Low birth weight is strongly correlated with an increased risk of adult diseases. Additionally, low birth weight might be a risk factor for asthma later in life.A systematic literature search of the PubMed database from 1966 to November 2013 was conducted. The criteria for inclusion of papers were as follows: case–control or cohort studies; the odds ratio (OR) or risk ratio (RR) estimates with the corresponding 95% confidence intervals (CIs) were presented, or there were sufficient data for calculation; and studies were published in English up to October 2013. Random-effect and fixed-effect meta-analyses, meta-regression, and cumulative meta-analysis were conducted.Thirteen cohort studies and 1,105,703 subjects were included. The overall pooled RRs (95% CIs) of asthma risk for low birth weight were 1.162  and 1.152 . In stratified analyses, the effect of low birth weight on childhood asthma was strong, particularly in studies conducted in Europe, those with a small sample size, and those published recently. A meta-regression analysis did not find significant determinants.This meta-analysis shows that low birth weight significantly increases the risk of childhood asthma. Asthma is a serious global health problem. Worldwide, an estimated 300 million people are affected by asthma. The global prevalence of asthma ranges from 1 to 21% of the population in different countries . PreviouThe fetal origins of adult disease hypothesis proposes that fetal adaptation to an adverse intrauterine environment could lead to permanent changes in individual physiology and metabolism . There iWe performed a systematic literature search of the PubMed database from 1966 to November 2013 using the following search command: birth weight and “asthma or wheezing or wheeze”. The abstracts identified by this search were screened to eliminate the obviously irrelevant abstracts . The criteria for paper inclusion were as follows: (i) case–control or cohort studies that focused on the association of low birth weight with childhood asthma (less than 16 years old); (ii) studies that presented the odds ratio (OR) or risk ratio (RR) estimates with the corresponding 95% confidence intervals (CIs), or sufficient data for calculation; (iii) normal birth weight as the reference category; and (iv) studies published in English up to October 2013. All publications providing sufficient information regarding the relation between low birth weight and childhood asthma were included, irrespective of whether this issue was their primary or secondary objective. We excluded studies that used asthma-like symptoms or other manifestations of respiratory impairment as an outcome, such as wheezing.The outcome of interest was childhood asthma. The definition of asthma was based on a physician’s diagnosis, or a history of asthma reported by their parents. Our primary predictor variable was low birth weight, which was defined as a birth weight of less than 2500 g. For any study to be included in the present study, its outcome and predictor definitions had to be consistent or adaptable with our definitions. Both outcome and predictor variables were dichotomous.Four investigators independently carried out data extraction of the following items: authors, publication year, study design, country, population age, diagnosis of asthma, adjustment for confounding , and effect size and corresponding estimates with 95% CIs. Two reviewers completed the quality assessment independently. A set of structured criteria modified from previous studies  were used to complete the quality assessment of publications. A higher score indicates higher quality. In the case of disagreement of extracted data, discrepancies were resolved by discussion and achieved consensus.2) value, which represents the percentage of total variation across different studies due to heterogeneity rather than chance. I2 values of 25%, 50%, and 75% have been related to low, moderate, and high heterogeneity, respectively [2 index ≥50%), and otherwise, the fixed-effects model was used. Subgroup analyses were stratified by geographic area and adjusted for the major confounder. Meta-regression analysis was used to investigate the potential sources of heterogeneity. Cumulative meta-analysis in the order of publication year was conducted to check homogeneity of the results. Publication bias was assessed by using the funnel plot, the rank correlation test, and the graphical test [We abstracted the multivariate-adjusted risk estimates (OR or RR). The unadjusted risk estimates were calculated using original data when the adjusted was unavailable. The CIs were transformed to a log scale and then the standard error was calculated. A pooled summary relative risk was calculated according to the fixed-effects model and a random-effects model. Statistical heterogeneity was assessed with the I-squared . Birth weight in the other two studies was less than 3000 g , 18. GenTwo studies reported data for the effect of low birth weight on the risk of future asthma as adjusted ORs , 16. The2 = 40.2%, P = 0.066), respectively. Both models showed similar summary effect estimates, indicating a significantly increased risk of asthma in relation to low birth weight. Table Five of the 13 estimates were directly from the original studies, and eight were transformed from the information available to comply with our categorization used in the meta-analysis. Figures 2 value representing the overall between-study heterogeneity was 40.2% (P = 0.066), which was moderate and acceptable in the present meta-analysis. Clinical heterogeneity among subgroup studies is shown in Table P >0.05, Table The ICumulative meta-analyses of all of the studies showed that the estimates gradually became consistent, and the corresponding CIs narrowed down in the order of publication year Figure . We alsoWe assessed the potential publication bias by using a funnel plot Figure . The funIn the present meta-analysis, 13 cohort studies and 1,105,703 subjects were included. By conducting a systematic review, we obtained an estimate that suggests that low birth weight among children increases the risk of future asthma. Children with low birth weight have an approximately 16% higher risk of asthma compared with those with normal birth weight. In stratified analyses, the effect of low birth weight on childhood asthma was strong, particularly in studies conducted in Europe, those with a small sample size, and those published recently. When the moderate heterogeneity was taken into account, meta-regression analysis did not show any significant determinants.Several limitations of this meta-analysis should be considered. First, misclassification of exposure was a potential source of bias in this systematic review, especially because of acceptance of different definitions of low and normal birth weight. The acceptance of low birth weight, including less than 2500 g or 3000 g, varied for different cohorts. Second, when the adjusted estimates were unavailable, the calculated estimates without adjustment were likely to have potential confounding. Third, restriction of analysis to articles published in English is another potential limitation. Furthermore, the effect of low birth weight on childhood asthma in the identified studies was not the primary objective, possibly leading to missing relevant data that was not evident in the title or abstract.Asthma is a serious global health problem, and its prevalence is increasing in most countries, especially among children . Meta-anBased on the present findings, low birth weight appears to be a significant risk factor for childhood asthma. If low birth weight can be considered as a modifiable risk factor, prevention of low birth weight could be associated with a decrease in the incidence of asthma. The purpose of this study was to evaluate the effect of low birth weight on the development of asthma later in life. In the present meta-analysis, we found that children with low birth weight had an approximately 16% higher risk of asthma. However, this association may be complicated by the fact that birth weight is not the only contributor to development of asthma. The effect of low birth weight on asthma is likely to be equally important compared with other risk factors, such as a family history of asthma and air pollution , 30.The potential mechanisms of the association between low birth weight and an increased risk of childhood asthma are not fully understood. There is a wealth of epidemiological evidence that lower birth weight is strongly correlated with an increased risk of adult diseases, such as hypertension, type 2 diabetes mellitus, and cardiovascular disease , 31. ThiIn our analysis, significant differences were also observed across subgroups stratified by geographic area, population size, and publication year. Although the overall between-study heterogeneity was moderate, clinical heterogeneity among subgroup studies was low, indicating a greater effect estimate stratified by subgroup. Furthermore, these stratified factors were not found to be significant potential determinants in meta-regression. As in every meta-analysis, the quality of the individual studies may largely influence the review results. In the present analysis, all of the included studies possessed a high quality score. This heterogeneity in the present meta-analysis was acceptable.In summary, the weight of evidence shows that low birth weight significantly increases the risk of childhood asthma. The potential mechanisms underlying this association are not well understood. With regard to the relation between birth weight and asthma, special attention should be paid to the effect of different birth weights in children. Large-sample, well-designed, prospective cohort studies, should be performed in the future.


