Since the Doi Moi reform 1986 economic conditions in Vietnam have changed significantly and positive health and health care developments have been observed. International experience shows that improved economic conditions in a country can reduce the risk of perinatal mortality, decrease the risk of low birth weight and increase the mean birth weight in newborns. The Health and Demographic Surveillance Site (HDSS) FilaBavi in Bavi district outside Hanoi city has been operational since 1999. An open cohort of more than 12,000 households  has been followed primarily with respect to demography, economy and education. The aim of this research is to study trends in birth weight as well as birth and delivery practices over the time period 1999–2010 in FilaBavi in relation to the social and economic development.Information about birth weight, sex, place and method of delivery, mother’s age and education as well as household economy of 10,114 children, born from 1999 to 2010, was obtained from the routine data collection in the HDSS.Over the study period the mean birth weight remained at the same level, about 3,100 g, in spite of increased economic resources and technology development. At the individual child level we found associations between birth weight and household economy as well as the education of the mother. Hospital delivery increased from about 35% to 65% and the use of Caesarian section increased from 2.6% to 10.1%.During the twelve years studied, household income as well as the use of modern technology increased rapidly. In spite of that, the mean and variation of birth weight did not change systematically. It is suggested that increasing gaps in economic conditions and misallocation of resources, possibly to overuse of technology, are partly responsible. During the last few decades, there has been a dramatic change in the economic conditions in Vietnam. Yearly income per capita has increased from $130 in the early 1990s to $900 in 2008. Poverty according to the World Bank definition (less than 1.25 US$ per person and day) has been reduced from 58% of the population in 1993 to 13% in 2008 . The proThe Health and Demographic Surveillance Site (HDSS) FilaBavi in the rural district Bavi started in 1999. An open cohort of about 12,000 households has since then been followed regularly. From 1999 to 2009, the median self-reported yearly income per household in FilaBavi increased from 5,990,000 Vietnamese dong (VND)  to 15,000,000 VND, taking inflation,  over the period, into account.In a situation of economic growth but with possibly widening gaps in socioeconomic conditions within populations there is an urgent need for surveillance of health and well-being. A vulnerable group is children, particularly the newborn and the very young. Birth weight is an indicator of the mother’s health and nutritional status. It is also an indicator of a newborn’s chances for survival, growth, long-term health and psychosocial development . Low birSeveral genetic and environmental factors influence the intrauterine growth of a fetus and hence the birth weight. The different strengths and prevalences of those factors lead to differences in birth weight between countries, ethnic groups and different social and economic contexts. At the household and individual levels variations occur due to a manifold of influences. For example demographic, social and economic conditions are known as determinants of health in general, including birth weight. It is so far not known if the economic changes in Vietnam have been associated with birth weight changes and changes in the proportion of low birth newborn. Therefore the primary aim of this paper is to study trends in birth weight together with the proportion of LBW newborn over the time period 1999–2010 in FilaBavi. There is also an aim to study trends in delivery place, presence of medical attendance and delivery type, particularly the use of Cesarean section (CS). Finally we want to study how birth weight and delivery characteristics are associated with economic and educational characteristics of the mother and the household. This will be done at the macro level, over time, as well as at the level of individual households.The HDSS FilaBavi started with a baseline study in 1999. Over 12,000 randomly selected households, with just over 50 000 persons, in 69 clusters (hamlets) in Bavi district 60 km west of Hanoi were included and interviews were conducted to obtain information about the households and the individuals living in these. At the same time the demographic monitoring started with household visits every three months to record vital events, births, migration and deaths. The site has been running since, with quarterly follow-up interviews. Renewed household surveys have been undertaken in 2001, 2003, 2005, 2007 and 2009 .The household surveys have given information about household economy and living conditions as well as individual information like education and occupation. The quarterly visits have been used to obtain information about vital events. The total number of live born children reported from 1st January 1999 to 31st December 2010 was 10,114. This paper presents results concerning these children.Information on birth weight, sex of the child, state of twins and date of last menstruation before pregnancy were reported by the mothers. The date for last menstruation was intended to be used for the estimation of the gestational age at birth. This information however, must be considered as fairly imprecise. The difference between the date of birth and the date for the last menstruation as reported by the mother can however be assumed to be rather strongly correlated to the gestational age at birth and is used as a proxy for the gestational age, subsequently referred to as Gestational age proxy (Gap).The following information about the newborns was used in the analysis of associations: birth weight, sex, Gap, place of delivery, medical attendance at delivery and type of delivery, specifically CS.For the mothers we used age and education classified in three levels  from the household surveys. Farming was the most frequent occupation in the rural area. Occupation was strongly correlated to education and was therefore not used in the analysis. About 94% of the population belonged to the Kinh ethnic group. We don’t present details about the other ethnic and occupational groups because they are small and therefore not considered in the analysis.Information describing economy was taken from the household surveys. The reported yearly household income and the household assets available (according to a specified list) were considered as indicators of economic resources. The number of household members was also used in the analysis.The main outcome variable is birth weight. We also give some results for the dichotomized, less informative but often used variable LBW. To explore possible associations with various background variables, linear regression models were used. As some mothers gave birth to more than one child during the 12 years, we used multiple two-level mixed linear models. The difference in the results between this approach and ordinary regression is indeed minor. LBW was analyzed using parallel multiple logistic models.To study the development over time for birth weight and delivery characteristics we used simple linear regression of outcomes on the independent time variable. Two approaches for analysis of associations between outcomes and background variables were used. In one we used all data in one model. However, associations might change over time and year-wise analyses were also used to attempt identification of such tendencies. All computational work was carried out using STATA, version 11.This study was a part of larger collaborative project between Vietnamese and Swedish researchers. It was approved by Hanoi Medical University and Ministry of Health, Hanoi and Bavi district People Committees and Bavi District Health Center, Hanoi, Vietnam. All households approached were informed about the purpose of the studies and their right to decline participation or withdraw. It was also clarified that strict rules for confidentiality should be adhered to. Information was given that all results shall be continuously disseminated to communities and authorities as aggregated information. Less than 1% of the households approached refused participation.Out of the 10,114 children born in FilaBavi, 5,389 were boys and 4,725 girls. The number of mothers was 6,860, where 4,093 had one birth and 2,305 had two. The maximum number of reported births for one mother was five. Birth weight information could not be obtained for 98 children, less than 1%. Not all children born in 1999 were included in the study because the first household survey was completed only in April 1999. Eight children were excluded from the analysis due to generally poor information. Table The absolute number of births increased over the period. Comparing 2000 and 2009 the increase was about 30% for boys and 10% for girls. As a consequence, the male to female sex ratio at birth (SRB) increased from 1.04 in 1999 to 1.19 in 2010 . Also, the use of CS became more frequent both for boys (2.6% in 1999 and 12.7% in 2010) and girls (2.7% in 1999 and 7.4% in 2010). These differences are statistically significant (p < 0.05)  in 2009 (150% increase). For the households in the lowest wealth-index quintile starting at 2,600,000 VND the increase was to 4,390,000 VND (69% increase). The highest quintile starting at 10,800,000 increased by 227% to 35.400,000. Reported household health expenditures roughly doubled during the period and were not much different between the income quintiles except that the lowest income group also reported somewhat lower health expenditure. The number of household assets increased modestly from 1999 to 2010. Household size remained stable.Two variables, Gap and child sex, were statistically significantly correlated to birth weight in all yearly multiple regression analyses as expected. Gap showed the strongest correlation coefficient throughout, around 0.30 and the regression coefficient indicated about 33 grams weight increase per week increase of Gap. The child sex variable showed a significant boy girl difference somewhat less than 100 g (p < 0.001). Mother age (increasing age associated with increasing birth weight), number of household members (more members - lower birth weight) and household assets (more assets - higher birth weight) occurred as significant for several but not all years.In the overall multiple regression analysis, birth weight was statistically significantly associated to Gap (35 g per week), child sex (106 g boy - girl difference), hospital delivery , education (36 g per education level) and number of household assets (12 g per asset) (p < 0.01). The very modest negative trend of birth weight over the years was not statistically significant in this analysis.In an analysis restricted to hospital delivered children we identified a statistically significant association between use of CS and birth weight. The mean weight for babies delivered with CS was 65 g higher (p < 0.01) than for other babies. The mean birth weight