Introduction. In Sub-Saharan Africa, excessive foetal head moulding is commonly associated with cephalopelvic disproportion and obstructed labour. This study set out to determine the associations of maternal pelvis height and maternal height with intrapartum foetal head moulding. Methods. This was a multisite secondary analysis of maternal birth records of mothers with singleton pregnancies ending in a spontaneous vertex delivery. A summary of the details of the pregnancy and delivery records were reviewed and analysed using multilevel logistic regression respect to foetal head moulding. The alpha level was set at P < 0.05. Results. 412 records were obtained, of which 108/385 (28%) observed foetal head moulding. There was a significant reduction in risk of foetal head moulding with increasing maternal height , maternal pelvis height , and raptured membranes . There was a significant increased risk of foetal head moulding with increasing birth weight  and duration of monitored active labour  in the final model. Conclusion. This study showed that increasing maternal height and maternal pelvis height were associated with a significant reduction in intrapartum foetal head moulding.  Foetal head moulding has been described as one of the responses of the foetus to cephalopelvic disproportion (CPD) associated with childbirth . CPD is The human female pelvis is prone to CPD as explained by its evolutionary description and adaptation between the bipedal gait and the need to allow the passage of a large brained foetus . MalnutrObstructed labour as a result of CPD remains common in Sub-Saharan Africa . In thisThe research leading to this paper was driven by a concern for the quality of foetal outcomes in the presence of foetal head moulding. Foetal head moulding has been associated with severe damage to the newborn child's brain –3. This This was a secondary analysis of data of 412 birth records from mothers whose active phase of labour was recorded on a WHO modified partogram. These 412 birth records meeting the study inclusion criteria were selected from a larger pool of 673 birth records obtained during the parent study (see http://www.openepi.com) with the following assumptions: α = 95%, β = 0.05, and ratio of exposed to unexposed = 1. This gave a total of 328 records to obtain a minimum risk difference of 20% assuming that 50% of the unexposed had foetal head moulding. This value of 328 records was increased by a 1.3 allowance for the design effect at multiple sites to give a final target sample size of 427 birth records. For each record we obtained information on site, maternal age, maternal weight, gravidity, symphysis-fundal height, augmentation of labour, and the observation of foetal heart rate, cervical dilation, head descent, strength of uterine contractions, and status of the foetal membrane, whether raptured spontaneously or artificially, at each of the routine two hourly examinations. In addition data was extracted on the following: liquor staining, observed foetal head moulding, presence of caput succedaneum, birth weight, sex of baby, duration of labour, and APGAR score at 5 minutes, for each childbirth record. A record was also made of the maternal pelvis height by each of the participating midwives who had been trained in how to make this measurement using a pair of rigid rulers held at right angles with the point of one ruler on the most anterior and superior palpable point of the pubis bone of the pelvis and the other ruler on anterior superior iliac spines as shown in The target sample size was 427 birth records of mothers who had normal deliveries. This was obtained using the sample size formula for cohort studies in the open EPI software  and exported to STATA 12  for eventual analysis. Descriptive statistics were generated using means with additional comparisons for differences between sites using ANOVA. Multilevel logistic regression, using the gllamm function with Poison's distribution methods to control for clustering of repeated examinations on mothers at the different sites, was used to calculate the Incident Risk Ratios (IRRs) for foetal head moulding against the various predictor factors. Stepwise backward multilevel Poisson's regression was used to identify the significant variables of interest in the final model. Maternal height was retained in the final model as one of the key anthropometric measurements under study. During analysis records with missing values were dropped. The level of significance was set as Ethical considerations for the parent study  includedIn P < 0.01).On multilevel multivariable Poisson's regression modelling the following previously significant variables become nonsignificant: cervical dilatation, foetal head descent, and strength of uterine contractions. We set out to determine the associations between maternal anthropometric measurements: maternal height and maternal pelvis height with intrapartum foetal head moulding in Ugandan mothers