Low birth weight is associated with an increased risk of cardiovascular diseases in adulthood. As abnormal cardiac autonomic function is a common feature in cardiovascular diseases, we tested the hypothesis that low birth weight may also be associated with poorer cardiac autonomic function in middle-aged subjects.th gestational week and birth variables immediately after delivery. For rMSSD, 1,799 men and 2,279 women without cardiorespiratory diseases and diabetes were included and 902 men and 1,020 women for BRS. The analyses were adjusted for maternal  and adult variables  potentially confounding the relationship between birth weight and autonomic function.At the age of 46, the subjects of the Northern Finland Birth Cohort 1966 were invited to examinations including questionnaires about health status and life style and measurement of vagally-mediated heart rate variability (rMSSD) from R-R intervals (RRi) and spontaneous baroreflex sensitivity (BRS) in both seated and standing positions. Maternal parameters had been collected in 1965–1966 since the 16In men, birth weight correlated negatively with seated  and standing rMSSD , as well as with standing BRS . These observations were verified using relevant birth weight categories . In women, birth weight was positively correlated with seated BRS , but none of the other measures of cardiovascular autonomic function. These correlations remained significant after adjustment for potential confounders .In men, higher birth weight was independently associated with poorer cardiac autonomic function at mid-life. Same association was not observed in women. Our findings suggest that higher, not lower, birth weight in males may contribute to less favourable cardiovascular autonomic regulation and potentially to an elevated cardiovascular risk in later life. Impaired cardiovascular autonomic function increases susceptibility to cardiac events and death in various populations –3. AbnorLow birth weight (BW) and impaired early growth have been related to an increased risk of developing various cardiovascular diseases and events –12. WhilThe purpose of the present study was to determine the association of early growth and size at birth with cardiovascular autonomic function in men and women when they had reached middle-age (i.e. the age of 46). To address this question, we examined the Northern Finland Birth Cohort 1966 (NFBC 1966) which is a large prospective study with extensive data on these same individuals from the fetal period to mid-age. We hypothesized that a low BW may be associated with poorer cardiovascular autonomic function in adulthood.st and December 31st 1966 in the Northern Finland were included in the prospective NFBC 1966 study . Starting from their mothers’ recruitment during their first visit to maternity health centers on average on the 16th gestational week, data have been collected on the subjects’ health, life style and socioeconomic status. The study has been conducted according to the Declaration of Helsinki and approved by the Ethical Committee of the Northern Ostrobothnia Hospital District in Oulu, Finland. The subjects have provided their written informed consent for the study.The subjects whose expected date of birth fell between January 1th to 28th gestational weeks. Paternal  socioeconomic status, mother’s age, weight, height, body mass index, parity and maternal smoking status were established. Paternal socioeconomic status , parity  and maternal smoking status (smoking ≥1 cigarette/day after 2nd month of pregnancy) were categorized using cutoffs adapted from Järvelin et al. 2004 [3) were calculated. Data about maternal weight gain were available for 903 mothers and were assessed as continuous variables and tertiles . Birth weight , birth length , gestational age  and percentiles of BW relative to gestational age  were also categorized using predefined cutoffs adapted from Järvelin et al. 2004 [The early growth and maternal data have been described in detail elsewhere . Brieflyal. 2004 . For exaA postal questionnaire on the participant’s health status and life style was conducted in 2012–2014. The questionnaires were mailed to all subjects whose addresses were known . The response rate was 66% . Subjects, who were living at known addresses in Finland, were invited to clinical examinations that were coordinated by the NFBC project center at the Center for Life Course Health Research (University of Oulu) with three laboratory units . A total of 5,861 (57%) subjects participated in clinical examinations between April 2012 and March 2014. The subjects entered the laboratory between 7:00 and 11:00 a.m. after an overnight fasting period (12 hours). Subjects were instructed to avoid smoking and drinking coffee during the examination day. Venous blood samples were drawn from an antecubital vein for the analysis of glycemic and lipid status. Serum glucose was analyzed using an enzymatic hexokinase/glucose-6-phosphate dehydrogenase method. Total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were determined using an enzymatic assay method. The concentration of glycated and total hemoglobin were measured using immunochemical assay methods. The ratio is reported as percent hemoglobin A1c (NGSP). The samples were analyzed in NordLab Oulu, a testing laboratory (T113) accredited by Finnish Accreditation Service (FINAS) (EN ISO 15189) . Systolic (SBP) and diastolic blood pressure (DBP) were measured three times in 1 minute periods  with an automated sphygmomanometer  in a sitting position from the right arm after 15 minutes of rest. After various measurements, including the measurements of weight, height and circumferences of waist and hip, the participants had a light meal 60–90 min before the assessments of cardiovascular autonomic function. On a separate day after an overnight fasting period (12 hours), a 2-hour oral glucose tolerance test was conducted for these participants without medication for diabetes according to the recommendations .The participant sat on a chair for instrumentation and the review of the protocol. A heart rate (HR) monitor  was used to record R-R intervals (RRi) with an accuracy of 1 ms. In about half of the participants (Oulu laboratory unit only) spontaneous BRS was also assessed. Standard lead-II ECG , breathing frequency , and blood pressure (BP) by finger plethysmography  were recorded during the protocol with a sampling frequency of 1,000 Hz . The finger cuff was adjusted so that the values of SBP and DBP assessed by finger plethysmography (left arm) did not differ by more than 10 mmHg from those measured by automated sphygmomanometer at the same time . Physiological calibration of finger plethysmography was then turned off. An arm sling was used to support the left arm during the measurements. These procedures which were conducted in the seated position lasted for a total of 5–10 min which was followed by stabilization of HR for at least 1 min before the recording started. After 3-min recording in a seated position, the participant stood up and remained still in a standing position for 3 min while breathing spontaneously. The first 150 s of recording in seated position and the last 150 s in standing position were analyzed.2) and high frequency  components of HRV, and their ratio (LF/HF) were analyzed [rd power of RRi (s) to remove RRi-dependency of rMSSD [The RRi data were edited based on visual inspection . Artefacts and ectopic beats were removed and replaced by local average. However, sequences with ≥10 consecutive beats of noise or ectopic beats were deleted. The RRi series with ≥80% accepted data were included in analyses. A total of 5,679 subjects attended RRi recordings of whom 5,473 (96%) had eligible HRV data for both phases of the protocol (seated and standing). Mean HR, root mean square of successive differences in RRi , spectral power densities  at low  for subsequent analysis of BRS by the alpha method if sufficient coherence (≥0.5) between LF oscillations in RRi and SBP was verified [Continuous ECG, BP and respiration signals were imported into custom-made standalone Matlab-based software . RRi and SBP values were extracted from the continuous ECG and BP recordings as discrete event series. Artefacts and ectopic beats were replaced using linear interpolation (<5% for accepted recording) and, thereafter, resampled at 2 Hz. Very-low-frequency components (< 0.04 Hz) were removed using the Savitzky-Golay method. A fast Fourier transform  was performed to analyze the LF power of RRi and SBP oscillations . Total sitting time during waking hours was established by asking the subjects how many hours on average they sat on weekdays and the responses were dichotomized (cut-off 11 h/d). To evaluate the sufficiency of sleep, the subjects were asked how tired they felt in the morning during the first half an hour . In the estimation of physical activity, the subjects were asked how often they participated in brisk physical activity/exercise during their leisure-time. The term 'brisk' was defined as physical activity causing at least some sweating and getting out of breath, corresponding to moderate-to-vigorous intensity. Six response alternatives were 1) daily, 2) 4–6 times a week, 3) 2–3 times a week, 4) once a week, 5) 2–3 times a month, and 6) once a month or less often. Three relevant classes were formed by combining two consecutive categories .In those individuals for whom there was HRV data , 255 subjects with diabetes based on previous or new diagnosis according to the criteria issued by the World Health Organization  were excluded . In addiThe distributions of the dependent variables were assessed by analyzing the skewness of the data and by visual inspection of histograms. In the case of skewed distributions , and, subsequently, also for continuous adult anthropometric  and cardiometabolic variables  as well as categorized adult life style variables . Maternal weight, adult weight and low density cholesterol were excluded from the independent variables list to eliminate collinearity  were further adjusted in multiple regression models (continuous early growth variables) or ANCOVA (categorized early growth variables), first, for maternal variables . Furthermore, birth length was positively related to standing LF/HF–ratio .In women, BW was associated with seated BRS . Categorized BW had no significant association with cardiac autonomic function. Categorized birth length  showed nonlinear association with standing rMSSD (one-way ANOVA p = 0.038), with the 22 for model = 0.029, n = 934) as well as maternal and adult variables . Birth length did not remain a significant factor underlying the standing LF/HF-ratio  or standing rMSSD  after adjustment for maternal variables.In multivariate analysis, BW remained a significant determinant of seated BRS after adjustment for maternal  on adult cardiovascular autonomic function of the offspring was also assessed. Univariate analysis (one way ANOVA) showed that the male offspring of overweight mothers had significantly lower measures of BRS in seated (p = 0.006) and standing (p = <0.001) positions and a similar tendency was observed with rMSSD . Maternal overweight was also associated with higher seated HR (p = 0.039) in men. In women, maternal overweight was associated with lower seated LF/HF (p = 0.015). As a continuous variable, maternal pregestational BMI was not related to adult cardiovascular autonomic function in men or in women. Maternal BMI and BW of offpring were significantly correlated in men  and in women .In a subsample with gestational weight gain data, higher gestational weight gain tertile was related to lower standing rMSSD and higher seated and standing HR  in men. As a continuous variable gestational weight gain was positively associated with seated LF/HF ratio  in men. After adjustments for maternal and adult variables, tendencies with LF/HF ratio (p = 0.050) and rMSSD (p = 0.086) remained. In women, a greater gestational weight gain was related to lower seated rMSSD and higher seated LF/HF ratio when assessed as a categorized  and as a continuous  variable. Continuous gestational weight gain remained a significant determinant of rMSSD (p = 0.045) after adjustments in women. A significant correlation between gestational weight gain and BW was observed in men  and in women .The principal finding of the present study was that BW was independently negatively associated with cardiac vagal activity and BRS at mid-life in men. In women, however, a similar association between BW and later cardiovascular function was not observed, the association between BW and seated BRS being even opposite. The findings in men were contradictory to our primary hypothesis and suggest that, instead of impaired prenatal growth, greater prenatal growth contributes to lesser