for children where the mother was not of Kinh ethnicity was similar to the mean birth weight of the majority population.CS is by necessity associated with delivery in hospital. We therefore studied the associations between hospital delivery and background factors only for deliveries other than CS. Statistically significant associations were observed for child sex, mother’s age and education and economic status. Boys were more often delivered in hospitals (from 36.3% in 1999 to 68.5% in 2010) than girls (from 34.9% in 1999 to 61.6%). The mother’s age was not linearly associated; there is a peak in hospital delivery for the age group 20–29. Economic status in this analysis turned out to be best represented by the reported monetary income.Increasing use of CS is monotonically associated primarily with increasing education and increasing mother age. There are tendencies for associations also with increasing economic status and male sex of the baby (p < 0.05).2 larger than 0.15, which means that the variation in the independent variables explained 15% or less of the variation in the dependent variable. The corresponding values for low birth weight were even lower.No model for birth weight had an RThe reported household monetary income appeared to be statistically significant associated with birthe weight in few analyses where the household assets variable was included. These variables are fairly strongly correlated to each other (r = 0.6). If the assets variable is removed however, income replaces it as being significantly associated with birth weight.The main finding in this study of the comparatively long time series is that the overall mean birth weight has been stable over the years in spite of a rather drastic economic and technological development. Most previous studies in Vietnam, and other countries, have found increases in the mean birth weight and reductions in the incidence of low birth weight over time periods with improved economy ,14-16. OIn the yearly analyses at the level of individual children we find associations between birth weight and indicators of economic resources as well as education. This is not a contradiction to the finding that the mean birth weight did not increase over years. First a certain time lag from economic changes to birth weight effects should be expected. Further, the general economic improvement does not necessarily influence on the general birth weight level, particularly if the economic and nutritional inequalities remain or increase. Over the years there can also be changes in household priorities for the use of economic resources.UNICEF has suggested that economic development alone does not automatically lead to improvement in nutrition. Good nutrition is an outcome of many factors both biological and social . Most prThe present study shows that the percentages of women who delivered in hospitals as well as women who delivered with CS, increased during the time period. This tendency might be an indication of increased confidence in technology. Along the same line, the use of ultrasound has become increasingly common. Possible overuse of ultrasound has been seen in another study in Vietnam in 2007 .Compared to results from urban Hanoi, the pregnant women in FilaBavi attended antenatal care later, had fewer visits and much fewer medical services . The heaA finding is that the percentages of women, who gave birth in hospitals as well as delivered with trained attendance, increased over the twelve years. Vietnam has a strict two child policy. From a recent study in FilaBavi, we know that the proportion of delivery in hospitals is higher among women with higher education and among mothers without previous sons in FilaBavi . Most liWe found that the use of CS increased over the 12 years in FilaBavi along with the increase of economic resources and mother’s education. This is in accordance with the result from a recent study in FilaBavi, in which CS use increased with education level and among women living at lowland areas or in richer households . CS has During the last 12 years, the male to female sex ratio at birth (SRB) has increased in Filabavi. The sex ratio at birth in 2010 was quite far from the normal. In Vietnam as a whole, SRB increased from 1.05 in 2001 to 1.12 in 2006 . This isThis study gives a picture of birth weight trends in FilaBavi during twelve years from 1999 and the incidence of LBW, delivery place, presence of medical attendance at delivery and type of delivery, particularly the use CS. We also found an association between birth weight and delivery characteristics on the one hand and economic condition of the household as well as educational characteristics of the mother on the other.The births studied are assumed to be all or close to all live births that actually took place in FilaBavi 1999–2010. Different small studies have been done comparing the numbers of reported births and deaths in FilaBavi with the official information given by local authorities. The latter reports roughly 10% fewer births. The deficit is higher regarding deaths .The quality of the birth weight information used must be judged knowing how it was obtained. Mothers have reported the information they received in hospitals or community health centers immediately after delivery. In the Commune Health Centers and the District hospital, the newborn children were weighed and measured directly after delivery wearing light clothes. The birth weight, recorded in the clinical records of the district hospital or in the delivery notes of the commune health station, was adjusted for the weight of clothes.In Vietnam, it is considered important to know and remember the birth weight of children. Three months after delivery, the field workers interviewed mother about birth weight, why recall bias should be low. We have also compared information of birth weight between the different kinds of interview, quarterly interviews in FilaBavi 1999–2010 and the quarterly interviews in FilaBavi and DodaLab 2008–2010 . The resBirth weight was measured by different health staffs working differently and using different equipment. Poor standardization can create bias and excess random variation. This source of error is shared with many studies and difficult to eliminate in any context. The health staff may also report the birth weight to the mother incorrectly, e.g. with a tendency to “increase” for low weight babies and “decrease” for high weight babies as a wish to avoid extremes and thereby “please” the mother. This could lead to underestimation of the proportions of low birth weight children and to a biased estimate of the standard deviation (underestimated). Gifts to the health care staff, often monetary, are important parts of the Vietnamese health care system.To explore possible bias a small study was done. For each year, 1999–2010, we collected the birth weight information for 30 randomly selected children from the records in the Bavi district hospital and compared the estimated means of birth weights with those obtained from the interviews with mothers. There were no trends over the 12 years in the birth weight means estimated using this particular data. The overall means were 3,110 g for boys and 3,047 g for girls. The corresponding estimates using the mother reports were 3,136 and 3,057 g, i.e. differences are 26 and 10 g. We also collected birth weight data for 40 children in each of two health stations for two years, 2005 and 2009. There was no large difference between the health station and the hospital data.During the studied twelve years there were improvement of economic conditions and education as well as increased expenditure for health care and use of health technology in a rural area of Vietnam. Surprisingly, no positive secular trend in birth weight was observed in this period. Some reasons can be that the increased economic resources are not distributed in an equitable way or not used in the best possible way. The research was carried out in one rural area of Vietnam and the results may not be representative for other rural areas of Vietnam. To better understand the mechanisms behind this result, similar studies in other areas of Vietnam would be needed. In future studies birth weight information should ideally be obtained from validated delivery registers to avoid biases.The authors declare that our findings have not been influenced by our personal or financial relationships with other persons or other organizations.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, TTK and CNTK were involved in the design of the study, supervised the study and revised the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/41/prepub


Different approaches have been used in case-control studies to estimate maternal exposure to medications and the risk of birth defects. However, the performance of these approaches and how they affect the odds ratio (OR) estimates have not been evaluated using birth-defect surveillance programmes. The aim of this study was to evaluate the scope and limitations of three case-control approaches to assess the teratogenic risk of birth defects in mothers exposed to antiepileptic medications, insulin, or acetaminophen.We studied 110,814 non-malformed newborns and 58,514 live newborns with birth defects registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) between 1967 and 2008. Four controls were randomly selected for each case in the same hospital and period, and three different control groups were used: non-malformed newborns (HEALTHY), malformed newborns (SICK), and a subgroup of SICK, only-exposed cases (OECA). Associations were evaluated using OR and Pearson's chi-square (P<0.01). There were no concordance correlations between the HEALTHY and OECA designs, and the average OR differences ranged from 3.0 to 11.5 for the three evaluated medicines. The overestimations observed for HEALTHY design were increased as higher OR values were given, with a high and statistically significant correlation between the difference and the mean. On the contrary, the concordance correlations obtained between the SICK and OECA designs were quite good, with no significant differences in the average risks.The HEALTHY design estimates the true population OR, but shows a high rate of false-positive results presumably caused by differential misclassification bias. This bias decreases with the increase of the proportion of exposed controls. SICK and OECA odds ratios cannot be considered a direct estimate of the true population OR except under certain conditions. However, the SICK and OECA designs could provide practical information to generate hypotheses about potential teratogens. Different case-control study designs have been used to estimate the risk of birth defects after medication exposure. These approaches differ in their definition and selection of the control group. Case-control studies with healthy newborn controls are widely used, especially for studying rare events such as birth defects. In South America, the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) has maintained a surveillance programme for birth defects since 1967 using a case-control design However, as has been laid out in previous works A