having spontaneous vertex deliveries. We found that only maternal pelvis height was associated with intrapartum foetal head moulding on final modelling. We found that for each centimetre increase in maternal pelvis height was associated with a significant 22% reduction in the risk of foetal head moulding compared with a borderline significant 3% reduction in the risk of foetal head moulding with each unit increase in maternal height, keeping all the other factors constant.the level of the symphysis pubis,” could influence the outcomes of labour due to its association with pelvis inclination [The significant reduction in risk of foetal head moulding associated with increasing maternal pelvis height  could belination . Accordilination . Thus weThis assumption of adequacy of the maternal pelvis diameters forms the basis of the second possible explanation for the significant reduction in the foetal head moulding with increasing maternal pelvis height. In Maternal height though retained in the final model was found to be nonsignificant see . There aSome of the limitations of this study include the small sample size for detecting the smaller risk ratios as was noted for maternal height and the additional challenges related to use of birth records in these settings . Proper In conclusion this study shows that increasing maternal pelvis height is associated with a significant reduction in intrapartum foetal head moulding. Increasing maternal height was associated with a nonsignificant reduction in risk of intrapartum foetal head moulding. This study shows that maternal pelvis height may be a good measure for the prediction of foetal head moulding by health workers in low resource settings thus aiding in early referral of mothers to the next level health facilities for better care. There is a need for more studies to standardise these measurements and identify clinically relevant cut-off values for use in various low resource settings as is seen in most of the remote and rural areas of Africa.


Birth asphyxia is one of the commonest causes of neonatal morbidity and mortality in developing countries. Together with prematurity and neonatal sepsis, they account for over 80% of neonatal deaths.To determine the incidence and mortality rate of birth asphyxia in Warri Niger Delta of Nigeria.Recovery of case notes of all the newborn babies seen from January 2000 to December 2007 at Central Hospital Warri and GN children’s Clinic, Warri, was undertaken. They were analyzed and those with birth asphyxia were further analyzed, noting the causes, severity of asphyxia, sex of the babies, management given.A total of 864 out of 26,000 neonates seen within this period had birth asphyxia. 525 (28/1000 live births) had mild asphyxia while 32% were severely asphyxiated. 61.5% of the asphyxiated were born at maternities, churches or delivered by traditional birth attendants or at home. Prolonged labour was the commonest cause of asphyxia and asphyxia was more in neonates from unbooked patients.The incidence of bith asphyxia in Warri is 28/1000. Majority of patients are from prolonged labour and delivery at unrecognized centres. Health education will dratically reduce the burden of asphyxia neanatorum as unsubtanciated religous beliefs have done a great havoc. Birth asphyxia is a major cause of neonatal death especially in developing countries and is defined as the inability of the newborn to initiate and sustain adequate respiration after delivery . Of the St century and Papile has commented on apgar score in the 21st century  of these patients was documented, including the duration of follow up. Deaths after discharge from the hospitals following birth asphyxia were not included in this study.From the twenty six thousand four hundred and twenty thousand neonates delivered or referred to these hospitals, eight hundred and forty had asphyxia, giving a rate of approximately twenty eight per one thousand live birth (28/1000).The yearly distribution of the incidence of aspyxia neonatorum is shown in Three hundred and thirty six, representing 40% of the asphyxiated babies were born in maternities and churches. Infact 61.5% of the babies were born in the maternities, churches, traditional birth attendants or at home. About 2.5% or twenty one of the babies were born in transit (delivered on the way to the anticipated place of birth). The mothers of five hundred and four babies did not book for antenatal care representing 60% of the asphyxiated babies.About 51% of the asphyxiated babies (which is four hundred and twenty nine) resulted from prolonged labour. Antepatum haemorrahage accounted for 10% of the cases. Only 25 of the asphyxiated babies were premature while multiple gestations accounted for 8%. Abnormal presentation including cord prolapse and cord prolapse with fetal distress accounted for 8%. Other causes apart from prematurity include hypertension in pregnancy which accounted for 12% of the cases, age of the mother, maternal pyrexia during the perinatal period, anaemia in pregnancy and others. These are shown in 324 had mild asphyxia which is 38.2% while 250 of these had severe birth asphyxia. These are shown in The mortality rate was 27.3% which is two hundred and twenty nine patients. Of these, 52%, about one hundred and nineteen had severe birth asphyxia. 