conceived counterparts. These findings are consistent with those of recent studies Among singletons, the increased risk of stillbirth was present for births resulting from fresh-embryo cycles of IVF or ICSI (but not frozen) and GIFT. Although an increased risk of stillbirth has been associated with IVF/ICSI relative to spontaneous conceptions and non-IVF treatments We also found increased risk of adverse outcomes among births from ICSI with fresh-embryo cycles, but the effects appeared considerably weaker than those seen for IVF. Studies of the Swedish IVF Registry Embryos transferred after cryopreservation may have better outcomes than those transferred fresh The contribution of maternal risk factors  to the observed treatment effects is unclear, as we did not adjust for infertility aetiology. The apparent differences in risk between IVF and ICSI may be due in part to factors related to both specific infertility treatments and adverse pregnancy outcomes, such as obesity We separated spontaneous conceptions to women diagnosed with infertility but never treated from those to women previously treated, and we consistently found that negative consequences were limited to those diagnosed but untreated. Some outcomes indicated serious disadvantage, such as a quadrupling in risk of stillbirth, a 7-fold increase in neonatal death and an over 250 g deficit in birth weight. Adverse effects of subfertility on birth size and gestational age at birth have been observed previously Twins conceived with any assisted conception treatment were slightly lighter than spontaneously conceived twins. They were modestly more likely to be born at very low birth weight, and to be born very preterm, and had the same risk of neonatal mortality. This supports existing observations of outcomes among twins conceived with infertility treatment This large population-based study linked all assisted conception births in the state to outcomes obtained from the birth register. Unlike many prior registry studies, our analytic approach accounted for clustering within woman (by sibship) and within twins Limitations include the absence of information about: changes of male partner during interpregnancy intervals; zygosity and chorionicity of twins; and whether twins and singletons were reductions of higher-order pregnancies. Data were not available for assisted conception pregnancies beyond 2002. While improvements in pregnancy outcomes after assisted conception have been noted in the intervening years, these are primarily attributable to reductions in multiple pregnancy Use of any assisted conception was associated with poorer perinatal outcomes for singletons than their spontaneously conceived counterparts. Diagnosed untreated infertility was associated with poor perinatal outcomes, but treatment of infertility at a different time was not. Outcomes from ICSI with fresh-embryo transfer and from IVF with frozen-embryo transfer were better than those from IVF with fresh-embryo transfer. ICSI with frozen-embryo transfer, despite lower per-cycle take-home baby rates and per-transfer singleton live birth rates Table S1Categories of assisted conception treatments for the time periods 1986–1992, 1993–1999 and 2000–2002.(DOCX)Click here for additional data file.


Background: Acrylamide has shown developmental and reproductive toxicity in animals, as well as neurotoxic effects in humans with occupational exposures. Because it is widespread in food and can pass through the human placenta, concerns have been raised about potential developmental effects of dietary exposures in humans.Objectives: We assessed associations of prenatal exposure to dietary acrylamide with small for gestational age (SGA) and birth weight.n = 79). Data on infant birth weight and gestational age were obtained from the Medical Birth Registry of Norway. Multivariable regression was used to estimate associations between prenatal acrylamide and birth outcomes.Methods: This study included 50,651 women in the Norwegian Mother and Child Cohort Study (MoBa). Acrylamide exposure assessment was based on intake estimates obtained from a food frequency questionnaire (FFQ), which were compared with hemoglobin (Hb) adduct measurements reflecting acrylamide exposure in a subset of samples  for SGA was 1.11  and the coefficient for birth weight was –25.7 g . Results were similar after excluding mothers who smoked during pregnancy. Maternal acrylamide– and glycidamide–Hb adduct levels were correlated with estimated dietary acrylamide intakes .Conclusions: Lowering dietary acrylamide intake during pregnancy may improve fetal growth. Indicators of intrauterine development, such as birth weight and small for gestational age (SGA), are predictors of infant survival and the prevalence of chronic diseases in adulthood . Diet duin utero, because acrylamide has been found to cross the placenta barrier in vitro  has previously been validated using urine metabolites as biomarker of recent