useful system have been proposed to post-marketing surveillance of fetal effects of medications using available sources from existing birth defect surveillance programs and globally organized through the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) The interpretation and usefulness of the epidemiological methods that include healthy and malformed controls have been discussed previously The aim of this study was to evaluate, using the ECLAMC's surveillance programme, the scope and limitations of three approaches to assess the teratogenic risk for birth defects in mothers exposed to specific medications during the first trimester of pregnancy: (a) antiepileptics, which are medications associated with a risk of birth defects; (b) insulin, which is a marker for pre-gestational diabetes, a chronic condition that is well known to be associated with birth defects; and (c) acetaminophen, which is a medication that is not associated with birth defects.Live-birth cases were those that were registered by the ECLAMC network, involving 102 maternity hospitals from 11 South American countries from 1967 to 2008 and covering 3,939,474 births. A total of 58,514 live births with isolated or multiple birth defects were registered with ICD-X BPA codes DHHS-IRB #1745, IORG #1315).A total of 110,814 non-malformed newborns from the same database were used as healthy controls. Data regarding medication use and illnesses during pregnancy were obtained by qualified physicians using standard interviews of the mothers before their discharge from the hospital at which they had given birth. Data were collected, reviewed and coded by the ECLAMC following the same standardized procedure used since 1967 The three medicines analyzed in this study were the following: antiepileptics (ATC code: N03A), including valproic acid (N03AG01); insulin (ATC code: A10A); and acetaminophen (ATC code: N02BE01). Exposures to vitamins and iron were excluded from the analysis in order to minimize bias, as exposure to these medications has not been proven to be teratogenic.RR). Similarly, in retrospective studies with non-malformed controls, the magnitude of each of these associations could be estimated by calculating the corresponding odds ratios (OR). As illustrated by the three-by-three table in Three different case-control designs were used in the present study:HEALTHY design: This was the classical case-control design. Cases included those infants with any of the birth defects . Four non-malformed controls were randomly selected for each case from all healthy newborns registered by ECLAMC in the same hospital and period. These controls showed no difference to total births with respect to maternal age, gravidity, and birth weight (HEALTHYOR) was calculated by the same method that was used for (M→BD)OR, (Subjects were considered exposed if their mothers reported the use of the study medicine during the first trimester of pregnancy (with or without other medications) and were considered non-exposed when their mothers reported no medication use. The magnitude of this association (R(M→BD), :(5)SICK design: This was a case-control design in which both the cases and controls were malformed. The cases were defined similarly to those in the HEALTHY design. Four newborns with birth defects other than the case were randomly selected from all malformed newborns registered by ECLAMC in the same hospital and period. The operative definition of exposed versus non-exposed was similar to that for the HEALTHY design. The SICKOR was calculated as follows ( follows :(6)OECA (Only-Exposed Cases) design: This approach only included malformed newborns who were prenatally exposed to any type of medicine, so this is actually a subgroup of SICK. Cases and controls were defined similarly to those for the SICK design. Malformed newborns whose mothers reported the use of the study medication were considered exposed subjects, and those whose mothers reported the use of medicines other than the ones studied were included as non-exposed. The OROECA is represented as follows ( follows :(7)Associations between the medicines and birth defects were assessed using Odds ratios (ORs) and Pearson's chi-square test at a level of significance of 1% (P<0.01). Ninety-nine percent confidence intervals (99% CI) were calculated for all birth defects in HEALTHY design. Each birth defect was analysed separately for antiepileptics, insulin, and acetaminophen use during the first trimester of pregnancy.For the available sample size and a medicine exposure around 1%, the minimum detectable OR is 2.0, with a power of 90% when the sample size is 2000 cases and 60% when sample size is 500 cases. Out of the 31 birth defects analysed in the present study, only two were found in less than 500 cases, and ten were found in more than 2000 cases.cρ) HELATHYOR and SICKOR estimates significantly deviated from the line of perfect concordance with the OECAOR estimates (taken as the baseline). Lin's coefficient increases in value as a function of the nearness of the data's reduced major axis to the line of perfect concordance (a measure of accuracy of data) and of the tightness of the data about its reduced major axis (a measure of precision of data).Lin's concordance correlation coefficient (d−mr) and the 95% limits of agreement (95% CI) were estimated and tested for significance using the Bradley-Blackwood test (F).Bland-Altman analysis of the limits of agreement B (“biased” odds ratio) is the observed OR; ORT (“true” odd ratio) is equals to 1, assuming there is not association among acetaminophen use and birth defects; and the letter i indicates SICK, OECA, or HEALTHY designs.Potential reporting/selection biases (in percentages) were calculated according Swan et al. 0 coefficient is the bias-intercept and the β1coefficient evaluate the increment of bias as a function of the proportion of exposed controls (slope of the curve).For each design, a linear regression model was applied to evaluate possible association between the bias and the proportion of exposed controls to acetaminophen:All statistical analyses were processed using Stata 12 SE .Out of the 3,939,474 total births that were registered by the ECLAMC, 58,514 newborns had a non-syndromic birth defect, of whom 48,971 had a single birth defect (83.7%), and 9,543 had two or more unrelated major birth defects (16.3%).The frequencies of exposure to antiepileptics and insulin for malformed newborns were more than twice those observed for non-malformed babies. A minor difference between these groups was observed in the percentage of exposure to acetaminophen . Considecρ = 0.07; 95%CI: 0.02–0.11), insulin , and acetaminophen . The average difference between these designs (HEALTHYOR−OECAOR) was 6.1 (95%CI: −1.9–14.0) for antiepileptics, 11.5 (95%CI: −11.8–34.7) for insulin, and 3.0 (95%CI: 0.98–5.06) for acetaminophen. The overestimations observed for HEALTHY design were increased as higher odds ratio values were given, with high and statistically significant correlations between the difference and mean (d−mr) for antiepileptics , insulin , and acetaminophen .When considering concordance, no significant correlation between the HEALTHY and OECA designs were observed for antiepileptics , insulin , and acetaminophen . There were no significant differences in the average values between SICKOR and OECAOR for antiepileptics , insulin , and acetaminophen .In contrast, significant concordance correlations were obtained between the SICK and OECA methods for antiepileptics  was identified by SICK and OECA approaches. While eighteen significant associations (including Spina bifida) with ORs ranging between 2.8 and 18.3 were observed using HEALTHY design see , row 1. Atrial septal defect (Q21.1), axial skeletal malformations , severe ear malformation (Q16.0 and Q17.2), and ventricular septal defect (Q21.0) showed a strong association with insulin exposure using SICK and OECA approaches. Fifteen significant associations (including the four birth defect groups described above) with ORs ranging between 4.2 and 74.6 were identified by HEALTHY design , row 2. There were no significant associations between the birth defects and acetaminophen (paracetamol) using the SICK and OECA designs, with the unique exception of a negative association (OR<1) with multiple joint contractures (Q74.3) using OECA approach. On the other hand, twenty-nine significant associations with ORs ranging between 2.3 and 6.3 were observed using HEALTHY design , row 3. The average proportions of exposure to acetaminophen in the 31 control groups (± SD) were 4.6% (±1.2); 12.9% (±2.9); and 1.3% (±0.4) for SICK, OECA, and HEALTHY design, respectively. While the mean biases (± SD) were 2.6% (±21.7) for SICK; −8.4% (±20.0) for OECA; and 293.4% (±112.1) for HEALTHY design.1 coeff. = −4.93; P = 0.127), and OECA  approaches, with overall R-squared of 0.08  and 0.01 , respectively. On the other hand, a significant decrease in bias with the increasing proportion of exposed controls was observed for HEALTHY design , with an overall R-squared of 0.28 ,No significant associations between the proportion of exposed controls and bias were detected for SICK , malformed newborns (“SICK” design), and malformed newborns exposed to certain medications (“OECA” design).The interpretation of the measures of association obtained with the different methodological approaches using non-malformed, malformed, or exposed malformed newborns as the control groups in the research on medication teratogenicity has been extensively discussed OR calculated from the formulas (1) to (7) could be expressed as follows:B) depends on the true value (ORT) and k that indicates the effect of bias on the estimated measures of association for each particular approach (i).Beyond the control group used, these risk estimates from case-control studies of birth defects are vulnerable to both reporting bias and selection bias  estimateki>1 and the BOR will over-estimate the true TOR. If, however, malformed controls are used and at least some of the malformations in the control group were positively associated with the study medication, this introduces a selection bias so-called teratogenicity non-specific bias ki<1 and the TOR will be under-estimated. Another possibility is that cases and non-malformed controls have poor recall but with non-differential misclassification bias of exposure; or that the use of malformed controls could be to balance out the selective recall by parents of cases, then ki≈1 and the effect of bias could be considered negligible.If cases and non-malformed controls have differential missclasification bias (reporting bias), then ki term is a function of the ratio of the observed odds of exposure to the true odds of exposure in cases to that in controls. Therefore, it is equivalent to the “selection odds ratio” describe by Kleinbaum It is important to note that the (1), (5), and (8), HEALTHYOR can be expressed as follows:(M→BD)k) or quantify the magnitude of bias on the estimated HEALTHYOR, unless the measurement of prenatal exposure has been collected before the birth-defect diagnosis (a prospective cohort design as a “gold standard”).This is the classic retrospective