43% of the deceased neonates had moderate asphyxia which translated to ninety eight patients, while twelve of these had mild asphyxia which is 5%. One hundred and fifty three of the deceased children were males and seventy six females, giving a ratio of 2:1.Mortality ratio as shown in 1 A study by Birth asphyxia remains a leading cause of neonatal morbidity and mortality in Nigeria.The incidence of 28/1000 live births in our study is slightly more than Airede’s experience of 26.5/1000 live births from Fox University, Nigeria (1991)  and anotThere was also no significant difference in the yearly distribution in Airedi’s study which was carried out over three consecutive years . Our stuThe incidence was higher in males probably because of females resistance to diseases as a result of their XX chromosomes, X being the site of immunoglobulin production, giving them double protection . Birth aOur study also showed that the major cause of asphyxia Neonatorum is prolonged labour, which is same result in other center . The incMortality rate in those with severe birth asphyxia was also similar with other studies . In factTH millennium goal. This is a major reflection of the obstetric care in the countries. Ignorance and poverty of the populace are other major reasons for birth asphyxia. Prof Babatunde Oshotumihien of Nigera as the minister of health tried to implement a policy where midwives will be posted to rural areas with an incentive of earning triple the salary of their contemporaries in the urban areas (Birth asphyxia remains a leading cause of morbidity and mortality in developing countries, not only neonatal mortality but under five mortality. It is also a major setback in achievement of the 4an areas . This wo


Intrapartum-related complications  are a significant contributor to deaths of newborns in Bangladesh. This study describes some of the perceived signs, causes, and treatments for this condition as described by new mothers, female relatives, traditional birth attendants, and village doctors in three sites in Bangladesh. Informants were asked to name characteristics of a healthy newborn and a newborn with difficulty in breathing at birth and about the perceived causes, consequences, and treatments for breathing difficulties. Across all three sites ‘no movement’ and ‘no cry’ were identified as signs of breathing difficulties while ‘prolonged labour’ was the most commonly-mentioned cause. Informants described a variety of treatments for difficulty in breathing at birth, including biomedical and, less often, spiritual and traditional practices. This study identified the areas that need to be addressed through behaviour change interventions to improve recognition of and response to intrapartum-related complications in Bangladesh. Worldwide, more than three million newborn babies die , and anoIn South Asia, an even greater proportion 52.3%) of under-five deaths occurs during the neonatal period, with 10% of all under-five deaths attributed to intrapartum-related complications 2.3% of u. UnskillThis paper focuses on the first stage of a three-phase, three-site study on prolonged labour and intrapartum-related complications in home-birth settings in Bangladesh. This study was a collaborative work between Emory University and three internationally-recognized organizations in Bangladesh: icddr,b, BRAC, and LAMB Integrated Rural Health and Development. The objective of this study was to understand how new mothers, female relatives, traditional birth attendants, and village doctors recognize and respond to a newborn with difficulty in breathing after birth in home-birth settings in three sites in Bangladesh.In this paper, we present the first stage of a three-phase study, an analysis of interviews with new mothers, female relatives, TBAs, and village doctors (n=240) in one urban and two rural sites in Bangladesh. In this analysis, we used successive freelisting techniques to elicit (i) how informants in these three sites recognized a healthy newborn and a newborn with difficulty in breathing at birth and (ii) informants’ descriptions of the causes, consequences, and care practices for a newborn with such breathing difficulties.The study was conducted at two rural sites (Matlab and LAMB) and one urban site (BRAC) in Bangladesh. Matlab Health Research Centre of icddr,b in Matlab, Chandpur district, is located in a densely-populated rural area of Bangladesh. Beginning in 1966, icddr,b has been continually operating a Health and Demographic Surveillance System (HDSS) for a rural population of approximately 220,000 and has been operating a