intakes . N-termiIn this study we explored the hypothesis that dietary acrylamide exposure during prenatal life might impair fetal growth, resulting in increased SGA and reduced birth weight in a large population-based cohort study in Norway: MoBa. We also aimed to identify population characteristics associated with higher intakes of acrylamide. The FFQ-based estimates of acrylamide intake were further evaluated by comparisons with measurements of acrylamide– and glycidamide–Hb adducts in a subset of the study participants.Population and study design. MoBa is a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health  , if gestational age at the child’s birth was < 28 weeks or > 42 weeks (n = 385), if data were missing on birth weight (n = 22) or maternal smoking during pregnancy (n = 817), or if the mother’s estimated energy intake was < 4,500 kJ or > 20,000 kJ (n = 796). In addition, we excluded women with missing  or improbable values for weight gain during pregnancy (< –30 kg or > 50 kg) (n = 463), leaving a study sample of 50,651 women. Because smoking is negatively associated with birth weight and is a significant source of acrylamide exposure, we performed additional analyses stratified on self-reported smoking during pregnancy .Women were eligible for the present analysis if they were recorded in the Medical Birth Registry of Norway (MBRN) and had singleton births, and they completed questionnaires 1 and 3 , baseline MoBa questionnaires covering information on sociodemographic characteristics, exposure to tobacco smoke during pregnancy, and general health; questionnaire 2 (during weeks 23–24 of pregnancy), which covered dietary information; and questionnaire 4 (when the child was 6 months of age), which collected information on maternal health at time of delivery, including maternal weight gain during pregnancy  . We thenDietary information. The MoBa FFQ (MoBa 2002) was used for calculation of acrylamide intake. This FFQ is a semiquantitative questionnaire designed to provide information on dietary habits and dietary supplement intakes during the first 4–5 months of pregnancy , normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥ 30.0 kg/m2). Sex of the child and weight of the mother at the time of delivery (kilograms) were collected from questionnaire 4. Maternal weight gain during pregnancy (kilograms) was calculated from weight reported at the start of pregnancy and at the time of delivery, as registered at the birth clinic on the women’s health card.Parity was classified based on data from both MoBa and MBRN and categorized as primiparous or multiparous. Data on maternal education attainment , age, and smoking were collected from questionnaires. Smoking during pregnancy was categorized as nonsmoker, occasional smoker, or daily smoker. Participants with unknown/missing values for education or father’s smoking were grouped in a “missing” category. Prepregnancy weight and height were self-reported at week 17 of pregnancy and used to calculate prepregnancy body mass index (BMI), which was categorized as underweight  that are expressed as means ± SDs. Maternal and newborn characteristics are summarized according to quartiles of energy-adjusted acrylamide intakes and differences across quartiles were tested using chi-square or Kruskal–Wallis tests.We used multivariable linear regression models to identify food groups that significantly predicted dietary acrylamide intakes and population characteristics associated with acrylamide intake.We used multivariable logistic regression models to estimate associations between energy-adjusted dietary acrylamide intakes during pregnancy (categorized according to quartiles or modeled as a continuous variable) and SGA at birth, and linear regression models to estimate associations with birth weight. Potential confounders were assessed from a wide array of variables available in MoBa and were retained in all final models if they resulted in a change in estimate > 10% for either SGA or birth weight. Covariates in final models were gestational age, parity, sex of the child, age of the mother, maternal prepregnancy BMI, maternal weight gain during pregnancy, and smoking during pregnancy. Other potential covariates  did not meet our criteria for confounding of associations with either SGA or birth weight, nor did maternal intakes of food groups such as snacks, sweets (including cakes and chocolate), dairy products, alcohol, or coffee, or intakes of supplements reflecting a healthy diet, such as fiber, folate, or folate supplements (data not shown).p for interaction > 0.10, data not shown). We confirmed that results were comparable after excluding preterm births , low birth weight children , and women with missing information for education  or partner’s smoking during pregnancy  (data not shown). Results were similar when analyses were repeated using estimated acrylamide exposure relative to body weight (micrograms per kilogram body weight per