cardioprotective vagal activity in mid-life.Several studies have detected an increased risk of developing various cardiovascular diseases and events in subjects with low BW ,10–12. LEven though the associations of BW and cardiac autonomic function to cardiovascular morbidities have been studied extensively, surprisingly little is known about the potential link between BW and autonomic function in later life. Furthermore, most of these studies have discussed the effects of low BW, and thus the effect of high BW on autonomic function has not been examined to the same extent. The studies exploring the association between BW and HRV in infants or children have reported impaired cardiac vagal or overall autonomic activity in subjects with low BW ,31,32. IVery few studies have examined the relationship between early growth and the properties of the baroreflex; in them, a positive association was observed between BW and BRS ,37. TherOur findings were sex-specific, with greater BW associating with lesser cardiac vagal activity and BRS at mid-life in men but not in women. Most studies examining the relationship between BW and autonomic function have not reported sex-specific results. There are some reports documenting a relationship between size at birth and later autonomic function in women but not in men . InteresMaternal hyperglycaemia in untreated pre-gestational diabetes and GDM, maternal pre-pregnancy obesity and excess weight gain during pregnancy appear to be independent risk factors for high BW in offspring –44 and mPonderal index expresses body weight relative to length and thus is often used to describe the ‘thinness’ or ‘adiposity’ of newborns . Our res2). However, our results suggest that BW makes a specific contribution to vagal modulation irrespective of prevailing mean HR.Our main results of BRS were observed in BRS measured in the standing position, corroborating evidence that the spontaneous BRS method reflects baroreflex physiology particularly if measured when the subject is standing . FurtherThe short recording period of RRi and BP may create a possible measurement bias, since the reproducibility of short-term recordings is weaker than that of longer recordings. For example, cardiovascular autonomic function is affected by the time from the previous meal, which although controlled, was relatively short in the present study. This was a tradeoff related to logistics and other competing priorities during these extensive series of measurements. Also, nicotine and caffeine withdrawal may have affected the measures of cardiac autonomic function. Spontaneous breathing may confound the spectral analysis of HRV and BRS . In subjA higher birth weight was associated with lower cardiac vagal activity and reduced baroreflex sensitivity at mid-life in men, regardless of potential confounding effects of maternal variables and mid-life life style and cardiometabolic factors. In women, the effect of early growth parameters to cardiovascular autonomic function was not clear. These findings suggest that greater, not depressed, prenatal growth may contribute to poorer cardiovascular autonomic regulation and the related cardiac risk in later life in men.S1 File(ZIP)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Limited introduction of the LNG IUS through mobile outreach in Kenya, without any special promotion, resulted in good uptake. And providers viewed it positively, particularly because of its noncontraceptive benefits. Increased provision of the LNG IUS can improve options for women needing highly effective reversible contraception. Limited introduction of the LNG IUS through mobile outreach in Kenya, without any special promotion, resulted in good uptake. And providers viewed it positively, particularly because of its noncontraceptive benefits. Increased provision of the LNG IUS can improve options for women needing highly effective reversible contraception. The levonorgestrel intrauterine system (LNG IUS) was developed over 30 years ago, but the product is currently too expensive for widespread use in many developing countries. In Kenya, one organization has received donated commodities for 5 years, providing an opportunity to assess impact and potential future role of the product.We reviewed service statistics on insertions of the LNG IUS, copper intrauterine device (IUD), and subdermal implant from 15 mobile outreach teams during the 2011 calendar year. To determine the impact of the LNG IUS introduction, we analyzed changes in uptake and distribution of the copper IUD and subdermal implant by comparing periods of time when the LNG IUS was available with periods when it was not available. In addition, we interviewed 27 clinicians to assess their views of the product and of its future role.P = .08) and was largely attributable to the copper IUD. All interviewed providers felt that the LNG IUS would increase uptake of long-acting methods, and 70% felt that the noncontraceptive benefits of the product are important to clients.When the LNG IUS was not available, intrauterine contraception accounted for 39% of long-acting method provision. The addition of the LNG IUS created a slight rise in intrauterine contraception uptake (to 44%) at the expense of the subdermal implant, but the change was only marginally significant , provider enthusiasm for the product was high. This finding, above all, suggests that a larger-scale introduction effort would have strong support from providers and thus increase the chances of success. Adding another proven and highly acceptable long-acting contraceptive technology to the method mix could have important reproductive health impact. The most recent example is from the United States, where it was approved 13 years ago. The LNG IUS is now more popular in the United States than any new contraceptive product introduced since 1992, including the DMPA (depot medroxyprogesterone acetate) injectable (1992), the vaginal ring (2001), the contraceptive patch (2002), and the etonogestrel implant (2006).,Cost is not the only consideration when contemplating the potential role and impact of the LNG IUS. Although the LNG IUS is a form of intrauterine contraception, as is the copper intrauterine device (IUD), it should not be viewed as simply another IUD. The LNG IUS and the copper IUD have striking differences in side effects and noncontraceptive benefits. However, in terms of effectiveness and other factors, the products have important similarities as well .4,5A noncommercial LNG IUS product is currently being introduced on a very limited basis into some programs in resource-poor countries through donations from the International Contraceptive Access (ICA) Foundation . Since inception in 2003, the ICA Foundation has donated nearly 50,000 LNG IUS devices to 19 countries.The more contraceptive methods available, the greater the contraceptive prevalence generally.When new contraceptives become available, they generally improve reproductive health in the affected population. In a multicountry analysis, Jain found that overall contraceptive use rises with increased method choice,At the family planning program level, it is important to know how a new product might alter the pattern of method uptake and services. For example, a new method might attract new clients and overburden the service delivery system, particularly if the new method requires more time and effort to provide. If a new method becomes popular, a program will need to purchase enough product to satisfy demand, and potentially decrease orders of other products if a contraceptive substitution effect occurs.During any product introduction process, providers' opinions are critical. Given their important role in contraceptive counseling,Since 2008, the Marie Stopes affiliate in Kenya (MSK) has provided free LNG IUS services to approximately 5,000 women. Thus, during this time, some clients had one additional long-acting reversible contraceptive (LARC) choice, which also includes subdermal implants and all types of intrauterine devices. We undertook this project at MSK to better understand the impact of the LNG IUS introduction efforts.We used anonymous MSK service statistics and interviews with MSK providers to evaluate the LNG IUS introduction activity. This research was approved by the Protection of Human Subjects Committee (of FHI 360) and the Kenya Medical Research Institute's Ethical Review Committee. The MSK providers voluntarily agreed to be interviewed through an informed consent process that was approved by these committees.The LNG IUS product was used in MSK's outreach program, which consists of 15 teams in different geographic regions of Kenya. Each team has 2 clinicians  and 2 care assistants; the teams visit catchment public-sector health facilities on a rotating basis to provide family planning services.We reviewed MSK's existing  reporting systems to tabulate the monthly number of contraceptive method insertion procedures for each of the 15 outreach teams during the 2011 calendar year. We developed an electronic database and entered into a spreadsheet the number of insertions for the LNG IUS, copper IUD, and subdermal implant. Of the 15 teams, 4 did not receive any LNG IUS in the study period and were excluded from the analysis. Of the possible 132 total available months across the 11 teams, 2 months with no LARC insertions  were excluded from the calculations. Thus, a total of 130 months of data were included in the analysis.t test to determine whether availability of the LNG IUS increased total IUD insertions, relative to the subdermal implant.For each team, we computed the mean number of monthly product insertions. In some months and in some teams, the LNG IUS was not available. Thus, we examined how the average proportions of total IUD (copper IUD plus LNG IUS) versus subdermal implant insertions varied per month, by whether or not the LNG IUS was available. We used a For feedback on the LNG IUS product, we interviewed 27 MSK providers. We asked a variety of questions to characterize their views and their clients' views on the new product.During the 2011 calendar year, the outreach program provided over 67,000 women with LARCs: 39% chose the copper IUD, 60% the subdermal implant, and 1% the LNG IUS . During P  = .08). The modest increase was largely attributable to the high volume of copper IUDs relative to the volume of the LNG IUS. The relative importance of the IUD versus the implant varied considerably across the different teams, regardless of whether the LNG IUS was available.The average proportion of women selecting either a copper IUD or LNG IUS rose slightly when the LNG IUS was available.During months when the LNG IUS was not available, IUD services accounted for an average of 38.9% of total LARC services . The aveAll interviewed providers felt that the LNG IUS would attract new clients to long-acting methods.In the survey of MSK providers, varying experiences with the LNG IUS were noted . For exaIn distinguishing the LNG IUS from the copper IUD, providers cited these main features: hormonal product (85%), reduces bleeding (52%), and 5-year duration of use (44%) . Nearly Dedicated LARC providers can help improve access to contraceptive methods.Introduction of the LNG IUS through the Marie Stopes/Kenya outreach program had mixed impact. On the one hand, availability of the LNG IUS did not appear to alter provision of standard long-acting reversible methods ; the pattern of service statistics did not change for the program as a whole and for most of the outreach teams that provided the LNG IUS. However, MSK providers unanimously believed the LNG IUS would attract new clients to long-acting methods, at least partly due to the important and unique noncontraceptive benefits that the technology offers. The high volume of copper IUD services  demonstrated high acceptability of this product among both providers and clients. Thus, this is another example of how dedicated LARC providers are successful at making important technologies available.A previous introduction assessment of the LNG IUS in Ghana had similar results to ours.Providers in our study candidly reported being most comfortable describing and providing the subdermal implant; this finding exposes some of the challenges for wider provision of intrauterine contraception. Reasons for being more comfortable with subdermal implants could simply be a function of higher client demand and thus more frequent counseling about and insertion of implants. However, if providers are reluctant to offer intrauterine contraception, due to perceived lack of expertise or for other reasons, a feedback loop of diminished contraceptive choices could develop. Although there is certainly no evidence that this is occurring at MSK, it is critical that providers maintain skills