case-control design . ConsideOur results showed high-sensibility and low-specificity to detect significant associations between each of the three medications and each birth defect using HEALTHY approach. Furthermore, the overestimations that were observed using this design were increased with higher odds ratios. Thus, we might assume that most of these associations are false positive results caused by differential misclassification bias .We have shown also that, at least in the case of acetaminophen, this bias effect inflates in average near to 300 percent the odds ratio and that the bias decrease with the increase of proportion of exposed controls. Therefore, if this bias acts in a similar way for different exposures, we expect a higher bias effect for rare medications. This interpretation is in agreement with our observations for antiepileptics and insulin, which have showed very low proportion of exposed and high odds ratios estimated by HEALTHY design for the majority of evaluated birth defects.The main advantage of using non-malformed controls in retrospective studies of potential teratogens is the possibility of estimating the “true” population odds ratio, but as it is shown in this and previous papers Our results are in agreement with the estimate of reporting bias for the retrospective ascertainment of exposure reported by Bar-Oz et al. SICK can be expressed as follows:(M→BD)≈k(M→OBD)k, and consequently:SICKOR is a measure of the relationship between the risk of the study medication causing the birth defect studied (M→BD) and the risk of the study medication producing congenital anomalies other than the birth defect under study (M→OBD). This SICKOR is then a measure of the teratogenic specificity of the medication, as previously reported T(M→OBD)OR≈1 and SICKOR will be a good approximation of the true odds ratio of interest (T(M→BD)OR).This approach uses malformed newborns as the control group. Based on HEALTHYOR, this approach affords the opportunity, under certain assumptions, to reduce the effect of reporting bias on the measure of association. Although it is important to reiterate that SICKOR is not a direct estimate of the true population odds ratio unless there is no association between the medications and other birth defects.In the present work, acetaminophen exposure showed no significant associations using SICK approach with average odds ratios around 1.0. Moreover, the observed average bias could be considered negligible (2.6%) with no relationship with the frequency of exposure. Thus, unlike (1), (2), (3), (4), (7), and (8), and OROECA can be expressed as follows:(M→BD)≈k(M→OBD)k and (OM→BD)≈k(OM→OBD)k. On the other hand, if the bias is mainly dependent on the type of birth defect, then (M→BD)≈k(OM→BD)k and (M→OBD)≈k(OM→OBD)k. Under either of these two scenarios, the measure of association can be expressed as follows:This methodology uses malformed newborns exposed to certain medications as the control group. We can develop the previous formulas T(M→BD)>1OR and T(M→OBD)OR≈1), and well-known associations are excluded from the analysis (T(OM→OBD)OR≈1), then OECAOR will be almost equal to the quotient between T(M→BD)OR and T(OM→BD)OR. Therefore, the OECAOR could be a measure of the degree of aetiological specificity of the defect under study. Then, if the study birth defect were related to other medications, the OECA approach would under-estimate the odds ratio of interest (T(M→BD)OR). However, when the study medication is a major cause of the birth defect under study (T(M→BD)>1OR and T(OM→BD)OR≈1), then OECAOR will be a good approximation of the true population odds ratio.Despite this complex relationship, if the study medication has a specific teratogenic effect  and (13), the relation between SICKOR and OECAOR can be expressed as follows:Under certain assumptions described in the formulas T(OM→OBD)OR≈T(OM→BD)OR). This was observed in our results, where good concordance correlations were found between SICK and OECA designs for atiepileptics, insulin and acetaminophen. Among the significant associations found, this was mainly evident in the case of antiepileptic and spina bifida.If the observed odds ratios for the SICK and OECA designs are similar, then it can be inferred that the odds ratio between other medications and other birth defects is equivalent to the odds ratio between other medications and the birth defect under consideration OR>T(OM→BD)OR). This was observed, for example, for insulin and ventricular septal defects although with small differences in absolute values.If OECAOR<SICKOR we would expect the opposite relationship (T(OM→OBD)OR<T(OM→BD)OR). While only minor differences were observed among the significant associations found, this was the case for, e.g. insulin and severe ear malformation, atrial septal defect, and axial skeletal malformations; and for acetaminophen and multiple joint contractures.On the other hand, if T(OM→OBD)OR≠T(OM→BD)OR), then only OECA is affected while the SICK is not.If other medication are associated with other birth defects in a different extent than with the birth defect under study (T(M→OBD)OR>1), then both SICK and OECA will under-estimate the true population odds ratios of interest (T(M→BD)OR).If the study medication is associated with other birth defects apart from the one studied OR), and for other medications and multiple joint contractures ((OM→BD)OR) in relation to the two odds ratios in the denominator, could explain this last finding.For acetaminophen exposure, no significant associations were detected using the SICK design, while an unexpected negative association was found with multiple joint contractures using the OECA approach. The higher odds ratios observed for acetaminophen and other birth defects  that showed that single-ingredient acetaminophen use during the first trimester of pregnancy does not appear to increase the risk for major birth defects Finally, the partial discrepancies between our results for the three medications evaluated and previous reports could be due to differences in the sample size, differences in reporting the exposure, differences in the definition of the exposure, differences in the use of a specific medication in different countries, and chance or true differences in exposure risks.An important issue discussed here is the selection of control group as a potential source of bias. In this regard, it is interesting to consider the strengths and pitfalls of the present work under the framework of the three principles of comparability described by Wacholder et al. in their classical series of papers Because the ECLAMC is a hospital-based program the trade-off between principles No. 1 and No. 3 is a reasonable concern, thus selection bias and information bias cannot be completely discarded. But while the selection bias could affect especially the malformed cases due to referral of prenatally diagnosed cases to hospitals serving high-risk pregnancies; we expect that the referral it be independent of the exposure assessment. Furthermore, the non-malformed controls registered by ECLAMC are not the typical “hospital controls”, that is to say, that were hospitalized for some different disease than cases, but they are selected from the total newborns from each hospital that participates in the ECLAMC program. Thus, the controls are also independently selected of the exposure assessment. In the present work, the non-malformed controls were randomly selected from all healthy newborns registered by ECLAMC in the same hospital and period of time (year) as the cases, and they showed no difference to total births with respect to maternal age, gravidity, and birth weight. In this sense, given that more than 95 per cent of births in South America occur in hospitals, it could be expected that these cases and non-malformed controls are representative samples from the same study population (“the study base”). With regards to principle No. 2, it is plausible that confounding structure may be specific for the study base of each hospital and period of time. Because the confounding by a factor is theoretically eliminated by eliminating variability in that factor, we have selected a random sample of controls born in the same hospital and same year as cases (case-control ratio of 1∶4) to try to control most of the underlying confounding structure.Another potential pitfall could be that the medications were grouped as acetaminophen, antiepileptics (irrespective of the type of medication), and insulin as a proxy for diabetes. However, we believe there is no major limitation because this study attempts to analyse the performance of case-control studies using three types of controls and does not evaluate the biological significance of the medication exposures and birth defects.The main strengths in this study are the standardised method in the diagnostic procedures for all malformed and healthy newborns included in the study, and the standardised procedure for medications reported using ATC codes. In addition, medicines and birth defects were reviewed and coded centrally.Case-control designs using three control types were compared. The approach using non-malformed controls (HEALTHY) showed a high rate of false-positive results presumably caused by differential misclassification bias. We have shown also that, at least in the case of acetaminophen, this bias decreases with the increase of the proportion of exposed controls. The methods using malformed (SICK) or only-exposed cases (OECA) showed a good concordance for antiepileptics, insulin and acetaminophen. Both approaches could yield similar results, depending on the relationship of the other medications with other birth defects (OM→OBD), and the relationship of other medications with the birth defect under study (OM→BD).SICK and OECA odds ratios cannot be considered a direct estimate of the true population odds ratio except under certain conditions. However, the SICK design could be effective to determine the teratogenic specificity of the medication, whereas the OECA approach could be useful to estimate the aetiological specificity of the defect under study.In birth defect surveillance programs that have not access to recruit non-malformed controls, the comparison between SICK and OECA designs could provide practical information to generate hypotheses about potential teratogens.Table S1Maternal age, gravidity and birth weight differences between the study sample of non-malformed controls and the total births in the period 1967–2008.(DOC)Click here for additional data file.Table S2Odds ratios, 99% confidence intervals, and P values of Antiepileptics exposure for birth defects, according to three case-control approaches: HEALTHY, OECA and SICK designs.(DOC)Click here for additional data file.Table S3Odds ratios, 99% confidence intervals, and P values of Insulin exposure  for birth defects, according to three case-control approaches: HEALTHY, OECA and SICK designs.(DOC)Click here for additional data file.Table S4Odds ratios, 99% confidence intervals, and P values of Acetaminophen exposure for birth defects, according to three case-control approaches: HEALTHY, OECA and SICK designs.(DOC)Click here for additional data file.