day), and when the residual approach was used to adjust for energy intake or body weight (data not shown). In addition, our results were comparable after increasing or decreasing the levels of exposure in a randomly selected 20% subset as a sensitivity analysis, and when we used error-in-variables regression  for acrylamide and 23 pmol/g Hb  for glycidamide. A strong correlation between acrylamide– and glycidamide–Hb adduct levels  was observed. Correlations between maternal acrylamide– or glycidamide–Hb adduct levels and energy-adjusted dietary acrylamide intakes estimated from the FFQ were 0.24  and 0.48  respectively ].After multivariable adjustment, increasing age, multiparity, lower educational level, maternal smoking, and paternal smoking during pregnancy were associated with significantly higher acrylamide intakes during pregnancy .p-values for all comparisons < 0.05).Birth weight and the frequency of SGA differed significantly by quartiles of energy-adjusted acrylamide intake during pregnancy . The freEnergy-adjusted acrylamide intake during pregnancy, modeled continuously or in quartiles, was significantly associated with SGA, with an adjusted odds ratio (OR) among all women of 1.11  for the highest quartile of acrylamide intake compared with the lowest quartile . AssociaAcrylamide intake was negatively associated with birth weight, with a multivariable-adjusted coefficient of –25.7 g  for birth weight for all women in the fourth quartile compared with women in the first quartile, and similar results after exclusion of smokers . StrongeIn this study, higher maternal dietary acrylamide intakes during pregnancy were associated with evidence of impaired fetal growth based on an increase in SGA and a reduction in birth weight; similar results were obtained after excluding women who smoked during pregnancy. Dietary acrylamide intakes estimated from the MoBa FFQ were correlated with measured Hb adduct levels in a subset of maternal samples. The three food groups that most strongly predicted high intakes of acrylamide were snacks, which included potato chips, nuts, and popcorn; fried potatoes; and crisp bread. Maternal age, parity, education, and exposure to tobacco smoke also predicted the intake of dietary acrylamide during pregnancy.n = 801).Our results are in agreement with findings from a recent study of associations between fetal growth indicators and prenatal exposure to acrylamide in mother–child cohorts from five countries in Europe . SignifiNegative effects of prenatal exposure to acrylamide on fetal growth have been observed in animal studies with doses of a few milligrams per kilogram per day, as reviewed by Diet is recognized as the primary source of acrylamide exposure among nonsmokers and non-occupationally exposed populations, because acrylamide is formed during cooking at high temperatures , particularly of carbohydrate-rich foods that contain the amino acid asparagine and reducing sugars . The aveSmoking was associated with higher dietary acrylamide intake in our study population. Although the interaction between acrylamide intake and smoking was not statistically significant, the association between acrylamide intakes during pregnancy and birth weight was stronger among smokers compared with nonsmokers. In contrast, the association with SGA was comparable among smokers and nonsmokers. Although tobacco smoke is the main source of exposure to acrylamide among smokers , the addThe observed correlation between FFQ data and acrylamide–Hb adduct levels (Spearman correlation coefficient = 0.24) is in agreement with results reported by other investigators, whereas the correlation with glycidamide–Hb adducts (0.48) is higher than previously reported . ConsistThe correlations between acrylamide intake estimates based on mid-pregnancy FFQs and Hb adduct levels in blood samples collected at delivery support the use of the FFQ for exposure estimation. In other studies in the general population, high within-person correlations of Hb adducts over time have been reported, suggesting that a single measurement may be a good indicator of average long-term intake . The modAcrylamide formation in food is affected by several parameters, such as cooking methods and doneness, that were not assessed by the FFQ . AnotherSelection bias, another potential concern, has been extensively explored in MoBa by Our finding that prenatal exposure to dietary acrylamide was associated with decreased birth weight and increased SGA has implications for public health at both early and later stages of life . The assIn this large population-based cohort study, higher prenatal exposure to dietary acrylamide was positively associated with SGA and negatively associated with birth weight, also after excluding smokers during pregnancy. The results suggest that prenatal exposure to dietary acrylamide may impair fetal growth. Reducing dietary acrylamide intake among pregnant women might be beneficial for fetal growth.