and confidence with all LARCs.A larger contemporary concern across sub-Saharan Africa is widespread absence of LARC services in public-sector settings, where providers and health systems as a whole typically rely on provision of short-acting methods. Providers are subject to many personal and external influences that can ultimately limit contraceptive choice for their clients.Our study in Kenya had important limitations. First, this introduction of the LNG IUS was not conducted in a promotional or scientifically rigorous way to measure the impact. For example, clients were probably not aware of the product until they spoke to the provider; thus, it is not possible to conclude anything about true demand for the LNG IUS. However, it is feasible that unmeasured word-of-mouth could have prompted some women to visit the clinic on MSK outreach days. Second, we did not conduct an experiment on the impact of the product introduction; the work was retrospective and observational of a program and not of a controlled intervention. Lastly, the quantity of LNG IUS  was very small relative to the other products ; if unlimited supplies of the LNG IUS were available, it is possible that a different picture would have emerged. For purposes of the analysis, we assumed that zero LNG IUS insertions in a given month meant that the product was not available at that time.The major strength of this LNG IUS introduction project is that it was done in a natural program setting, where clinicians simply offered the new product without a research aim or protocol. Also, MSK had several years of experience with the LNG IUS before data collection and interviews took place. Thus, perhaps the provider feedback is a more experienced and reflective view of the LNG IUS technology.,The LNG IUS was developed in the 1970s and is long overdue for introduction into resource-poor settings. High product cost is the current barrier to more widespread use. New LNG IUS products made by Indian companies are currently available in India,


This paper examines how to best be with women during birth, based on a phenomenological description of the birth experience. The first part of the paper establishes birth as an uncanny experience, that is, an experience that is not only entirely unfamiliar, but even unimaginable. The way in which birth happens under unknowable circumstances  creates a set of anxieties on top of the fundamental anxiety that emerges from the existential paradox by which it does not seem possible for a body to give birth to another body. Would homebirth provide a remedy to the uncanniness? The result yielded by medical studies is confirmed by the phenomenological perspective taken here: homebirth might be reassuring for some, but not for everybody; choice of birth place is important. Once the birth process starts happening, another layer of strangeness is added: it turns out to be an experience of radical passivity and waiting, normally. The question thus becomes how to best care for somebody who is exposed to uncanniness, passivity, and waiting. Martin Heidegger’s concepts of care and discourse prove useful in examining how to facilitate rather than interrupt this process. It becomes necessary to think beyond verbal communication towards a wider concept of communication that involves silence and intercorporeality. Birth requires a special kind of being-with as being-there. The birth process is undoubtedly a very unusual experience. This experience will be approached here from the phenomenological perspective, meaning that a description of the experience or of what it is like to give birth will be attempted. The purpose of this description is to explore how to best be with a woman who is giving birth.The phenomenological description yields strangeness or unfamiliarity as the pervasive character of the experience. While this result is not as such surprising, it will be helpful to examine this strangeness more closely with respect to its different dimensions. Such differentiation will make it possible to see how even the more mundane dimensions of the experience become affected by the fundamental uncanniness of birth as an experience that is unimaginable. Furthermore, the uncanniness of birth is exacerbated by the fact that passivity and waiting are normally a crucial part of the process. The question thus becomes how to best be there for somebody who is exposed to passivity and uncanniness.In caring for a woman (or couple) undergoing this uncanny experience, it is significant to consider the radical clash between the perspective of the woman facing this experience for the first time  whereas the midwife undergoes this experience from the outside every day. Taking the other’s perspective is thus crucial. But at the same time, if the care works out well, caring for somebody in such a limit situation can make the carer appear like an angel: a super-human guide and guardian. In the best case scenario, midwives reassure us that miracles (or what seems like one due to its inconceivable character) are possible. In the worst case scenario, they can make us wanting to escape: from the situation and from our bodies, neither of which is possible.There are several factors contributing to a good birth experience, and our focus here lies especially with the situational and communicative ones. If the character of the experience is determined by uncanniness, one possible response appears to be homebirth, or making oneself at home to counter-act the strangeness of the experience. In the case of homebirth, midwives are crucial. Yet it turns out that if the relationship between midwife and mother or couple works well in terms of communicating within and responding to the situation, the question of place becomes secondary: a caring midwife can make us feel at home in such a way as to override the surrounding circumstances. While choice of birthplace is important, the quality of care is more important for alleviating fears than the question of home versus hospital.When the birth happens is unknown. From a certain point of pregnancy onwards, it could be basically any day, any moment. There is thus a constant sense of uncertainty which makes itself present especially around any deviations from the everyday, such as travels.1Where the birth happens is unpredictable, and yet needs to be pre-selected. In other words, it is necessary to decide between the locally available possibilities  while still bearing in mind that in the end, it might nonetheless be an entirely different place. A birth that starts at home might be moved to the hospital, a planned hospital birth might end up happening at home, and that is not to mention more unusual locations like vehicles of transportation.Who will be present is uncertain, and yet very much worth pondering. For example, if the father is supposed to be present, it is worth imagining and discussing whether both sides are comfortable with this, and what his role would be, bearing in mind again that there are limits to anticipating the actual course of events. A major factor of uncertainty concerns the health professionals present: normally, midwives. Under most circumstances, the midwives encountered in the situation will be strangers, and it is worth mentally preparing for this.2gender of those present is unknown, and especially of healthcare professionals: a male midwife would initially be a shock to most birth-giving women.The How the birth happens is unforeseeable. Will the process be long or short? Will it require medical interventions or not? There are lots of unknowns, and some of them deserve imaginative engagement. For example, does a water birth seem desirable or not? If the process is prolonged, where and how should the waiting happen? What would my ideal birth look like, and what is completely unfathomable for me? How can these findings be conveyed in a birth plan? Despite the need and usefulness of planning, there are many dimensions that remain unforeseeable since I cannot anticipate what my body will feel like during the process, and to what extent this undermines my previous intentions and plans.How the birth will be possible is unimaginable. In addition to the factors of ‘how’ mentioned under (e), there is a deeper dimension to the unforeseeableness of how the birth will happen. This is not a matter of how exactly will it happen, as in the previous point, but more a ‘how on earth will it happen’? The most fundamental problem is that birth as an event is unimaginable. I cannot imagine my body giving birth, I cannot imagine that such an event is possible. And even after it has happened to a person once or more, there is still some level on which the experience remains inconceivable.Any pregnant woman will to some extent imagine the birth process. That is a normal attempt at coping with an unfamiliar experience, and it is a useful attempt since it helps making some crucial decisions, including the decision as to where this experience should take place. Our first step will be a closer exploration of the dimensions of strangeness that characterises birth.Antigone. In the first choral ode of Antigone, the nature of the human is designated as the most uncanny (Greek deinon) among many uncanny things. Our relation to uncanniness is relevant because it is a dynamic one. We experience the world as uncanny on some basic level because we did not bring it about, but were born or ‘thrown’ into it, and into a particular time and space, without ever being able to fully grasp this uncanny world. However, we do not stop at this encounter with the world as uncanny, but try to make ourselves at home in the midst of this uncanniness. As we do so, we create higher levels of uncanniness. We strive to make ourselves at home in the midst of that which overwhelms us, and yet, we ourselves have a tendency to overstep the boundaries of the familiar. In this respect, human nature is excessive. Humans surpass “the limits of the homely”  and yet at the same time, entirely possible . At this point, the unimaginable character of birth will be explored further with the help of Martin Heidegger’s concept of the uncanny that elucidates how humans tend to deal with uncanniness— namely, by creating higher levels thereof. Heidegger explains this tendency through a line from Sophocles’s ancient tragedy techne that humans engage to fight illness is medicine which was known already to the ancients, but began taking on its natural scientific shape in the seventeenth century. Medicine thrived in the twentieth century, and it was at that time that births started taking place in hospitals.One of the most important overwhelming powers against which humans react by creating higher levels of uncanniness is nature. In the choral ode, nature is represented by natural elements like the earth and the sea, which have inexhaustible energies and confront us with their waves, circles, and cycles. Exposed in this fashion, we do not give up; we rise to the challenge, making ourselves at home in the midst of that which overpowers us. One crucial manifestation of our link to nature that confronts us with uncanniness is illness. Illness will be used here as a general example for uncanniness; this is not to imply in any way that pregnancy is an illness . Illness means that our bodies fail us, as it were, and become affected in detrimental ways by internal or external factors. Illness is particularly uncanny because the affected individual normally does not understand it (at least not fully), yet depending on the extent of the illness, it can affect our existence wholly and to its core. The craft or am my body rather than merely having a body, and that my body is lived and experienced rather than a merely physical body.When the possibility of giving birth in a hospital became historically a widespread possibility, this certainly meant a significant reduction of fatalities for birth-giving women as well as for infants. Yet at the same time, it created a new level of uncanniness, in line with Heidegger’s description of the human tendency to evoke higher levels of uncanniness in combating previous uncanny phenomena. Medicine in general fits the Heideggerian description as a higher level of uncanniness that replicates some of the features which make illness so uncanny. Just as we do not usually understand illness, we also tend to not comprehend medical treatments. Medical professionals are not always eager to explain, and the facts are usually quite complicated indeed. Yet at the same time, medicine affects our existence fundamentally. When I ‘take’ my body to the doctor and experience discomfort at the realization that she might indeed only be interested in my body as a physical object, this unease creates an opportunity for the phenomenological discovery that I It will not be