Maternal, Child Health and Family Planning programme since 1978. Four subcentres provide 24-hour nursing and midwifery services. In 2007, forty-four percent of births took place at home, and the neonatal mortality rate was 20.6 per 1,000 livebirths, with 29% of these deaths attributed to intrapartum-related complications.Manoshi, a community-based intervention aimed at reducing maternal, neonatal, and child death and addressing other diseases in urban slums in Dhaka. The two largest slum areas—Korail (3 delivery centres) and Kamrangir Char (7 delivery centres) were chosen as the sites for the study. In 2006, the neonatal mortality rate in Dhaka's urban slums was 43.7 per 1,000 livebirths  serves a population of approximately one million, with LAMB Hospital serving as a referral centre for a broader population of 2 to 2.5 million. From the LAMB CHDP area, four geographical areas (unions), with home-birth rates ranging from 65% to 92%, were selected. Data from verbal autopsy showed that, in 2007, the average perinatal mortality rate was approximately 48 per 1,000 births, and 41% of early neonatal deaths were attributed to intrapartum-related complications.This was the first phase of a larger study funded by Emory University Global Health Institute, focusing on recognition of and response to prolonged labour and birth asphyxia.To ensure the breadth and depth of terms and concepts, we obtained a sample of 100 informants at each site—20 each from five different groups that are important in the home-birth setting. They included: (i) women of reproductive age who gave birth in 2007; (ii) older female relatives (aged 50-70 years) living in the extended family and potentially influential in matters relating to childbirth ; (iii) traditional birth attendants (TBA); (iv) village doctors ; and (v) skilled birth attendants (SBA) who provided care at local hospitals and subcentre clinics. The sample-size for each subgroup was calculated based on an assumed low level of cultural sharing (0.50), and high degrees of accuracy (0.95) and confidence (0.95) -13. We iThe study protocol was approved by Emory University's Institutional Review Board, the Ethical Review Committee of icddr,b and the LAMB Research Ethics Committee. The BRAC Management Technical Committee reviewed and approved the proposal, and the study was allowed to proceed after ethical review was approved by icddr,b. Trained interviewers obtained voluntary verbal informed consent from all informants.The research team developed a semi-structured questionnaire to elicit local words and short phrases associated with newborns . The questionnaire consisted of open-ended questions to elicit spontaneous responses, using successive freelisting, a technique that asks informants to list all the local terms (or items) they know in a particular domain . For theAt each site, there were at least two trained interviewers who conducted face-to-face interviews in the local language Bangla at a time and place convenient for the informant. Many of the interviewers had a background in social science, and all received training from the study investigators. During data collection, quality was ensured through verification at the conclusion of each interview, daily debriefing about interviews among study teams, and communication among team leaders and principal investigators, if questions arose. In addition, each interview was audio-recorded, and interviewers recorded informants’ verbatim responses directly against the completed questionnaire.Information in the completed forms was transcribed and translated into English and uploaded into EZ-text, a software for qualitative data management . Using aFollowing the initial development, three rounds of coding were used for further refining the codebook, with inter-coder reliability statistics (kappa) calculated for each round. At this point, the two coders coded the entire set of responses from one site—Matlab (n=100)—with a reliability check taking place at the midpoint and completion of coding. Upon completion of coding, discrepancies were discussed and resolved by mutual agreement. The process was repeated for the responses from BRAC and LAMB, with the final codebook developed, tested, and refined across all three sites.We retained all codes which had high inter-rater reliability (kappa >0.8) and that were also mentioned by >20% of informants (for at least one site) or were of theoretical interest. We summarized frequently-mentioned signs of both a healthy newborn and a newborn with breathing difficulties and the causes and care practices associated with such a baby across all three sites in tables and charts. In analyzing similarities and differences across sites, we also used quotes from respondents to emphasize and clarify the quantitative findings.Throughout the study, deliberate steps were taken to ensure that results were culturally relevant and meaningful. These protections included close communication between