The global atmospheric circuit generates a permanent electric field between the Earth surface and outer atmosphere  detect electric fields around plants and learn to use them to decide whether or not to visit flowers. Using a Faraday pail to measure electric fields generated by bees and plants, the team described how a bee visit temporarily modifies the electric charge of (Petunia) flowers, suggesting that floral electric properties could be used by future visitors to assess the reward value without necessarily needing to probe the flower.Writing in e et al.  demonstrTo explore this possibility, the authors used differential conditioning in which bees were trained to associate an electrically charged feeder (30 V) with a sucrose reward (CS+) and an uncharged feeder with an aversive quinine solution (CS−). After extensive training , bees chose the rewarding feeder in around 80% of trials. Similar levels of performance were observed when bees were trained with two feeders carrying the same charge but different electric field patterns (homogeneous vs. bull's eye shape), indicating that these insects can learn both the magnitude and geometry of an electric field. Bees learned to perform even better in discrimination tasks if the two feeders differed both in color (shade of green) and their electric field pattern compared to if they differed only in color. Natural electric fields around flowers may therefore contribute to the multimodal sources of information that bees use to learn and memorize floral rewards, in conjunction with color, pattern, shape, texture, humidity, or warmth  in various contexts, including during the “waggle dance”: the figure-of-eight-shaped circuit performed by foragers upon their return to the nest to communicate the location of rewarding flowers to nestmates (Von Frisch, In another study published in the s et al.  went a sTo identify the sensory receptors involved in electroreception the authors used proboscis extension response conditioning, a classical paradigm to study olfactory learning and memory Tadeka, . HarnessThe observation that insects can sense electric fields is not new. Indeed, it has long been known that electric fields induce a range of behavioral responses in ants, cockroaches, mosquitoes, fruit flies, and bees [reviewed in Jackson et al. ]. Howeve


Childbirth is an important transitional life event, but one in which many women are dissatisfied stemming in part from a sense that labour is something that happens to them rather than with them. Promoting maternal satisfaction with childbirth means equipping women with communication and decision making skills that will enhance their ability to feel involved in their labour. Additionally, traditional antenatal education does not necessarily prepare expectant mothers and their birth support partner adequately for birth. Mindfulness-based interventions appear to hold promise in addressing these issues. Mindfulness-based Child Birth Education (MBCE) was a pilot intervention combining skills-based antenatal education and Mindfulness Based Stress Reduction. Participant experiences of MBCE, both of expectant mothers and their birth support partners are the focus of this article.A generic qualitative approach was utilised for this study. Pregnant women between 18 and 28 weeks gestation, over 18 years of age, nulliparous with singleton pregnancies and not taking medication for a diagnosed mental illness or taking illicit drugs were eligible to undertake the MBCE program which was run in a metropolitan city in Australia. Focus groups with 12 mothers and seven birth support partners were undertaken approximately four months after the completion of MBCE. Audio recordings of the groups were transcribed verbatim and analysed thematically using the method of constant comparison by all four authors independently and consensus on analysis and interpretation arrived at through team meetings.A sense of both ‘empowerment’ and ‘community’ were the essences of the experiences of MBCE both for mothers and their birth support partner and permeated the themes of ‘awakening my existing potential’ and ‘being in a community of like-minded parents’. Participants suggested that mindfulness techniques learned during MBCE facilitated their sense of control during birth, and the content and pedagogical approach of MBCE enabled them to be involved in decision making during the birth. The pedagogical approach also fostered a sense of community among participants which extended into the postnatal period.MBCE has the potential to empower women to become active participants in the birthing process, thus addressing common concerns regarding lack of control and satisfaction with labour and facilitate peer support into the postnatal period. Further education of health professionals may be needed to ensure that they respond positively to those women and birth support partners who remain active in decision making during birth. Childbirth is an important transitional life event, yet there is a large body of literature reporting maternal dissatisfaction with labour and childbirth experiences-10. In pPromoting maternal satisfaction with childbirth, then, is linked to women accessing relevant information to make informed choices rather than simply consenting to decisions relevant to their labour and birth-15. BeinIn addition to neglecting skills acquisition, traditional childbirth education does not actively promote prenatal mental health, both of expectant mothers and their birth support partners. This is of concern due to the relationship between prenatal mental health and postnatal maternal outcomes and foetal development; as well as child development-19. GiveOne approach that holds significant promise in promoting psychological resiliency is the use of mindfulness-based interventions,22. MindMindfulness Based Childbirth Education (MBCE) is a novel combination of skills-based antenatal education and Mindfulness Based Stress Reduction (MBSR). It is an eight week, one session per week program and was run as a pilot intervention by a childbirth educator who is also a specialist antenatal yoga and mindfulness meditation teacher. Each session lasted approximately 2.5 hours and was for both expectant mothers and their birth support partner. Participants had homework CDs related to mindfulness meditation and were encouraged to undertake daily practice of techniques learnt. Readings related to antenatal education were also assigned, including review articles from the Cochrane Library. Results of its feasibility and outcomes of the MBCE protocol for first time mothers are reported elsewhere . Participants’ experience with the classes is the focus of this paper.A generic qualitative approach using foTo be included in the study, pregnant women (between 18 and 28 weeks gestation) had to be over 18 years of age, healthy, nulliparous with singleton low-risk pregnancies and not taking medication for a diagnosed mental illness or taking illicit drugs. The study took place in a metropolitan city in Australia with participants recruited through a range of strategies including newspaper articles, online pregnancy forums, email lists and flyers at hospitals, birth centres and organisations that offer antenatal education classes. Eighteen expectant mothers ) and their birth support partners completed MBCE. Sixteen expectant mothers were married or living with a partner, 14 were tertiary educated - including four with a postgraduate qualification, eight planned to use obstetrician-based care, three opted for midwife-based case and seven chose some form of shared care. Ten delivered in a private hospital. In terms of characteristics of labour, 10 were spontaneous with 11 births by caesarean section. All women reported establishing breastfeeding after birth. Twelve new mothers and seven birth support partners (6 partners and one new mother’s mother) participated in the focus groups which occurred approximately four months after completion of the program to ensure all participants were at least six weeks post-birth.Two focus groups lasting approximately forty five minutes were undertaken – one for mothers and one for their birth support partners. It was important to obtain the perspective of both the mother and the birth support partner as their experiences and perceptions of the program may have differed. Concurrent but separate groups ensured that both members of each mother/birth support partner dyad felt confident to speak openly, particularly if their perceptions and experiences differed from each other. The focus groups were facilitated by experienced focus group facilitators (YH and CF). Written consent to participate and for the audio recording of the group was obtained from each participant.Following verbatim transcription, data were analysed thematically using the method of constant comparison-26. As sEthical approval to undertake the study was received from the Human Research Ethics Committee of the University of Western Australia.A sense of both ‘empowerment’ and ‘community’ were the essences of the experiences of MCBE for mothers and their birth support partners. The interactive and experiential delivery of the MBCE program facilitated the empowerment of each individual and couple during the birthing process. Additionally, among the group a sense of community was fostered and maintained, and extended beyond the MCBE sessions and birth of participants’ babies. Notions of ‘empowerment’ and ‘community’ thus permeate the themes identified during data analysis for this study which were labelled ‘awakening of my existing potential’ and ‘being in a community of like-minded parents’. Although, for the purpose of clarity, the themes are presented discretely, they are inextricably linked in dynamic and complex ways. Direct quotes have been used throughout to illustrate how participants’ experiences support the themes, and numbers (i.e. mother 1 or birth support partner 3) have been used to ensure confidentiality.‘Awakening of my existing potential’ relates to the feelings and expectations, both of the mothers and their birth support partners, about their competence, abilities and understandings of what would be required of them during childbirth. These feelings and expectations also pattern their reflections on the MBCE sessions and of labour and birth. Participants reflected on their feelings prior to attending MBCE and described how they wanted to fulfil their respective roles during the birthing process, but did not have a real understanding of exactly what that role might entail. As one mother stated:…at that point of my pregnancy which was two months … , I don’t feel I had the knowledge and … I had no expectations of what the course was actually going to be about and so it was just improving, building my knowledge and giving me the strength and ability to be in control of the situation and so it [attending MBCE] was. just more about building that understanding of what it all meant to be pregnant and to have a baby and all those sorts of things. (mother 3).Prior to commencement of MBCE, birth support partners in particular, described being unaware of exactly what their role during the birthing process would be. The feelings of birth support partners are exemplified in the following quote:I came in [to begin the MBCE program] thinking “what do I need to know?” But yeah I didn’t have… expectations of … all this stuff I can learn and I was sort of just blissfully unaware of my role. (birth support partner 3).Our finding is consistent with that of Johnson who founFor an experienced birth support partner, (the mother of a pregnant woman), awakening of existing potential was not related to being unaware of what her role in the birthing process may entail, rather it was a reminder, or in her words, a ‘rekindling’ or a remembering of knowledge of options and experiences during birth:I’ve always been aware of…alternatives [for childbirth] and things like that, but I think it was just…rekindling those sorts of things, those feelings I’d had. (birth support partner 6).An important part of awakening existing potential for the mothers was the development of confidence within themselves and their body’s capacity to birth:I think my expectations changed throughout the course as