An epidermal cyst is a common benign subcutaneous tumor and rarely develops malignancy. We report a case of an undifferentiated cutaneous squamous cell carcinoma (SCC) that arose from an epidermal cyst on the left side of the neck. The epidermal cyst had rapidly increased in size and presented cauliflower-like tumor. Histological study revealed undifferentiated squamous cell carcinoma that was arising from the epidermal cyst. An epidermal cyst is a common benign subcutaneous tumor and rarely develops malignancy. We report a case of an undifferentiated cutaneous squamous cell carcinoma (SCC) that arose from an epidermal cyst on the left side of the neck.18F-FDG positron emission tomography (PET) showed neither distant metastasis nor lymph node metastasis. We suspected that the tumor was a SCC arising from an epidermal cyst.A 65-year-old man presented with a cauliflower-like tumor from a cyst on the left side of the neck . He repoβE12, S100, melan A, desmin, αSMA, and myogenin were negative. Therefore, we diagnosed a primary cutaneous SCC.A surgical excision of the tumor with 1 cm margin was performed. The pathological examination was consistent with an undifferentiated SCC arising from an epidermal cyst Figures  and 3. TAs the surgical margin was negative but close to the bottom of the cyst, postoperative radiation therapy is additionally planned.Reported rates of SCC arising from epidermal cysts range from 0.011 to 0.045% . There iThe nature of the stimulus for malignant transformation in an epidermal cyst is uncertain . It has Primary treatment for a neoplastic cystic lesion is wide excision with adequate margin . It is pIn cutaneous SCC, tumor size larger than 2 cm, gender, preceding lesions, histological findings such as the degree of the differentiation, and location of tumors have been reported as prognostic factors of local recurrence, metastasis, and disease-specific death , 3, 5, 6


Good infant growth is important for future health. Assessing growth is common in pediatric care all over the world, both at the population and individual level. There are few studies of birth weight and growth studies comparing urban and rural communities in Vietnam. The first aim is to describe and compare the birth weight distributions and physical growth (weight and length) of children during their first year in one rural and one urban area of Hanoi Vietnam. The second aim is to study associations between the anthropometric outcomes and indicators of the economic and educational situations.st March, 2009 to June 2010, were followed monthly from birth to 12 months of age in two Health and Demographic Surveillance Sites; one rural and one urban. In all, 14,199 measurements each of weight and length were made. Birth weight was recorded separately. Information about demographic conditions, education, occupation and economic conditions of persons and households was obtained from household surveys. Fractional Polynomial models and standard statistical methods were used for description and analysis.Totally 1,466 children, born from 1Urban infants have higher birth weight and gain weight faster than rural infants. The mean birth weight for urban boys and girls were 3,298 grams and 3,203 grams as compared to 3,105 grams and 3,057 grams for rural children. At 90 days, the urban boys were estimated to be 4.1% heavier than rural boys. This difference increased to 7.2% at 360 days. The corresponding difference for girls was 3.4% and 10.5%. The differences for length were comparatively smaller. Both birth weight and growth were statistically significantly and positively associated with economic conditions and mother education.Birth weight was lower and the growth, weight and length, considerably slower in the rural area, for boys as well as for girls. The results support the hypothesis that the rather drastic differences in maternal education and economic conditions lead to poor nutrition for mothers and children in turn causing inferior birth weight and growth. Growth of children is influenced by maternal, environmental, genetic and hormonal factors. Nutrition is assumed to be the one of the most important factors for the growth of infants . Some reAt the individual level, children are followed over time. Growth of the single child is compared to a growth chart, which is a diagram showing standard weight for age, length or height for age, weight for height and other anthropometric measures as functions of child age. The graphic description most often includes mean with standard deviations as functions of child age, or in the case of weight, of length or height. This follow-up is used to evaluate deviations of the growth in individual children which could be early signs of ill-health.In Vietnam there has been a dramatic improvement in economic conditions since the Doi Moi reforms starting in 1986; income per capita has increased from $130 to $900 from the early 1990s until 2008. Absolute poverty has been reduced from 58 percent of the population in 1993 to 13 percent in 2008 . The perA hypothesis is that birth weight is lower and that growth is slower in the rural area due to different nutritional conditions that could in turn be related to economic resources and education. The first aim of this study is to describe and compare the birth weight distributions and physical growth (weight and length) of children from birth to 12 months in one rural and one urban area of Hanoi, Vietnam. A secondary aim is to study associations between the anthropometric outcomes and variables indicating the economic and educational situations.The study was conducted in two Health and Demographic Surveillance Sites (HDSS), one urban and one rural, in Hanoi, the capital of Vietnam. Dongda is an urban district in central Hanoi with about 352,000 inhabitants. Three communes, among 21, in the district, were strategically selected to have different economic levels. In each commune a representative