independent coders located in the United States and local research teams of native Bangla speakers at each site. Other quality control measures included a glossary of local terms to aid in translation and coding and frequent inter-rater reliability checks during coding.In all three sites, the majority of informants were married and Muslim. All of the village doctors were men, and the other informants  were all women. Women of reproductive age were younger, had lower parity, and reported receiving higher levels of education than both elder influential women and the TBAs. Across all sites, the male village doctors reported the highest levels of formal education. Informants from the BRAC site, located in Dhaka, reported higher income than informants in rural areas .Informants were asked to describe the characteristics or the signs of a healthy newborn and a newborn with difficulty in breathing at birth. Specifically, informants were asked to describe the breathing pattern, colour, crying, movement, and other signs, indicating either a healthy newborn or a newborn with breathing difficulties. Informants depicted the breathing of a healthy newborn with a number of non-specific signs, including deep breathing, rapid breathing, indeterminate breathing, and most commonly, slow breathing. While a majority of informants from BRAC (75%) and Matlab (61%) stated that a healthy newborn had slow breathing, this answer was less common for respondents from LAMB (38%). In fact, slow breathing was the most commonly-identified sign of difficulty in breathing at birth for informants from the LAMB site (59%). The most frequently-mentioned descriptions of a newborn with difficulty in breathing at birth varied between sites, with ‘no breathing’ highest for the BRAC site (65%) and ‘gasping’ highest for Matlab (48%).Across all sites, informants were fairly consistent in their characterization of the sounds and movements of healthy newborns and newborns with breathing difficulties. Healthy newborns cry  and move vigorously (≥95%) while newborns with breathing problems have no cry (≥54%) and no movement (≥65%).In general, whitish colour was associated with a healthy baby, with over 60% of informants mentioning this in all sites. Blackish colour was most frequently associated with a baby with difficulty in breathing at birth . The reverse was also common, as in two locations (BRAC and Matlab), a sizeable number of informants (over 20%) in each site cited blackish colour as a sign of a healthy baby while 19% of informants at LAMB and BRAC and 20% at Matlab cited whitish colour as a sign of a baby with breathing difficulties.alga batas), and the mother or the baby getting cold during pregnancy .More informants from LAMB (34%) mentioned obstructed labour  as a cause of breathing difficulties at birth compared to informants from BRAC (14%) or Matlab (18%). Across all sites, informants were consistent in their description of the baby getting ‘stuck’ in the mother's uterus. A woman who gave birth in 2007 recounted:The baby can't take breath, when it becomes stuck at mother's mouth of uterus .An informant from the LAMB site echoed this view:The baby is stuck in the mouth of the uterus because the mouth of the uterus is narrow; the baby can't come out easily, they have difficulty in breathing .Informants perceived that injury to the baby, including mishandling, frequent vaginal exams, rotating the child, mismanagement of labour, and injury in mother's abdomen could cause breathing problems. This belief, while expressed across all sites, was a prominent response among informants from BRAC (36%) compared to the LAMB site (9%) and Matlab (10%):dai (home-based birth attendant) holds the baby's neck and pulls to make baby out from abdomen, the baby gets pressure and, after birth, the baby can't take breath .During delivery, if the Across sites, informants attributed malnourishment and weakness of both mother and newborn as contributing to difficulty in breathing at birth:If the mother cannot take food in her pregnancy period, then her baby has malnutrition, and it may have the breathing problem .Due to the mother's lack of nutrition, meaning when she is pregnant, she didn't eat fruits properly; so, she has no strength, she can't push to deliver; so, the baby comes late; for this reason, they have difficulty in breathing .Informants also perceived traditional and spiritual causes for difficulty in breathing at birth. Informants from Matlab  and BRAC , and to a lesser extent, from LAMB  perceived coldness of either mother or baby  as a cause:Baby gets cold from mother. If mother [takes] bath late in the evening or eat cold rice, do not dry her hair for long time, the baby in the womb will get cold and cause breathing problem later .If mother touches cold water several times during pregnancy, then the baby also gets cold and just after birth, that baby can't take breath .While not seen in informants’ responses from the LAMB