well… My expectations upon myself to have a labour and deliver this baby, you know, feeling very empowered. So it was really great to see… as we went along and just the confidence I think has grown in the group and by the end of it [MBCE] everyone was like “yes, you can do this”. So it was very transitional I think from the outset. (mother 2).During their actual labour and birth, the mothers’ confidence was realised through their using the techniques learned during MBCE to stay in the moment and maintain a sense of control. One mother describes it as follows:I wouldn’t have thought I could have done this [birthed], but after [MBCE] ] I knew I could do it and I was doing this [mindfulness] and I just found it very good to be with myself at this stage [during labour]. (mother 4).Despite both mothers and their birth support partners benefiting from MBCE, however, it was the women who were the drivers behind their attendance.For me it went “oh yeah” sure, I’ll do this [attend MBCE sessions] ‘cause I kind of have to. (birth support partner 4).The use of the term ‘drag’ was quite commonly used, both by mothers and birth support partners, as the means by which the mothers ensured attendance by their birth support partners, reflecting common perceptions of how the decision was made to attend:I actually had to drag my husband along to the first session here, but after the first session he was wanting to come. So that was good (mother 7).After initial attendance, birth support partners as well as the mothers could see the real value in attending MBCE: I just found it [MBCE] incredibly useful and valuable and I’m so glad I got dragged along. (birth support partner 1).It was clear from the findings of our study that the women wanted their partners fully involved in the experience of birth, not only because of the support they could provide during labour, but also because of the transitional nature of their relationship – from being a couple to becoming a family. These findings are echoed in the literature. AlthougDuring labour and birth, it was apparent that the awakened potential of mothers and birth support partners was enacted through being informed, active and questioning in the birth process, and working as a team and staying calm.The knowledge of the birthing process and options for birth, and the confidence mothers and birth support partners gained through the pedagogical approach taken in MBCE enabled them to be active rather than passive participants in the birthing process. The overall effect of this is captured in the following quote from one of the birth support partners:I think the empowerment for us was we had this knowledge and were confident enough to say to the doctor “let’s wait”… you know, “Can we do this?”. Otherwise if we hadn’t of (sic) gone to this course, I think we would have gone there [hospital] and just like “whatever you say doctor”, you know…“whatever you recommend we’ll do”. This just let us sort of make our, make it feel like it was more our decision than being told what to do. (birth support partner 4).The overall effect is also captured by a mother:I was being induced by that Thursday morning and if I hadn’t done this course, like I was booked in and I was in there thinking “Why? Why am I being induced and I didn’t need to be?” And I eventually, actually with the help of my birth partner rang and said “nah, we’re not having the induction” and went into labour spontaneously that night……it [MBCE] probably changed the outcomes of my labour which I was really happy with. (mother 2)As a result of attending MBCE mothers and birth support partners had the confidence to discuss issues with health professionals and were able to ask and respond in an informed way. For the majority of participants, this resulted in a positive response from health professionals including for example, answering questions and providing information in a truthful and respectful manner:If she (mother) asked a question they [health professionals during birth] answered it truthfully. So they didn’t leave, even the negative things – like with the epidural “well this can happen, X percentage in every, you know”. So at least there was an awareness. (birth support partner 6).Additionally, health professionals – particularly midwives – were open to accommodating the needs and wishes of the mothers and birth support partners:We [mother and birth support partner] had midwives and our midwives were really receptive to what we’d learnt and brought to the table and they were really supportive as well with what we wanted to try. (birth support partner 2).Thus many women and their birth support partners in this study were treated with respect by caregivers during birth. There is global evidence in the literature that women’s satisfaction with experiences of childbirth is strongly correlated with a woman’s sense of control during labour,5,37,38 It is important to note that the dimension of control that has shown to be most important for satisfaction with childbirth is the one that staff members are most able to facilitate: the way that women perceive they are being treated. That is, women want to be treated with respect and as an individual – as a subject and not an object – and haA small number of participants in this study, however, described how being informed and confident strained their relationship with attending health professionals:I was still very flexible and I was open to options, but because my birth plan said only Caesarean in case of emergency my labour team was too scared to offer me a Caesarean almost, because they knew I didn’t want it and because I had, I was never going to be able to deliver naturally. I actually think I scared them off and I can’t help but wonder if I hadn’t been so focussed on that, whether or not I might not have had to have my baby into special care nursery, and all the scheme of events that ended up happening might not have happened. (mother 5).This finding suggests that, despite the plethora of research highlighting the importance of women being involved in decision making, health professionals may be accustomed to passive and accepting ‘patients’ and find it more challenging when a woman and their birth support partner are more actively engaged in the decisions around the labour and birth process.Not only those who experienced an uncomplicated labour and a normal vaginal birth felt they were active and well informed in the birthing process. For those mothers whose birth did not proceed as they had hoped - for a number of reasons - also reflected positively on the birthing experience:I also thought that it [MBCE] made me think about little things that I might not have considered which made my labour experience better….And despite the fact that I really had what most people would say was a horrible labour experience and a very painful labour experience, I still came out of it going “you know what. I’m really glad I had that experience and I feel empowered by that experience”. (mother 5).Thus, our study provides further evidence for the growing literature on the importance of choice and being in control for satisfaction in the birthing process, irrespective of whether what mothers hoped for in childbirth was realised or not.Being mindful adds a further dimension to our understanding of the importance of control for satisfaction with childbirth. For the participants, being mindful related to being aware of choices that were made as they progressed through labour.You can have this idea of what you want, but you need to remain flexible and as long as you are aware of the choices that you’re making as you progress, which is about being mindful and being mindful of this… choice that I’m faced with right now and I can go either way. Even if you’d have to go the way that it wasn’t in your plan, you can come out of it on the other side thinking that I had this really positive experience and I’m really happy with it. (mother 2).Participants contrasted what they learned at MBCE and how it was delivered, with more traditional hospital-based antenatal classes. They considered that attendance at MBCE provided information that is not often provided during antenatal classes run through hospitals on a range of options they could avail themselves of during the birthing process. Participants were also exposed to different scenarios which may occur during labour and birth and rehearsed how they might respond through the use of role-play and rehearsal.I attended the [antenatal] classes at [name of hospital]… I found them very superficial … very small snippets of information and not a lot of opportunity to discuss and share different points of view. So I found that this workshop [MBCE] gave me a lot more empowerment and a lot more information about alternate courses of action and different scenarios, so I’d be prepared [during labour]. (mother 3).The use of experiential learning and the provision of a wide range of information engaged the women’s birth support partners. This pedagogical approach was in contrast to and counteracted some of the weaknesses of more traditional antenatal classes where a lack of discussion or group work was a consequence of their didactic style of delivery. ImportaThere is evidence to support the provision of non-traditional childbirth education programs such as MBCE with the literature suggesting women and their birth support partners are seeking more than the traditional approach to antenatal education and information. For example, participants report wanting a range of teaching approaches, to cater for a range of learning styles,43,44. AThe sense of empowerment that resulted from the knowledge and confidence gained during MBCE enabled mothers and their birth support partner to stay calm during labour and birth. As two birth support partners reflected:I know she [mother] did [felt empowered] which made me just feel calm then. (birth support partner 1).Another partner echoed this sentiment: In a sense having that calmness, [was due to] just that fact that you had that bank of knowledge.…Whereas if you didn’t have the bank of knowledge…then it would have, maybe been worse (birth support partner 6).Being mindful and putting into practice the mindfulness techniques taught during MBCE was also seen by participants as supporting them to remain calm during the birthing process:I used it [mindfulness] during the birth a bit…It just got us to stay calm, especially when things started going a little bit wrong, just reminded us to calm down again and put your head down, calm down again and keep going. (birth support partners 5).The metaphor of the eye of the storm was used by a number of participants as a way of describing their sense of calm in what they perceived as an ‘out of control’ external environment. The notion of individual control within an uncontrollable environment was broadly discussed by both mothers and birth support partners. For example:It [mindfulness] provided me with….a sense of calm and a sense of being in control, even though everything around me was out of control. (mother 7).As the previous quote shows, remaining ‘calm’ is also constructed as being ‘in control’ – an important influence on birth satisfaction. The women reported using the techniques for relief from pain and during contractions – two areas that Green and Baston examined in their study of 1,146 women at one month antenatally and six weeks postnatally birth….And I could provide support [to her]. just kept us informed and knowing you know what questions to ask and when. (birth support partner 4).There is evidence in the literature that where the birthing woman and her birth support partner present as a unified ‘team’, healthcare professionals are more likely to view them as individuals, where the birth support partner has a unique role, and as an interdependent couple. SupportWhen it came to early parenting, however, participants reported being less prepared than they were for birth for the challenges they were presented with. As one mother reflected:Even though my birth experience was horrific I felt empowered through the whole thing. As soon as he was born I lost that kind of empowerment. I didn’t know what was right, what was wrong, what my role was, when to question, when not to question. So