possible to examine here the character of medicine in general and possibilities of remedying the discomfort often felt in the face of its uncanniness. Yet the topic has some direct implications for birth. The pain involved in the process and the possibility of complications create an affinity between childbirth and illness, but at the same time, it is often and rightfully pointed out that birth is not as such a medical condition and should not be treated in this fashion. Particularly in terms of uncanniness, the hospital atmosphere can be fear-inducing rather than fear-alleviating.How do homebirths fare when it comes to uncanniness? An important 2011 study of the UK situation conducted by Peter Brocklehurst showed that homebirths do not increase the likelihood of birth complications. However, the case of women giving birth for the first time (“nulliparous”) differs from that of women who have given birth at least once before (“multiparous”). For nulliparous women, the danger of stillbirths and perinatal injuries were slightly, but indeed only minimally,Brocklehurst thus concludes that his “results support a policy of offering healthy women with low risk pregnancies a choice of birthsetting” including homebirths and non-obstetric midwifery units , which is more disruptive to the mother-infant-bonding experience than being in a hospital to begin with. It should also be noted that homebirth is only safe for the infant in countries where transferring the infant to a hospital for any complications or concerns is easy and fast.Yet there are other factors as well, and some of them might well be open to change while others can be anticipated beforehand by an exercise in the imagination. One aspect of birth that is crucial and yet often neglected is the significance of waiting. It is a common yet mistaken assumption that the birth process simply gets more and more difficult as it advances. Rather, the final phase is often easier than the previous one, already because the end of the process is coming tangibly closer and because being able to participate (by ‘pushing’) is in certain ways easier than passively waiting. The significant role of waiting makes it advantageous to prepare for some entertainment or other accessories. That is where the home context seems to provide many advantages; yet an often disregarded factor needs to also be taken into account: midwives. In general, if the preference for the home is motivated by the desire to maintain a familiar context and atmosphere in preparation for an uncanny encounter or experience, it must be noted that the arrival of midwives into the home context will in any case mean an encounter with strangers. Only under exceptional circumstances will the midwife be a familiar oneAdmitting a stranger into my home creates a situation that calls for hospitality, as we learn from Jacques Derrida,Moreover, the tension between mundane and fundamental levels plays out for hospitality as well. There is a level of fundamental hospitality involved in the birth experience.When it comes to an imaginative engagement with homebirths, hospitality thus needs to be part of the imaginative scenario as well as the potential need to be transferred. However, if the decision is nonetheless for a homebirth, the possibility of transfer should in the situation itself better not be too much on the woman’s mind. Considering other options creates a general atmosphere of uncertainty or indecisiveness that is unhelpful. One of the biggest advantages of homebirth is the possibility to stay put, in all senses. Once the baby is born, everybody is immediately there, home, where they can stay, recover, and celebrate together—and the home is home again, just even more so, substantially enriched by the new arrival.Overall, we have seen that there can be advantages as well as disadvantages to a homebirth, and the need for an imaginative engagement with birth thus gets confirmed. Such exercises in imagination should also include a dimension of birth that is crucial yet often neglected, partly due to the temptation to focus immediately on the crucial point of the process: the actual birth, that is, the appearance of the baby. But a substantial part of the process is determined by passivity and waiting, and those are difficult to deal with in their own right, but even more so when waiting for something fundamentally uncanny to happen.Passivity is something we neither value nor consider much. A phenomenological description of birth shows that this is a mistake. However, when we initially explore birth, the same inhibitions emerge that determine our relation to passivity in general. Just like it is a negative characteristic to describe somebody as “passive”, there is also an impression that a more active engagement is conducive to giving birth. The “Active Birthing” movement symbolises this conviction. Passivity in birth is usually associated with hospital births and more precisely, medicalised birth. By contrast, qualitative research on birth as inspired by existential phenomenology tends to focus on the woman as “subject” rather than treated “object,” where “subject” is often interpreted in terms of autonomy and activity.11The existential phenomenology of birth presented in this article places an emphasis on passivity and thus counters the everyday as well as current research emphasis on activity in birth. This is not to deny but merely to supplement the significance of active birth. A few preparatory clarifications are in place. Firstly, a general reminder concerning the position taken here: it is not our purpose to argue against hospital births, as should be clear from the previous section. The result of our considerations was merely to encourage imagining and give women freedom of choice concerning their preferred place of childbirth.Waiting is crucially a temporal phenomenon, and our body plays no intrinsic role in it.In waiting, time expands, and nothing in the world provides a remedy. Nothing? In normal experiences of waiting, we often wish we had brought a book, or a conversation suddenly provides distraction. During labour, conversations are difficult and not very desirable. But other forms of distraction can well be helpful especially during the initial stages. It might indeed not be a bad idea to bring a book.Admittedly, the moment will come when distraction through entertainment is no longer possible, and that is when the body makes itself so present that a kind of Cartesian mind–body-dualism becomes desirable. In other words, there is a strong desire for body and mind to be detachable in such a way that the body could be left, at least momentarily, by that part of us which is responsible for thinking, feeling, and experiencing. Of course, there is no experiencing without body, and no thinking and feeling either, though the latter might be less obvious. Pain thus undermines Cartesianism on the level of experience rather than on the logical level, and it undermines it exactly because dualism would be desirable in such a moment yet remains all the more so impossible.But how to best assist somebody who is facing an inevitable yet uncanny experience, and one that involves waiting and passivity? If the time of waiting has not robbed the woman of all energy and determination, the final phase becomes manageable exactly because it is clear that it is the final phase. Therefore, creating conditions for ‘good waiting’ and ‘good passivity’ is crucial. Others are crucial in this respect because others affect us most. Others have always already affected me and will continue to affect me. Since birth is a particularly volatile situation, it is crucial to understand better how others affect me, especially on the level of care and communication.cura) and common sense understandings, Heidegger makes it clear that the everyday notions of ‘concern’ or ‘worry’ will not lead us to the primordial meaning of care. The deepest meaning of care is ontologically so fundamental that it becomes synonymous with existence. Our existence is care because our existence is an issue for us , taking the care away from him or her (Heidegger vorspringende Fürsorge), not taking his or her place, but giving the care back to the Other. This caring-for treats the Other not as a “what which it takes care of” but strives to help the Other “to become transparent to himself [or herself] in his [or her] care and free for it” (ibid.).While his overall sense of care refers to the world in general and also our dealings with objects, they can be shown as relevant for healthcare relations.This distinction has direct implications for midwives and health professionals helping in the birth process. Although Heidegger certainly does not discuss this example, it would be true to say that birth (just like anxiety) individualises: nobody can give birth for me. Nonetheless, the way in which the situation of birth creates a dependence on others makes it tempting to wish that the Other could ‘leap in’ for me. Yet this leaping in cannot ultimately be helpful. Once it feels like the process is out of my hands and I no longer conceive of myself as the most crucial participant, it becomes tempting to treat myself or think of myself as a helpless object. Conceiving of myself as an object is relatively easy, due to my split nature of being subject/object which Heidegger, to avoid misunderstandings easily created by this traditional terminology, re-conceives as our being ‘thrown project’: I am thrown into the world like an object, yet I am also a project of multiple possibilities. Care means having to negotiate myself as thrown project.Abnormal states like sickness or pain easily create a situation in which my self-perception changes in such a way that I would like to distance myself from my body. Pain is existentially threatening exactly because it makes me aware that I am unable to escape. Being (rather than having) a body means that existence is a ‘no way out’ situation, as far as my corporeality is concerned. As a result, ‘leaping in’ care is particularly dangerous in the health profession: the patient all too willingly accepts the invitation to take further distance from the already alienated body and expect for the Other to take over. While such trust in professionals appears helpful in cases of sickness where actual medical intervention is necessary, it can only be helpful in childbirth if the situation indeed takes a turn to the problematic and thus medical. For ‘normal’ birth, ‘leaping in’ creates problems since it will become obvious quite soon that nobody can give birth for me; so I have to accept this body back. Much more helpful and less frustrating is thus a form of care that ‘leaps ahead’, trying to free myself for taking care of myself and helping me to realise that the responsibility is indeed mine.Rede).How can this best be achieved? Heidegger does not provide precise guidelines, but it becomes obvious that it is a matter of relational attitude. In order to examine my relation to the other more closely and see how different attitudes manifest themselves, it will be useful to invoke the second major dimension of existence in which being-with others happens: discourse . While it is very useful to have homebirth available as an option for those women whose fear of the unfamiliar is alleviated by the home context and especially for those who are not giving birth for the first time, homebirth is not for everybody. Some women feel more reassured by the hospital context when it comes to an unfamiliar experience, and it should also be noted that nobody can anticipate how they will feel and experience their own bodies in such an extra-ordinary situation. Efforts to make the hospital more home-like and increase privacy are thus a crucial contribution. Yet even more important is the focus on the quality of care because as human beings, we are most affected by our relations to other humans, especially in a situation that is uncanny and in which we are dependent on the help of others. Reflections on discourse, listening, care, and compassion are thus very important .17Being with somebody who is undergoing an experience of uncanniness and passivity requires compassion.It means trying to make the Other comfortable in the midst of uncanniness, passivity, and waiting. This is a tremendously difficult task, and one that involves knowing how to be there for the Other with and without words. It involves patience, silence, listening, flexibility, and other modes of being with the Other by being there for them. But if the midwife establishes successful care relations via discourse in the wider sense developed here, she might actually be experienced as an angel of sorts who comes as a guide or guardian in the encounter with the uncanny and makes the seemingly impossible possible.