ward was selected. The populations of these, totally close to 40,000 persons in 11,500 households, were defined as the DodaLab HDSS in 2007 . Bavi isHousehold surveys were undertaken in both sites during late 2007 and 2008 as well as during 2009 to obtain information about demographic conditions, education, occupation and economic conditions of persons and households. In both sites, all households are routinely visited every three months to record vital events, birth, death, migration and pregnancies.st March, 2009 to 30th June, 2010, in DodaLab and FilaBavi, were invited to enroll their child in the study. Children with congenital and malformation diseases (two in DodaLab and six in FilaBavi) were not invited. About 1%, totally 15 with 12 in DodaLab, of the mothers did not give consent and the child was not enrolled. Altogether 12 children were born as twin and were not used in the present analysis. Low birth weight infants  were included in the analysis, since their growth potential was considered as normal [The parents of all children reported to have been born alive from 1s normal . The meaTotally 1,466 children were used to analyze growth during the first year of life. The 540 DodaLab children provided 4,964 measurements each of weight and length. In FilaBavi 926 children contributed with 9,235 measurements. Totally 14,199 measurements were analyzed, that is 9.7 measurements per child.Birth weight information was provided by the mothers, who reported the measurement made at the hospital or commune health centers immediately after birth. For less than 1% of the children birth weight information was not obtained. The information about birth weight has been analyzed separately from the subsequent measurements of growth.Given the mother's consent, children were registered for the study and scheduled for measurement of weight and length every month from one month after birth to the age of 12 months. The percentages of scheduled measurements actually done were 65% for DodaLab and 77% for FilaBavi. The frequency of missed measurements increased with the age of the infant. The percentage of children actually followed to at least 11 months was 80% in DodaLab and 90% in FilaBavi.Standardized equipment for measuring the child recommended from Hanoi Medical University was used. A number of commune health centre staff members in DodaLab were trained specifically to measure children. In FilaBavi, a number of the permanent interviewers were trained to measure children. The principle of measurement was that the same field worker should assess a child at each visit using the same equipment. Weight was measured to the nearest 10 gram with the child in light clothes using a portable infant scale. Length was measured to the nearest centimeter in horizontal position using a length board. Two person worked together in order to have valid and reliable measurements .The difference between the date of birth and the date for the last menstruation reported by the mother can be assumed to be correlated to the gestational age at birth. In spite of the likely underestimation of the true pregnancy time the difference is used as a proxy for the gestational age and will subsequently be referred to as the Gestational age proxy (Gap).Data describing economy and education were taken from the household surveys conducted 2009 in the two sites. At household level we considered the reported yearly household income and the household assets available (according to a specified list) as indicators of economic resources. The number of household members was also studied.For the mothers we studied age and education . In the urban area the dominant occupational category was office and service employment. Farming was the most frequent occupation in the rural area. However, occupation is strongly correlated to education and has not been used in the analysis.Assessments of associations between the dependent variable birth weight and the independent area, sex, mother's age, education occupation, reported household income and sum of household assets were made using linear regressions. No distinction of term or preterm children was made but the Gap indicator was used as an indicator of gestational age.The statistical description of weight and length growth has two objectives, the estimation of mean and variation of attained weight and length as functions of child age and the corresponding growth velocity also as a function of child age. Theoretically the velocity functions are the first derivatives of the attained weight and length functions.Several methods have been suggested for statistical description and analysis of growth data . The ambDifferences in growth between the sites and child sex and other independent variables were assessed using two- level, mixed effect linear models. The dependent variables were the relative residuals (logarithmic for weight) from the overall fitted Fractional Polynomials.The deviations from the WHO standard curves were evaluated for statistical significance using the child specific means of relative deviations from the standards.Growth velocity was calculated as the first derivative of the fitted fractional polynomials.In addition the average growth velocity for each child over the first year, obtained through collapsing the dataset to child level was used.Three linear regression models were used for the analysis of birth weight and residuals from the growth curve:Model A. independent variables: area , Gap and child sex.Model B. independent variables: area , Gap, child sex, education and household assets.Model C. independent variables: area , child sex, Gap, education, household assets, mother age, household income and number of household members.The software used for all analysis was STATA version 11. In the analysis we used only singleton children.Approval of the project was obtained from the Scientific and Ethical Committee of Hanoi Medical University, Hanoi Health