I actually found that that almost detracted a little bit from the birth experience and what I learnt through the course. (mother 3).Mindfulness training was seen as valuable in restoring calmness in the face of an unsettled baby and, as such, an important tool that new parents could use to regain a sense of calm and control:When the child’s screaming for hours on end, you deal with it a lot better [using mindfulness] than you might have otherwise….Sometimes I can tell what … path I might have gone down otherwise if I hadn’t done it ‘cause there are times where you can be very stressed by a screaming baby. (mother 1).It was also seen as valuable for being in the moment with a newborn baby. As one mother noted:I found it [mindfulness] really helpful after I gave birth. For the first six weeks I think, just when he [baby] doesn’t know me and I don’t know him and sitting on the couch, like for hours, in the middle of the night, just then being able to be in that moment and know where I was. That’s when I felt that I used the tools the most. (mother 5).A number of birth support partners also continued to use mindfulness in the postnatal phase, suggesting MBCE has value beyond birth. As one birth support partner stated:I think the mindfulness training was…one of the most valuable things. For me that’s one of the things that I feel like you keep after, you sort of keep on using….I tend to use it in other situations as well. (birth support partner 1).The saliency of mindfulness techniques in the postnatal period is also noted by Duncan and Bardacke who makeI’m normally fairly relaxed …every now and then when I’m eating I’ll try and eat slower. That’s about it. (birth support partner 3).This suggests that the ongoing use of mindfulness techniques among participants postnatally was not uniform.It was through the interaction that occurred in the MBCE sessions that participants got to know each other and developed bonds with other soon to be parents. From this, a sense of ‘community’ was borne.I loved hearing other people talking and challenging concepts and I think I got the most out of that, just the group interaction and participation. Yeah, it was really good. (mother 3).Participants in MBCE valued the opportunity to share experiences and valued the knowledge that came from hearing the views and opinions of others. The interaction was considered particularly useful where individuals or couples were struggling with particular issues, as hearing that others were, or had experienced similar challenges was validating and learning how they overcame them was instructive:It was interesting to hear either “this is what I’m struggling with”, then you’d kind of , “ok”, then I could think about that, or hear someone say “who’s struggling with this?” and you think “that’s the same - we have” and you kind of feel a bit oh, “ok”. (birth support partner 5).The opportunity that the MBCE program provided for the sharing of information and experiences for the participants is reflected in the literature. Sharing experiences of pregnancy is argued to promote relationships among women,50. Not Hearing that others were experiencing similar challenges was also considered by participants in MBCE to reduce any sense of isolation:Well you don’t feel isolated. If someone else is burdened, I might completely know what they’re feeling, or whatever. (birth support partner 6).The pending birth of their baby was appropriately a ‘top-of-mind’ issue for the participants in MBCE and discussions about options for, and opinions about, the place of delivery was raised as valuable by those who had not yet made a decision:.When we were deciding where to have the baby and then hearing where other people were having babies I think we got better ideas about maybe going elsewhere or other places that, that hearing people’s recommendations and stuff. (birth support partner 2).Having similar experiences of pregnancy and preparing for birth was the common ground on which participants were able to initially relate to each other and bond, but the connections became social as well. As one participant noted, the bonds were such that week after week, you know, it became a bit of a club I suppose. (birth support partner 6).The sense of community that permeated both the MBCE sessions continued well beyond childbirth. For example, a Facebook site was established which enabled the virtual flow of information and support between mothers and, for one new mother, filled the void after birth until she was able to join a new mothers’ group:For me my mother’s group hasn’t started and it doesn’t start ‘til next February (2 months hence) so I felt, I have felt very isolated in that. There hasn’t been anyone with a baby the same age as what I’m going through, the same things at the same time so I can say “hey, my baby’s got a rash. What are you guys using? I’m using this … on my baby… is that helping”. And we’ve actually some of us have done that on the Facebook website. Yeah, we’ve been sharing… tips so that has been a good thing. So definitely have now…having like a group website set up I think has been really helpful, ‘cause we’ve shared different tips and things and that’s been helpful for me again. (mother 5).Research attests to the expansion of social networks that results from attendance at antenatal classes. In a national cohort study of 1,197 participants in Sweden, researchers found that, although participation in antenatal classes had no impact on first-time mothers’ experiences of childbirth, they were instrumental in expanding the women’s social network. The exiThrough the innovative combination of MBSR and a pedagogical approach that encompassed role-playing and discussion, MBCE participants felt empowered during birth and able to maintain a sense of control even if the birth did not proceed as planned. A sense of being in control was apparent both for birthing mothers and their birth support partners. Thus, MBCE has the potential to address common concerns in the literature regarding the relationship between a sense of control and satisfaction with the birthing experience. It also has potential to engage the birthing mother’s birth support partner in a meaningful way in antenatal education and birth. The sense of community that developed across the program was strong and was sustained into the postnatal period. This enabled the new parents to continue to support each other during early parenting – another area highlighted in the literature that traditional antenatal education inadequately addresses.The experiences of participants in this study suggest that health care professionals generally responded positively to them, when proposed procedures were questioned or more information was sought. This, however, was not always the case indicating that further professional development and education should be undertaken with healthcare professionals. Because health care professionals operate in line with organisational policies and culture, work undertaken at the institutional level is also necessary to ensure that birthing women and their birth support partners are listened to and have their input valued, that is, an experience that becomes the norm across healthcare settings.The findings reported have limitations in that they are from a pilot study with participants homogenous in terms of their socio-demographic characteristics and geographic location. Therefore, further research is required on a larger scale and across a more diverse cohort of expectant mothers, including multiparous women, and their birth support partners to provide stronger empirical evidence of the efficacy and effectiveness of MBCE in terms of facilitating satisfaction and a positive birth experience for the childbearing women and their birth support partners.MBCE: Mindfulness-Based Childbirth Education; MBSR: Mindfulness-Based Stress Reduction.The authors declare they have no competing interests.CF – facilitated focus group, analysed data, drafted manuscript, YH – facilitated focus group, analysed data, provided critical feedback on manuscript, SB – analysed data, provided critical feedback on manuscript, JB – analysed data, provided critical feedback on manuscript. All authors read and approved the final manuscript.CF has a background in sociology is a teaching and research academic in the School of Population Health at the University of Western Australia. Her main research is in the area of psychosocial women’s health.YH is the Professor of Midwifery, a joint appointment between Curtin University and King Edward Memorial Hospital. Her research interests include antenatal education, perinatal mental health and breastfeeding.SB is a midwifery clinician and academic. The current focus of her scholarly work is on organisational learning in relation to innovation and the adoption of evidence in healthcare settings.JB is a childbirth educator and specialist pregnancy yoga teacher and trainer. Her research focus on mindfulness, modern yoga studies and feminist philosophy.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/12/126/prepub


Early genetic and environmental factors have been discussed as potential causes for the high prevalence of asthma and allergic disease in the western world, and knowledge on fetal growth and its consequence on future health and disease development is emerging.This review article is an attempt to summarize research on fetal growth and risk of asthma and allergic disease. Current knowledge and novel findings will be reviewed and open research questions identified, to give basic scientists, immunologists and clinicians an overview of an emerging research field.PubMed-search on pre-defined terms and cross-references.per se. Several studies have found a correlation between a rapid weight gain after birth and development of asthma or wheezing in childhood.Several studies have shown a correlation between low birth weight and/or gestational age and asthma and high birth weight and/or gestational age and atopy. The exact mechanism is not yet clear but both environmental and genetic factors seem to contribute to fetal growth. Some of these factors are confounders that can be adjusted for, and twin studies have been very helpful in this context. Suggested mechanisms behind fetal growth are often linked to the feto-maternal circulation, including the development of placenta and umbilical cord. However, the causal link between fetal growth restriction and subsequent asthma and allergic disease remains unexplained. New research regarding the catch-up growth following growth restriction has posited an alternative theory that diseases later on in life result from rapid catch-up growth rather than intrauterine growth restriction Asthma and allergic disease are multifactorial. Several mechanisms seem to influence their development. Additional studies are needed before we fully understand the causal links between fetal growth and development of asthma and allergic diseases. The prevalence of asthma and allergic disease has increased in many nations around the world This area of research is quickly expanding and several mechanisms have been proposed to influence fetal growth. The aim of this article is therefore to summarize current knowledge on fetal growth, and its association to the development of asthma and allergic disease, in order to identify the most urgent research questions and their clinical implications.A PubMed/Medline search was performed with the following MeSH-terms: [children OR child OR childhood] AND [birthweight OR birth weight OR birth length OR head circumference] AND [atopy OR asthma OR atopic OR allergy] AND [fetal programming OR fetal growth] and original articles identified and reviewed. Articles that reported on birth characteristics or fetal growth and asthma/allergic disease in the offspring, particularly those published within the last 10 years, were included and placed in sections related to subject; birth characteristics and asthma/respiratory disease in the offspring, birth characteristics and allergic disease in the offspring; mechanisms that influence fetal growth and their association to asthma or allergic diseases, and catch-up growth or post natal weight gain after fetal growth restriction in association with asthma or respiratory