We assessed the incidence of infants born small-for-gestational-age (SGA) and large-for-gestational-age (LGA) in an Italian cohort over 20 years (1993–2013). Furthermore, we investigated maternal factors associated with SGA and LGA births.th year over a 20-year period, specifically examining data for 1993, 1998, 2003, 2008, and 2013. Infants with birthweight <10th percentile were defined as SGA, and those with birthweight >90th percentile as LGA. Data collected included newborn anthropometry, birth (multiple vs singleton), maternal anthropometry, previous miscarriage, gestational diabetes, hypertension, and smoking during pregnancy.A retrospective review of obstetric records was performed on infants born in Chieti  covering every 5p < 0.05), while greater pre-pregnancy BMI and gestational diabetes were risk factors for LGA births .There were a pooled total of 5896 live births recorded across the 5 selected years. The number of SGA (+60.6 %) and LGA (+90.2 %) births increased considerably between 1993 and 2013. However, there were no marked changes in the incidence of SGA or LGA births . Maternal factors associated with increased risk of SGA infants included hypertension, smoking, and previous miscarriage (all There was an increase in the number of SGA and LGA births in Chieti over the last two decades, but there was little change in incidence over time. Most maternal factors associated with increased odds of SGA and LGA births were modifiable, thus incidence could be reduced by targeted interventions. Birth size is an essential parameter to consider in the clinical evaluation of newborns. Either weight or length at birth represent the expression of growth in utero as a result of maternal, placental, and fetal factors, and have been historically used to identify newborns at potential risk of complications early in life . In addiThere is considerable variation in the prevalence of infants born SGA (4.6–15.3 % across Europe) . The varSize at birth has been reported to vary over generations –11. DuriAs a result, we aimed to assess the trends in SGA and LGA births over a 20-year period (1993–2013) in Chieti . In addition, we investigated the maternal risk factors associated with SGA and LGA births.Ethics approval for this study was not required, since i) it was an audit; ii) it was confined to anonymised and unidentifiable data that are routinely collected at the S.S. Annunziata Hospital (Chieti); and iii) study findings would not affect patient care.th year on all infants born in the Department of Obstetrics and Gynecology, S.S. Annunziata Hospital, between 1st January 1993 and 31st December 2013 . This is the largest maternity hospital in the province of Chieti, covering approximately half of all births.The province of Chieti  has a population of 397,395 (2012 census), mostly of Caucasian origin. Data were retrospectively collected for every 5http://www.inescharts.com/). According to the Italian Neonatal Study (INeS) reference charts [th and 90th percentile (−1.28 to 1.28 SDS); SGA, defined on a birthweight and/or length <10th percentile (<−1.28 SD); and LGA, defined on a birthweight and/or length >90th percentile (>1.28 SD). Classification of newborns from multiple pregnancies as SGA or LGA was based on specific percentile curves [A retrospective review of obstetric and delivery records was performed, including information on sex, gestational age, anthropometry (birthweight and length), and birth order. Note that when assessing birth order, miscarriages at less than 20 weeks of gestation were disregarded . Gestatie curves . Unless Maternal height, pre-pregnancy BMI, conception , birth (multiple vs singleton), and delivery  were recorded. Maternal factors, such as previous miscarriage, parity, chronic illnesses, gestational diabetes, hypertension (including pre-eclampsia) , and useThe factors associated with SGA or LGA birth were identified using stepwise linear regression analysis with significance levels of 0.4 and 0.2 required for a variable to enter and stay in the model, respectively . The various parameters included at model entry were: birth year, gestational diabetes, maternal hypertension, maternal ethnicity, maternal age, smoking during pregnancy, alcohol consumption during pregnancy, previous miscarriage, conception , birth (multiple vs singleton), sex, and birth order. Subsequent models were also run on the subgroup with maternal anthropometric data, with the addition of maternal height and BMI into the models. Odds ratios (OR) are provided with 95 % confidence intervals in brackets. The agreement in SGA or LGA classifications according to birthweight and birth length was evaluated using the Cohen’s kappa statistic. All statistical tests were two-tailed and significance was maintained at the 5 % level.There were a pooled total of 5896 live births recorded across the 5 specific years covered by this study, mostly of Caucasian ethnicity (97.5 %). Detailed pregnancy information and birthweight data were available for 5759 live births (97.7 %).Pregnancy outcomes for the whole cohort are reported in Table p = 0.028), were hypertensive (OR 2.93 (2.11–4.06); p < 0.0001), or had a previous miscarriage (OR 1.35 (1.08–1.68); p = 0.008).The odds of being born SGA were greater in the offspring of mothers who smoked tobacco during pregnancy (OR 1.49 (1.05–2.14); p = 0.028), and in those born to mothers with gestational diabetes (OR 1.80 (1.25–2.57); p = 0.001) or who did not smoke during pregnancy (OR 1.61 (1.04–2.48); p = 0.032).Conversely, the odds of being born LGA were greater in males (OR 1.21 (1.02–1.43); 2 increase in BMI there were higher odds of having a LGA baby (OR 1.10 (1.07–1.13); p < 0.0001) but lower odds of having a SGA baby (OR 0.94 (0.91–0.98); p = 0.002). The odds for every 1 cm increase in height followed an identical pattern: being for LGA 1.06  and for SGA 0.94 .Maternal anthropometric data were available for a subset of 3071 live births (52.1 %), and these data were re-analysed incorporating maternal pre-pregnancy BMI and maternal height into stepwise regression analysis. For every 1 kg/mData on birth length were available for 3792 infants 64.3 %), as this parameter was not routinely recorded until the last decade. As a result, birth length data were available for 10.9 % of births in 1993, 6.2 % in 1998, 70.2 % in 2003, 94.5 % in 2008, and 93.1 % in 2013. Maternal pathologies and pregnancy outcomes observed amongst these births are reported in Table .3 %, as This study shows that there was an increase in the number of SGA and LGA newborns in Chieti over a 20-year period, but this was a result of increased birth rates. The incidence of SGA and LGA births varied over time, and there were no marked changes observed. Maternal factors associated with increased odds of SGA babies included maternal hypertension, smoking in pregnancy and previous miscarriage, while greater pre-pregnancy BMI and gestational diabetes were risk factors for LGA births.In a recent prospective cohort data of 75,296 newborns from 12 European countries 1983–2006), the prevalence of SGA births varied from 4.6 % in Finland to 15.3 % in Portugal, with a rate of 9.1 % reported in  Italy (Lazio) –2006, th, 23, 24.In regards to LGA births, there has been a progressive increase in rates reported in several countries over the last decades , 13. HadThere are a number of maternal factor known to be associated with an increased risk of delivering a SGA or LGA infant , 18. ConA previous miscarriage represented an additional risk factor for SGA birth in Chieti. A spontaneous miscarriage, which occurs in approximately 15 % of clinically recognized pregnancies , has beeIn accordance with existing evidence , 38, we Infants can be defined as SGA or LGA based on birthweight, birth length, or both . In our th year, so that it is not possible to ascertain what the incidence of SGA and LGA births was in the intervening years. Nonetheless, our study covers comprehensive pregnancy information and birthweight data.The main limitation of our study was the lack of complete maternal and newborn data on the whole cohort. In particular, the reduced number of infants with maternal anthropometric and/or birth length data could possibly limit the applicability of specific findings across the whole population. In addition, we only provide annual data collected every 5In summary, the incidence of SGA and LGA births has not markedly changed in Chieti over the last two decades, even though numbers of babies born small and large have increased due to a growing population. However, most of the maternal factors observed to be associated with increased odds of SGA and LGA births are modifiable. Thus, it is important that interventions target women both before and during pregnancy to reduce SGA and LGA incidence, and consequently minimize potential short- and long-term adverse effects on offspring health.