Bureau and Dongda district authorities. The proposal was approved by the Ministry of Health and permission for the study was given after the baseline survey. All mothers of infants were informed about the purpose of the studies and their right to decline participation or withdraw. Consent for participation was given by all mothers of the included infants.Wide and highly statistically significant differences in mean birth weight were found between the urban and rural areas. Table Table Table The estimated growth curves differed statistically significantly between the sites for both sexes Figure . The meaLines showing the WHO growth standards published in 2006 [Estimated attained weight (grams) and limits for plus and minus two standard deviations at 90, 180, 270 and 360 days of age differed between the two sites (Table The estimated attained length (cm) and limits for plus and minus two standard deviations at 90, 180, 270 and 360 days of age also differed between the two sites Table . The resEstimated weight growth velocity and length growth velocity at 90, 180, 270 and 360 days decreased throughout the first year of life in both sites Table . The difThe associations between growth and the independent variables described in Table The main findings of the study are the differences between urban and rural areas in birth weight as well as in the subsequent growth, attained weight and length and growth velocity. For birth weight the differences between boys and girls were expected as was also the associations with the gestational age proxy. The latter is the variable with the strongest correlation to birth weight and is in turn related to subsequent attained weight and length.The area variable in itself, urban vs. rural, is of no importance when other variables, with large differences between the areas, are introduced in Model C. Some of the added variables are not statistically significantly associated to birth weight or growth but obviously form an intricate pattern that "replaces" the area variable. This finding is the same in the analysis of birth weight and in the analysis of growth. Another common finding is that there are associations between growth and household assets and education, particularly for weight growth.2) and that the largest part is contributed by the area and sex variables meaning that rather small fractions of the variation in birth weight and growth are explained by the associations with Gap, area and child sex differences and the social and economic variables.Growth velocity for weight differs between the areas for both child sexes. The length growth velocity is lower for rural girls. It shall be noted that all regression models have quite low values for the determination coefficient  later, had fewer visits and much less of specific medical services than in the urban mothers . DiffereSeveral conditions and factors have been shown as associated to poor growth of infants with nutrition as the most important ,29. The In Vietnam, the total fertility rate in the rural areas was higher than in the urban area  but the The differences in weight gain between rural and urban infants found in this study are established at an early age. One important factor may be differences in breastfeeding patterns, especially the duration of exclusive breastfeeding. The absolute differences in growth of infants between urban and rural areas increased with increasing ages. Use of different types of supplement food for infants in the two sites could explain this.Infants in the urban area are likely to have easier access to child health care than rural infants. Some barriers to access child health care in rural areas in Vietnam, like distance and long travel times, do exist. Financial, sociocultural, language, ethnicity are other possible barriers together with lack of knowledge, awareness and inequalities in quality of health care .The differences of length growth between the two sites were comparatively smaller at low ages, but increased in absolute terms during infancy. This result is in agreement with results of studies from China where urban children were taller than rural children at all ages from one to 12 months of age ,7. One sDifferent standards for child growth have been published by various institutions and international organizations. Recently, the World Health Organization (WHO) launched growth standards in 2006. These were constructed to show child growth under ideal conditions . AnotherCompared to results of a study in urban Hanoi in the 1990's, the birth weight and growth of infants in the present study are higher for both sites , indicatOne limitation of the study is the short follow-up time. One year is not enough to study if differences tend to decrease or increase as the children get older. The ambition for further research shall be to continue follow-up to at least 5 years to see if the rural children catch up with urban children or if the gaps are further widened. Also the exploration of overweight tendencies will require longer follow-up. Certain unavoidable differences between the study designs, data collection and administrative procedures might be seen as limitations. For example the two cadres of interviewers have different employment conditions. But the good training and the quality control have probably minimized this problem. The situation that there are unequal sample sizes in the two areas is not optimal for comparison.The research was conducted in two sites within the capital of Vietnam. These areas are generally considered to have rather good socioeconomic conditions compared to the rest of country. Even so, the birth weights and growth of infants are higher in the urban area than in the rural area. This suggests that differences are likely to occur also in other, comparatively poorer, settings in Vietnam.Mean birth weight as well as weight growth of infants, described both as attained weight at different ages and growth