site, informants from both BRAC (16%) and Matlab (20%) attributed breathing difficulties of the baby at birth to evil air or evil spirits:If the evil air touches the mother when she goes outside in the mid-noon or night, her baby would have the breathing problem .During pregnancy period if mother moves outside at dawn, then evil spirit comes and catches the baby's neck with pressure in mother's abdomen; then after birth, that baby can't take breath .Informants were asked to name the things that are done to help a newborn with difficulty in breathing at birth, both at home and in a health facility. As the focus of this analysis is on home-based care, we analyzed only the responses addressing home-based care practices. In addition to biomedical care practices , informants also mentioned traditional (massage with oil and soaking/stirring the placenta) and spiritual care practices .No single care practice was mentioned by more than 40% of informants at one site. Soaking or stirring the placenta, the most frequently-mentioned home-based care practice for informants from Matlab (38%), was only mentioned by 10% of respondents from the BRAC site and none from the LAMB site. An elder influential woman explained the rationale for this care practice:Dai puts the placenta into the cold water because then the breath comes to the baby … [because] if the placenta is made wet in the cold water, then the baby begins to take breath .A village doctor said:If the placenta is moved/stirred on warm water, then gradually, the baby starts to breathe. I also do this. I suggest others to do that. By this way, the baby was kept alive … [because] the baby can take oxygen from the placenta .Informants across all three sites mentioned massaging the baby with oil, mustard, or garlic as a treatment:Garlic and oil they heat up, and they massage their [baby's] hands and legs so that the baby will be warm and will get healthy .In addition to these traditional treatments, informants in all sites described spiritual care practices, including exorcisms, blessed blows, and amulets intended to help the newborn breathe:kobiraj do exorcism; so that the baby can take breath .The traditional healer fakir; massage the blessed oil on her/his body… to save the baby from evil spirit .Give the baby blessed blow, amulets, blessed oil by a Biomedical treatments mentioned by informants included mouth-to-mouth breathing, covering or wrapping the baby in cloth, and stimulating the baby:They blow in the baby's mouth so that the breath will come, and it will cry .Wrap the baby so that baby remains warm. In this way, baby might start taking breath .Dai gives pat on the back of baby …after giving pat, the baby starts crying. When baby cries, baby can take breath The findings from this study indicate fairly consistent agreement in terms of signs, causes, and treatments for babies with difficulty in breathing at birth, with some variation among sites. These findings are important to focus the development of health education messages to identify babies with difficulty in breathing at birth and ensure appropriate care and treatment.Across all sites, respondents reported not crying or moving at birth as a sign of a breathing problem. However, there was some variation among sites in terms of the rate of breathing. In Matlab and BRAC sites, slow breathing indicated a healthy baby while, in the LAMB site, slow breathing indicated both a healthy and an unhealthy baby. There was also discrepancy in terms of the colour of the baby. In all three sites, respondents differentiated between ‘white’ and ‘black’ colour of the baby. Some respondents perceived a ‘white-colour baby’ to be healthy, and others perceived the same baby to be unhealthy. The same finding was true for babies perceived to be ‘blackish’ in colour. The variation among respondents, both within and between sites, reflects the challenges in identifying and describing the breathing patterns and colour of both healthy and unhealthy newborns.alga batas) was cited as a cause of difficulty in breathing at Matlab and the BRAC site. While evil spirit was not cited in the LAMB site under questions relating to the cause of difficulty in breathing at birth, spiritual treatments for breathing difficulties  were described with similar frequency across all three sites. In South Asia, babies are perceived to be vulnerable to illness and susceptible to evil spirits in the first month of life  is feasible, especially in settings where home-based birth is the norm, and community-based cadres are available (Overall, this study provides useful findings on how women, village doctors, and traditional birth attendants in three diverse sites in Bangladesh differentiate between healthy babies and those with perceived difficulty in breathing at birth. The findings demonstrate that there are common signs and symptoms to identify babies with difficulty in breathing at birth as well as causes and treatments. As a consequence