Evidence shows exposure to ambient air pollution during pregnancy was associated with an increased risk of adverse birth outcomes, such as preterm birth, low birth weight and intrauterine growth retardation, but the results for birth defects have been inconsistent.10, SO2 and NO2 were obtained from Haikou Environmental Monitoring Center. Logistic regression analysis was used to evaluate these associations.The data on birth defects was collected from the Birth Defects Monitoring Network of Haikou city. Air pollution data for PM10 levels  and SO2 levels  for the second month of pregnancy. In the third month of pregnancy, the risk of birth defects was also related to PM10 levels  and SO2 levels .The risk of birth defects was related to PM10 and SO2 during the second and third month of pregnancy may associated with the risk of birth defects.The study provides evidence that exposure to PM Air pollution not only contributes to global warming but also has deleterious effects on the human health . Childre defects .Birth defect is a part of a spectrum of adverse birth outcomes that may be associated with exposure to ambient air pollution. They have been a global public health issue, which are the main causes of early miscarriage, perinatal death and child disability. In China, the estimated prevalence is around 4% to 6% ,12. Appr2), nitrogen dioxide (NO2), and particles with an aerodynamic diameter of ≤10 um (PM10).There is growing evidence suggesting that ambient air pollution during pregnancy is associated with congenital anomalies. However, there has been limited research on the effect of air pollution during critical periods of pregnancy on birth defects. Based on air pollution monitoring network and birth defects surveillance system, we investigated whether maternal exposure to air pollution was associated with elevated birth defect risk in infants delivered between 2009 and 2011 in Haikou city, Hainan province. And we explore the sensitive gestations during which air pollution affect birth defects most significantly. We focused on air pollutants such as sulfur dioxide , neonate gender, and age of mother.10, SO2 and NO2 were obtained from Haikou Environmental Monitoring Center. Hourly readings were obtained for PM10, SO2 and NO2. A daily average was calculated for PM10, SO2 and NO2.For the period January 2009 to December 2011, air pollution data for PMWe calculated the exposure parameters from the monthly average concentrations for the duration of pregnancies from 2009 through 2011. We also calculated the average concentration over the days of gestation for first, second and third month of gestation as this is the critical period of gestation associated with birth defects .The effect of ambient air pollution on birth defects was estimated by logistic regression. We used odds ratio (OR) as a measure of the relation between exposure to air pollution and the risk of birth defects. We estimated adjusted OR using multiple logistic regression analysis and present the results as OR, along with 95% confidence interval (95% CI). We adjusted for risk factors that could potentially confound the relation between birth defects and air pollution. These factors were maternal age , maternal race , infant sex , birth weight (<2500/≥2500 g), gestational age (<37/≥37 weeks). We could not consider alcohol, tobacco and drug use during pregnancy, because these data are not recorded in the Haikou birth certificates. Statistical analysis was conducted using SPSS for Windows version 13.0.χ2 = 3.70, P = 0.05), shorter gestational age , low birth weight  and Han race .Characteristics of infants with or without birth defects are presented in Table 2 and PM10 showed no difference among three years (P > 0.05). The level of SO2 in 2011 was highest among three years, and there is difference among these years (P < 0.05).Descriptive statistics for air pollution levels during the study period are shown in Table 10 levels, particularly in the third month of pregnancy .Table 10 in the third month of gestation, after adjusting for other two air pollutants.Table 10 was 1.021 (95% CI = 1.008-1.034) for the third month of pregnancy.Table 10 levels  and SO2 levels  for the second month of pregnancy. In the third month of pregnancy, the risk of birth defects was also related to PM10 levels  and SO2 levels .Table 10 levels  and SO2 levels . In the third month of pregnancy, the risk of birth defects was also related to PM10 levels  and SO2 levels . The most susceptible time periods in pregnancy for the effects of SO2 and PM10 were the second and third month of gestation. SO2 is a major air pollutant produced from coal and oil combustion, which has significant impacts upon human health. Particulate matter includes a variety of pollutants that are suspended as particles in the air, such as road dust, ash and smoke.Birth defects are the main causes of perinatal death, missed abortion, and child disabilities and have been a global public health issue. They are generally caused by several factors. Risk factors which contribute to birth defects include genetic factors, environmental factors, chemicals and maternal elements . Our stu10, NO2, SO2, CO and O3 was examined and results showed that O3 was associated with an increased risk of aortic artery and valve defects and SO2 was associated with cleft lip with or without cleft palate [2, PM10, SO2, and O3) and found a statistically significant association between PM10 and patent ductus arteriosus [10 and atrial septal defect, and SO2 and ventricular septal defect [10, NO2, O3 and CO during each of the first three months of pregnancy was examined and the results only showed the association between CO and increased risk of cardiac ventricular septal defects, O3 and an increased risk of aortic artery and valve defects [There have been inconsistent results across previous studies that have examined associations between ambient air pollution and birth defects. And, each of these studies found only one or two associations. For example, in Brisbane, Australia, exposure to PMteriosus . The resl defect . In Sout defects .Compared with previous studies, one potentially important difference is that we estimated the effect of air pollution as categorical exposure, whereas other studies estimated the effect of air pollution as continuous exposure ,19. UsinPrevious studies have shown that maternal exposure to air pollutants can have teratogenic effects. Possible mechanisms of air pollutants on birth defect remain speculative. Air pollutants might be involved in the development of skeletal malformation via hemodynamic, anoxic events, oxidative stress, and toxicity to certain cell populations during pregnancy .10 exposures. Thus, the timing of PM10 exposure is consistent with embryo development. However, we also found a reduced risk associated with increased SO2 exposures in the second and third month, which might suggest these fetuses are vulnerable when exposed to SO2. We can not rule out ascertainment bias due to prenatal diagnosis as well as selective abortion of fetuses with birth defects. This observation on PM10 and SO2 might suggest that a different effect of air pollutants on birth defects.In our study, we observed an increased risk of birth defects for second-month and third-month PMOur study had several strengths. We conducted a large, population-based analysis using a high-quality birth defects monitoring network with air pollution monitoring data from Haikou Environmental Monitoring Center. To allow adjustment for the possible effect of weather on birth defects, some meteorologic factors, such as daily average temperature, humidity data were collected from Haikou Meteorological Bureau. We adjusted for several confounders in the logistic regression analysis to eliminate the factors as a potential explanation for our results. Our study used a large number of birth records based on birth certificates, which reduces uncertainties due to selection bias which is more common in smaller studies. Despite these efforts, however, residual confounding is possible. First, the monitoring period was 28 weeks’ gestation to 6 days after delivery, and babies with birth defect detected more than 7 days after delivery would be missed. And we can not study the effect of air pollution on infants with birth defect more than 7 days after delivery. Second, we assigned concentrations of air pollutants from the monitoring sites to all women residing in a large area rather than measuring each pregnant woman’s exposure to each pollutant during pregnancy. Second, several factors including maternal smoking, occupational exposures, and vitamin supplement use might be potential risk factors for birth defect. We were unable to evaluate, because they are not adequately reported on Haikou birth certificates.10 during the second and third month of pregnancy may contribute to the occurrence of birth defects. To date, a limited body of evidence has linked maternal exposure to ambient SO2, NO2 and PM10 to the occurrence of birth defect. Further studies are needed to address these associations.Our study contributes to a growing body of epidemiologic literature on the adverse reproductive effects of air pollution exposure. Our results suggest that exposure to PM


Understanding the genetic contribution(s) to the risk of preterm birth may lead to the development of interventions for treatment, prediction and prevention. Twin studies suggest heritability of preterm birth is 36–40%. Large epidemiological analyses support a primary maternal origin for recurrence of preterm birth, with little effect of paternal or fetal genetic factors. We exploited an “extreme phenotype” of preterm birth to leverage the likelihood of genetic discovery. We compared variants identified by targeted sequencing of women with 2–3 generations of preterm birth with term controls without history of preterm birth. We used a meta-genomic, bi-clustering algorithm to identify gene sets coordinately associated with preterm birth. We identified 33 genes including 217 variants from 5 modules that were significantly different between cases and controls. The most frequently identified and connected genes in the exome library were IGF1, ATM and IQGAP2. Likewise, SOS1, RAF1 and AKT3 were most frequent in the haplotype library. Additionally, SERPINB8, AZU1 and WASF3 showed significant differences in abundance of variants in the univariate comparison of cases and controls. The biological processes impacted by these gene sets included: cell motility, migration and locomotion; response to glucocorticoid stimulus; signal transduction; metabolic regulation and control of apoptosis. Despite significant advances in the care of pregnant mothers and infants, preterm birth remains a leading cause of newborn morbidity, mortality and hospitalization in the first year of life in the United States . In deveA precise estimate of the contribution(s) of genetic factors to preterm birth has been difficult to achieve –17. TwinAttempts to identify the genetic contributions to the risk of preterm birth have been pursued widely , 25, 26.a priori connection to preterm birth , PhyloP [prediction of a conserved (>0.95) or non- conserved (<0.95) site], and chromosome position .In order to focus on putatively relevant variants, we eliminated the bulk of the identified variants for immediate investigation because they were equally common in cases and controls. Using a Markov Chain Monte Carlo (MCMC) Fisher Exact Test, we created a 2 x 3 contingency table for zygosity testing to compare the frequency of homozygosity for the reference allele, heterozygosity or homozygosity for the minor allele. The results are shown in For each patient , we built a gene list for each patient for GSEA. In order to ensure that we analyzed enough genes in each patient to conduct gene set enrichment, we relaxed the significance threshold on genes from p <.05 to p <.1. We ran GSEA on each patient’s gene list independently . We used-value was calculated indicating the probability that the observed counts could have resulted from randomly distributing the associated GO terms between our genes and modules. GOstat corrects for multiple comparisons by employing a false discovery rate, p <.05.We sought to provide a representation of the biological processes encompassed by these gene sets using the Gene Ontology (GO) Database. The Gene Ontology Database describes genes in terms of their associated biological processes, molecular functions and cellular components. Using GOstat, the genes shown in the clusters were tested for their statistical association with GO terms . The proS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableGenes from each module were used in GO to describe biological functions.16 Each biological function and module number is shown for the nine clusters. Modules are shown as large solid figures. Connections (“edges”) between biological functions in different clusters are shown.(DOCX)Click here for additional data file.


Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼3 Å (∼diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2–0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.Hyperkalemia, a condition in which serum potassium ions (K Since the K+–oxygen interactions balance the energy lost due to the removal of the water molecules , it becomes energetically favorable for K+ to move through the filter. However, when Na+ shed their hydration shells, they are too small to interact effectively with the optimal number of oxygen molecules in the ion channels, making it energetically unfavorable for them to pass through the filter. Due to the pore size and composition, microporous zirconium silicate drug candidates can effectively mimic the highly selective nature of physiologic K+ channels in the body.Physiologic ion channels take advantage of the differing diameters of ions to selectively filter certain cations . For exa2+, there are a number of clinically relevant reasons why a Ca2+ counter ion would be a poor candidate. The target population for ZS-9 therapy is likely to be patients with chronic kidney disease (CKD), who are at increased risk for hyperkalemia as the kidney is responsible for>90% of K+ excretion. Since CKD patients have difficulty buffering increased Ca2+ loads, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines caution against high Ca2+ intake in these patients + as the counter cation in the cation exchange, there have been issues with Na+ loading due to the lack of cation specificity that necessitates the use of high doses of SPS to achieve efficacy + was also not considered ideal. Ultimately it was decided that partial protonation  would provide the optimum composition.During the drug development process, it was important to select counter ions that would be appropriate for the target patient population. Aside from limited ability to take up Ca+ by total weight. Unlike organic polymers such as SPS, ZS-9 is an inorganic cation exchange crystalline compound that has a high capacity to selectively entrap monovalent cations, specifically excess K+ and ammonium ions, over divalent cations such as Ca2+ and magnesium (Mg2+), as it traverses the GI tract. Because ZS-9 is not systemically absorbed, the risk of systemic toxicity is very low, as demonstrated in three prospective, randomized, double-blind, placebo controlled studies in over 1100 patients The form of ZS-9 under development for therapeutic use is a non-absorbed, insoluble, free-flowing, odorless, tasteless, white crystalline powder with a specific particle size distribution profile>3 µm. The molecular formula of sodium zirconium cyclosilicate has a specific, and constant, ratio of zirconium and silicon atoms and contains less than ∼8% Na+, the aim of this publication was to characterize the structure, mechanism of action, and ion exchange properties of ZS-9 as a potential therapeutic in the treatment of patients with hyperkalemia.Based on the high specificity of ZS-9 to entrap K1 radiation (λ = 1.5406 Å) using a MiniFlex-600 diffractometer . The software suite Jade 9.5 Professional  was used to perform the full pattern least squares Rietveld calculations. With the refined atom positions, the interatomic distances were calculated using ATOMS version 6.0 . The size of the pore opening was calculated by subtracting twice the atomic radius of oxygen  from center–center oxygen–oxygen interatomic distances.The interatomic distances of atoms forming the pore of ZS-9 were calculated from the Rietveld structural refinement. For this, a sample of ZS-9 was dried and ground in an agate mortar, then placed into a powder X-ray diffractometer. Data were collected at room temperature from 5–80° 2-theta with monochromated Cu α+, in addition to Ca2+ and Mg2+ at different ratios . After 2 hours of gentle agitation at room temperature, an aliquot was taken from the supernatant and the cations quantified by ion chromatography using a Dionex Model ICS-1100 , coupled to an AS-DV autosampler.Equal concentrations (100–200 mg) of ZS-9 or SPS was added to 20 mL solutions containing standard ppm concentrations of K+The effect of pH on the KEC of ZS-9 at 0.5, 5 or 50 mg/ml was determined in media buffered to mimic the pH of different portions of the human gastrointestinal (GI) tract and which contained a specified amount of K+ at pH 1.2 (SGF), pH 4.5  or at pH 6.8  at 37°C with constant agitation. Aliquots of 5 mL of the solutions were removed at 0, 5, 10, 20, 30 min and 1, 2, 4, 8 and 24 hrs and the K+ concentration quantified by atomic emission spectroscopy using a Shimadzu AA6200 spectrophotometer  and an air–acetylene gas mixture.In a second study, ZS-9 (2 mg/ml) was incubated in solutions containing 2500–3500 ppm K6]-2 units. The counter ions located within the micropore channels provide electrical neutrality to the structure. The framework–counter ion interactions are electrostatic in nature, i.e., ionic bonds.Based on the structural solution for zirconium silicate proposed by Bem et al. Detailed analysis of the structure reveals that the pore opening in the ZS-9 framework is composed of an asymmetrical seven-member ring . On ave+, Ca2+ and Mg2+ are summarized in 2+ and Mg2+ were below 0.05 mEq/g, the analytical method lower limit of quantification (LLOQ). Based on this LLOQ, ZS-9 had a>25-fold selectivity for K+ over either Ca2+ or Mg2+, whereas the selectivity of SPS for K+ was only 0.2–0.3 times its selectivity for Ca2+ or Mg2+. SPS was found to be highly selective for Ca2+.The exchange capacities of ZS-9 and SPS for the different solutions containing KThe ZS-9 KEC increased proportionally with concentration over the 0.5 to 50 mg/mL ZS-9 range tested. There was no significant effect of pH on the KEC of ZS-9 at 50 mg/mL but at ≤5 mg/mL there is a dose dependent decrease in KEC with decreasing pH. At a pH of approximately 1.2 and at concentrations of 0.5 and 5.0 mg/mL the binding capacity of ZS-9 was decreased by 91 and 67%, respectively compared to the binding capacity observed in neutral media .+ over time in the different pH media following incubation with ZS-9 in the second study are presented in +, which reversed soon thereafter. In the simulated small intestinal fluid (pH∼4.5), there was an immediate uptake of K+, followed by a small release, with equilibrium reached in about 20 minutes. In the simulated large intestinal fluid (pH 6.8), there was a rapid uptake of K+ during the first 10 minutes, followed by continued, but slower, uptake .The concentrations of K, uptake  over the+ ion is similar to that of the ZS-9 pore (∼3.0 Å), indicating that K+ cations can fit more effectively within the lattice structure of ZS-9 after they shed their hydration shell.The substantial differences in the sizes of monovalent and divalent cations  can be u+ channels to achieve its selectivity for capturing K+ ions. Hydrated cations, such as Na+ and Ca2+, have larger ionic diameters >Na+>H+. For non specific compounds the majority of the potassium exchange is confined to the colon where there is a large K+/Na+ ratio (8∶1) but due to its high specificity for potassium, ZS-9 is expected to work along the entire length of the GI tract.The selectivity of ZS-9 for K+ ions by ZS-9 at pH 1.2, which reverses with time. However, as the pH increases, there was a rapid and sustained uptake of K+. The pH of the human stomach lumen varies between 1 and 3 + uptake is dependent on the amount of ZS-9 present, the composition of the ionic environment and time of contact. While K+ uptake is likely limited at very low pH due to a large excess of protons, based on the in vitro data, some K+ exchange will likely begin in lower pH environments in the presence of higher concentrations of ZS-9 and increase as it passes along the GI tract due to the higher potassium concentrations and luminal pH. This is supported by the fact that statistically and clinically significant decreases in serum K+ occurred within 1 hour of dosing in three clinical studies + from baseline to one hour after the first 10 g ZS-9 dose compared to respective placebo groups  + were observed in patients with the highest baseline serum K+ values + levels was rapidly achieved (median of 2.2 hours) and maintained. ZS-9 exhibited an overall safety profile, including GI tolerability, similar to placebo in all three studies Experiments in environments mimicking the GI tract showed what appears as an early uptake of KZirconium has been used extensively in both dental and medical applications because of its high biocompatibility and very low toxicity. Zirconium is widely used in dental implants, middle ear implants, and other restorative practices with large amounts embedded in the body + when compared to currently available options.If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K