velocities were different between the investigated areas in Vietnam. The birth weight was lower and the growth considerably slower in the rural area, for boys as well as for girls. The corresponding differences in length growth of the infants were more modest but increased with age during the first year of life. The results support the hypothesis that the rather drastic differences in mother education and economic conditions leads to poor nutrition for mothers and children in turn causing inferior birth weight and growth. The importance of health care utilization and breastfeeding are two areas that will need further exploration.The authors declare that our findings have not been influenced by our personal or financial relationship with other person or other organization.HNT led and supervised the fieldwork and data management. She also drafted and completed this paper. BE assisted in the research design as well as in the statistical analyses, interpretation of results and revising the manuscript. HA, LNT, CNTK, MP and GB were involved in the design of the study, supervised the study and revised the manuscript. All authors have read and approved the final manuscript.Huong Nguyen Thu MD, researcher and pediatrician of the Research Institute of Child Health and the National Hospital of Pediatrics in Hanoi, Vietnam. She is also a PhD student of the Nordic School of Public Health in Gothenburg, SwedenBo Eriksson PhD, Professor emeritus of the Nordic School of Public Health in Gothenburg, SwedenLiem Nguyen Thanh MD, PhD, Professor and Director of the Research Institute of Child Health and the National Hospital of Pediatrics in Hanoi, VietnamChuc Nguyen Thi Kim PhD, Associated professor of Hanoi Medical UniversityMax Petzold is PhD, Professor of the Nordic School of Public Health and the Gothenburg University in SwedenGöran Bondjers MD, PhD is Professor of Gothenburg University in SwedenHenry Ascher MD, PhD, Associate professor of Nordic School of Public Health, Gothenburg, SwedenThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/12/26/prepub


Introduction. Trauma, including suicide, accidental injury, motor traffic accidents, and homicides, accounts for 73% of all maternal deaths (early and late) in NSW annually. Late maternal deaths are underreported and are not as well documented or acknowledged as early deaths. Methods. Linked population datasets from births, hospital admissions, and death registrations were analysed for the period from 1 July 2000 to 31 December 2007. Results. There were 552 901 births and a total of 129 maternal deaths. Of these deaths, 37 were early deaths (early MMR of 6.7/100 000) and 92 occurred late (late MMR of 16.6/100 000). Sixty-seven percent of deceased women had a mental health diagnosis and/or a mental health issue related to substance abuse noted. A notable peak in deaths appeared to occur from 9 to 12 months following birth with the odds ratio of a woman dying of nonmedical causes within 9–12 months of birth being 3.8 (95% CI 1.55–9.01) when compared to dying within the first 3 months following birth. Conclusion. Perinatal services are often constructed to provide short-term support. Long-term identification and support of women at particular risk of maternal death due to suicide and trauma in the first year following birth may help lower the incidence of late maternal deaths. The maternal mortality rate (MMR)  in Australia in 2010 was 7/100,000 confinements –5.The extent of late maternal deaths (those occurring >42 days after delivery and up to one year of birth) is reported to be underestimated by up to 50% in most studies conducted which utilised multiple collection means to calculate rates , 4, 6–8.Trauma, including suicide, accidental injury, motor traffic accidents, and homicides, is the leading nonobstetric cause of late maternal death in the United States  and accoThe aim of the study is to evaluate the rate and causes of maternal mortality up to one year following birth utilising linked data methodology to ascertain accurate rates of maternal mortality and the potential role played by nonmedical causes in these deaths.Perinatal data recorded in the NSW Midwives Data Collection (MDC), hospital admissions recorded in the Admitted Patient Data Collection (APDC), and deaths recorded in the Registry of Births, Deaths and Marriages (RBDM) and the Australian Bureau of Statistics (ABS) were provided by NSW Department of Health for the period from 1 July 2000 to 31 December 2007. The MDC is a population-based surveillance system containing maternal and infant data on all births of greater than 400 grams birth weight or 20 weeks gestation. The APDC is a collection of records of all services to admitted patients provided by New South Wales Public Hospitals, Public Psychiatric Hospitals, Public Multi-Purpose Services, Private Hospitals, and Private Day Procedures Centres. The NSW RBDM and ABS contain mortality information for deaths occurring in NSW and Australia.The linked datasets were provided by the NSW Centre for Health Record Linkage (CHeReL) following approval by the Data Custodian . Probabilistic data linkage techniques were utilised for these purposes and deidentified datasets were provided for analysis. Probabilistic record linkage software works by assigning a “linkage weight” to pairs of records. For example, records that match perfectly or nearly perfectly on first name, surname, date of birth, and address have a high linkage weight, and records that match only on date of birth have a low linkage weight. If the linkage weight is high, it is likely that the records truly match, and if the linkage weight is low it is likely that the records are not truly a match. This technique has been shown to have a false positive rate of 0.3% of records .The deaths recorded in the ABS data were compared to those recorded in the NSW RBDM to enhance the identification of episodes and duplicates were removed. Those deaths