disease. Cross-references were reviewed and additional articles were checked.The literature search identified 107 original articles, 29 of which were included in the article. Approximately 350 additional cross-references were reviewed and 24 of them were found relevant. Several studies have looked at associations between anthropometric measures  and asthma or allergic diseases in childhood or adolescence. Most studies have shown a correlation between low birth weight P < 0.01).A prospective population-based study followed children born in large American cities through maternal interviews at 1 and 3 years of age A prospective birth cohort study in Finland found no correlation between gestational age and asthma, but children with a birth weight below 2,500 g had a higher risk of asthma, 12% vs. 8% for those with a higher birth weight In a prospective birth cohort study from Boston, children born ≥ 36 weeks of gestation, who had one parent with asthma, allergy or hayfever, were followed to the age of 6 years Some studies have found that the association between low birth weight/gestational age and asthma/respiratory illnesses seems to weaken with time in utero and during childhood, personal smoking, socio-economic status, asthma and gestational age. Children with larger weight gain between birth and age 3 years were more likely to have impaired lung diffusing capacity, indicating that postnatal growth also has an impact on adult lung function.The associations between birth weight, postnatal growth and adult lung function were assessed in an unselected prospective birth cohort by A prospective birth cohort study assessed the correlation between low birth weight for gestational age and lung function in infancy P < 0.05) for each millimetre increase in CRL and the odds of having asthma ever decreased by 5% , indicating that reduced fetal size in the first and second trimester is associated with reduced lung function and increased asthma symptoms at age 5 years. In the recently published 10-year follow-up of the Aberdeen birth cohort, the associations between fetal measurements and asthma remained In the Aberdeen birth cohort study, pregnant women were recruited at a routine ultrasound during the first trimester P = 0,046).Another group lead by Pike et al. studied fetal growth during different periods in pregnancy in 1548 full-term children 2010. Birth weight and length were measured at birth and growth rates were calculated using the results from the antenatal ultrasound examination. The children were followed up to the age of 3 years. A low growth rate during week 11–19 was associated with an increased risk for non-atopic wheeze (10% per SD decrease) whereas a low growth rate later on in pregnancy (week 19–34) seemed to be associated with atopic wheeze  environmental and genetic factors. Twin siblings share genes , intrauterine exposures, maternal factors and early environment. In addition, twins often differ in birth weight and body mass index (BMI) over time in utero. Another twin study from Sweden on adults We have recently shown an increased risk of asthma with a 1000-g decrease in birth weight, OR 1.6 (95% CI 1.4–1.8) This area is not as explored as for asthma. Most studies have found a positive correlation between gestational age and atopy A cross-sectional study reported a non-significant positive correlation between birth weight, birth length and gestational age and subsequent atopic sensitization Whether or not fetal growth was associated with asthma and atopic dermatitis was examined in a population of male military conscripts in Denmark Katz et al. studied the presence of hayfever, asthma and eczema in a large cohort of adolescents in Sheffield, United Kingdom, by linking information on birth characteristics to questionnaire data on present symptoms in 11-to-16-year-olds 2003. Hayfever was positively associated with anthropometric measurements such as head circumference OR 1.2 (95% CI 1.0–1.5) and birth weight OR 1.2 (95% CI 1.0–1.4), and also with gestational age; children born before 37 weeks had higher risk of hayfever and those with GA > 41 weeks had lower risks, although not significant. No correlation was found between anthropometric measures and asthma or eczema. Carrington et al. drew the same conclusion regarding eczema 2006 while Turner et al. found a correlation between improved fetal size between first and second trimester and a higher incidence of eczema at the age of 10 years OR 2.5 (95% CI 1.2–5.3) 2011.P = 0.84). These results, combined with our previous findings of an association between low birth weight and asthma In a twin study, we recently found a correlation between birth weight and atopic eczema Several mechanisms have been suggested to determine fetal growth, most often related to the feto-maternal circulation. Disturbances in the development of the placenta and umbilical cord, on a geneticSeveral studies have shown an association between offspring asthma and low socio-economic statusMaternal smoking causes fetal growth retardation Previous studies have proposed that pregnancy could be associated with a skewing of the immune system from a Th1-type to Th2-type response at the maternal-fetal interface. This skewing may be an essential factor for implantation of the embryo as well as pregnancy itself, by preventing a rejection of the antigenic fetus by the mother's cell-mediated response of Th1 cells Placental development begins when cytotrophoblast cells attach the embryo to the uterine wall Preeclampsia is a severe complication affecting 2–8% of pregnancies world-wideIn vitro and in vivo studies have shown increasing levels of soluble fms-like tyrosine kinase 1 and soluble endoglin and a decrease in the level of vascular endothelial growth factor and placental growth factor. Dysfunctional endothelial cells release vasoactive mediators which perturb haemodynamic function by shifting the balance to vasoconstriction with decreased organ perfusion, oedema and hypertensionAltered levels of angiogenic factors are believed to have an important role in the development of preeclampsia For the fetus preeclampsia can result in intrauterine growth restriction (IUGR) and preterm delivery. IUGR affects about 3–5% of all pregnancies and is believed to occur during the second half of pregnancy By measuring the uterine artery mean resistance index with Doppler velocimetry during the first trimester, Dugoff et al. found that women with a high mean resistance index had a fivefold higher risk of developing IUGR later in pregnancy (95% CI 1.6–8.7) 2005. This may be a way of identifying patients at risk, who can be followed more closely during the rest of the pregnancy.One group of children at risk for IUGR is twins and especially monochoriotic twins. Several studies have found that an unequal distribution of the placenta is a major reason for differences in birth weight and selective IUGR in monochoriotic twin pregnancies In accordance with the finding that allergic disease is associated with shorter waiting time to pregnancyResearch in fetal programming of subsequent disease susceptibility is increasingly focusing on the paradigm that gene regulation beyond the DNA-sequence – epigenetic modulations – could play a key role in the aetiological link between fetal growth and asthma and allergic disease The transformation of genotype into asthmatic and atopic phenotypes may also be influenced by imprinted genes, such that the predisposition to asthma and allergic disease is present when transferred from the mother, but silenced when transmitted by the father, making maternal history of asthma and allergy more important for the offspring's subsequent morbidity Fetal growth impairment is associated not only with disturbances in the placenta, but also with umbilical aberrations. In velamentous cord insertion, the umbilical cord inserts into the fetal membranes, unprotected by Wharton's jelly (WJ), and then travels within the membranes to the placenta instead of inserting into the middle of the placenta as it develops Wharton's Jelly is a gelatinous substance, normally surrounding the umbilical cord, which helps resist external pressure and serves as a physical buffer, regulating the feto-placental circulation Umbilical cord cytokines are thought to play a key role in regulating the maturation of the fetal immune system, thus conditioning it for postnatal responses against allergens and pathogens. Previous studies have attempted to evaluate the relationship between umbilical cord cytokines, fetal growth One study of umbilical cord cytokines and the risk of asthma and allergic disease showed that higher concentrations of IFN- γ were protective against asthma in 6-year-old children, but not against atopy, and that higher concentrations of TNF were protective against atopy, but not asthma in utero, measured as restricted fetal growth, can be linked to mismatched development of thymus relative to immune function The thymus is a key organ in the human immune system and has long been known to be affected by fetal growth restriction and postnatal malnutrition One mechanism that has been much discussed is dysanapsis, the fact that airway size is not necessarily related to lung size Catch-up growth in childhood is a strong predictor of non-communicable diseases in adulthood P < 0.01). The respiratory rate rose by 5% per SD increase in infant weight gain (P < 0.01). This is in line with the concept of mismatch, where epigenetic mechanisms have been suggested to play a role Although impaired fetal growth has an independent effect on childhood asthma To study if infant weight gain patterns after birth were associated with asthma development later in childhood, a randomized prospective study on 2-to-3-year-old children at risk of asthma was performed in the CARE network A birth cohort study that investigated children at birth and at the age of three found that the children in the lowest birth weight group had an increased risk of respiratory illness Most prospective studies on fetal growth follow women from early pregnancy onwards. However, both environmental and genetic factors are known to influence fetal growth and some of these factors might change as the women become pregnant. To address this problem, the Southampton Women's Survey recruited 12 583 women between the ages of 20 and 34 years, measured their characteristics pre-pregnancy, and followed those who got pregnant and also their future children P < 0.05). However at follow-up at the ages of 6 and 11 years this was no longer significant. It is possible that the weight gain of infants need to be more closely monitored in the future, especially those at risk of developing diseases  due to the fact such randomization is ethically and biologically impossible. Most studies are based on data collected retrospectively in utero than singletons Since twins have the same gestational age and often differ in birth weight When studying disease-discordant twins, these types of confounding factors can be taken into account since twins are generally brought up together and analyses within-twin pairs control for unmeasured environmental and socio-economic factors during childhood.Fetal growth retardation can be detected ultrasonically and the fetus closely monitored until birth. Children at risk can thus be identified early and followed over time to receive proper medication early if symptoms develop.To further understand the interplay between genetic and environmental factors in childhood and adolescent asthma and allergic disease, prospective studies should be performed with well characterized subjects. A better understanding of the effect of fetal growth is a key to developing new diagnostic tools as well as prophylactic interventions to reduce the burden of asthma and allergic disease. Twin studies play an important role in the detection of undiscovered genes, but may be even more central in answering the most challenging of all questions: how the environment interacts with genetics in these two outcomes. Future studies may also include women from pre-pregnancy and follow them prospectively during pregnancy and delivery, and follow the offspring in early life, to ascertain measures of fetal growth  in relation to subsequent asthma and allergic disease