which were recorded as occurring within 365 days of a birth (as noted in the MDC) were included in the datasets. Utilising the unique identifier, the APDC was then searched for admission data prior to the birth, admission during the birth, and admissions which occurred between the birth and the maternal death for associated diagnoses and co-morbidities.Ethical approval was obtained from the NSW Population and Health Services Research Ethics Committee, Protocol no. 2010/12/291.Maternal death and associated causes were categorised using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM)  as recorDescriptive statistics (frequencies and proportions) were calculated. Demographics comparisons, events by time from birth, and risk of death by suicide were compared to the general female population. All analyses were conducted using IBM SPSS v.19.During the 6-year time period, there were 552 901 births and a total of 129 maternal deaths. Of these deaths, 37 occurred within 42-day time period following birth, equal to an early MMR of 6.7/100 000 confinements occurring following the recorded birth after 20 weeks gestation. The remaining 92 deaths occurred in the interval between 42 days and 365 days following birth, equal to a late MMR of 16.6/100 000. The demographics of all women in the cohort are summarised in Forty-eight (37%) of all deaths were the result of nonmedical causes or trauma, four of which occurred in the early time period and 44 in the late time period. The deaths were further divided into four categories: intentional self-harm, accidental injury, transport accidents, and homicide. The reasons for death are outlined in n = 32) had a mental health diagnosis and/or a mental health issue related to substance abuse  noted on an admission to hospital during pregnancy, birth, or in the interval between the birth and their death. The greatest percentage of such comorbidities was noted in women who died from suicide  or accidental injury .Of the 48 women who died as a result of nonmedical causes, 67%  in the cohort was also examined in comparison to the age-specific death rates in the Australian population with a resulting relative risk of suicide of 0.9 .We have shown that suicide and accidental injury are the two leading causes of death for women within one year of birth, contributing to 62% of all causes during this period, a similar result to that shown by Cliffe et al.  in NSW iMental health diagnoses and/or drug or alcohol dependence occurred in 73% of women who died as the result of intentional self-harm or accidental causes. These issues were highlighted during the pregnancy and/or during the birth admission or during postnatal admissions and were therefore known to health professionals prior to death, a finding reported by Austin. The use of screening tools such as the Edinburgh Perinatal Depression Scale (EPDS)  has beenOther factors noted in the deceased cohort were the high rates of smoking during pregnancy (>2.5 times more likely to smoke) and almost double the rate of pregnancy-related medical conditions when compared to those women in the cohort who survived, conditions which may also be indicative of lower socioeconomic status within the deceased cohort. The women in the deceased cohort had smaller birth weight babies, born at shorter gestations and who were admitted to a neonatal intensive care unit at a rate more than seven times higher than the remaining cohort. The cascade of smoking during pregnancy, early birth, lower birth weights, NICU admission and perinatal mortality is displayed in the deceased cohort. The stress of these events on women has been well documented and such risk factors are seen frequently in women diagnosed with postpartum depressive symptoms , 28. ComBy dividing the first year after birth into three-monthly increments, it can be seen in In developed countries, women have a high expectation that the period following childbirth will be both positive and fulfilling and that the changed circumstances of motherhood will improve the overall quality of life. Women in our society are frequently shown, for example, in the media, a picture of motherhood that is not factual in nature and promotes unrealistic expectations . The reaThe strengths of this study are the size of the dataset available for analysis, the accuracy of the linkage process, and the depth of coding which is attached to admission data. The weaknesses lie in the lack of socioeconomic and sociodemographic details available which would add a more detailed dimension of analysis to occur.This study sought to examine maternal mortality up to one year following birth and to ascertain rates of maternal mortality and the role played by nonmedical causes in these deaths. During the 6-year time period, 37 deaths occurred within 42 days following birth with 92 deaths occurring in the interval between 42 and 365 days. Forty-eight of the deaths were the result of trauma, which mainly occurred after 42 days following birth. There appears to be a spike in maternal deaths in the period of nine to twelve months postpartum and this may well correspond to a reduction in perinatal services and other support or/and an increase in stressors as women are reentering the workforce. There is a strong association with women who have co-morbidities, in particular mental health and/or substance abuse. There was high rate of obstetric complications and intervention, low birth weight infants, admission of infants to NICU and perinatal mortality. Perinatal services are often constructed to provide short-term support. Long-term identification and support of women at particular risk of maternal death due to suicide and trauma in the first year following birth may help lower the incidence of late maternal deaths.The term “perinatal” covers the period from conception to one year postpartum. Services need to remain cognisant of the needs of new mothers throughout this vulnerable period.