of our focus on comparability across sites, we were limited in our ability to fully capture the complexities within each site, for instance, the differences between different categories of respondents, such as older and younger women. Additionally, while respondents from the LAMB site did not mention stirring or soaking the placenta as a treatment for difficulty in breathing, they mentioned other placental practices, which were not included in the analysis because these were not among the most frequently-mentioned care practices across sites. Although beyond the scope of this study, future research, such as in-depth qualitative analysis of responses from each individual site, would be appropriate to address these limitations. Likewise, although a single codebook and coding strategy was applied consistently across sites, differences in interviewers, interview techniques, and local terminologies may explain some of the heterogeneity of findings across sites. Despite this, the consistency in findings across sites is encouraging and provides some evidence that recognition of intrapartum-related complications may be easier than other health complications of the newborn, such as infection. However, recognition of the problem is the first step, and appropriate and timely care-seeking is essential, especially for intrapartum-related complications where death can occur minutes after birth if not appropriately managed.Intrapartum-related complications account for 23% of all deaths of newborns in Bangladesh . This stThis research was funded by a grant from the Emory Global Health Institute. We would like to thank Daniel Hruschka, Khaleda Jasmin, Stacy Saha, Afroza Khanom Roza, Swateeprova Rahman, Tammanna Gazi, and Shahinoor Akter for their contributions to this research.


A large literature has indicated a robust association between birth spacing and child survival, but evidence on the association of birth timing with physical growth in low and middle income countries (LMICs) remains limited.Data from 153 cross-sectional Demographic and Health Surveys (DHS) across 61 LMICs conducted between 1990 and 2011 were combined to assess the association of birth timing with child stunting (height-for-age z-score <−2). A total of 623,789 children of birth order 1–5 contributed to the maternal age analysis, while the birth spacing dataset consisted of 584,226 children of birth order 2 and higher. Compared to 27–34 year old mothers, maternal age under 18 years was associated with a relative stunting risk of 1.35 (95% CI: 1.29–1.40) for firstborn children, whereas the relative risk was 1.24 (95% CI: 1.19–1.29) for mothers aged 18–19 years. The association of young maternal age with stunting was significantly greater for urban residents and those in the top 50% of household wealth. Birth intervals less than 12 months and 12–23 months had relative risks for stunting of 1.09 (95% CI: 1.06–1.12) and 1.06 (95% CI: 1.05–1.06) as compared to a 24–35 month inter-pregnancy interval, respectively. The strength of both teenage pregnancy and short birth interval associations showed substantial variation across WHO region. We estimate that 8.6% (6.9–10.3%) of stunted cases in the South Asian DHS sample would have been averted by jointly eliminating teen pregnancies and birth intervals less than 24 months, while only 3.6% (1.5–5.7%) of stunting cases would have prevented in the Middle East and North Africa sample.Postponing the age of first birth and increasing inter-pregnancy intervals has the potential to significantly reduce the prevalence of stunting and improve child development in LMICs. Approximately 16 million teenagers (under 20 years of age) give birth each year worldwide, of which more than 90% reside in low and middle income countries (LMICs) Approximately one-third of children under age 5 in LMICs, or about 314 million children, are currently affected by linear growth restriction or stunting While previous studies have documented associations between birth timing and child physical growth The dataset utilized for this study was pooled from 153 cross-sectional Demographic and Health Surveys (DHS) conducted 1990 to 2011 in 61 low and middle income countries. DHS are nationally representative surveys of households that collect a wide-range of data with emphasis on maternal and child health indicators. The 61 DHS countries  were excluded due to implausible height-for-age z-scores (HAZ) (< -6SD or >6SD), and an additional 138 children (0.1%) were excluded due to missing covariate information. The maternal age analysis was restricted to 623,789 children of birth order 1–5 due to the implausibility of having more than five children during the teenage years, while the birth interval dataset included all 584,226 children of birth order 2 and higher.Maternal age and birth spacing was assessed by self-report of the mother. Given that exact dates of conception are not available within the DHS dataset, we follow the previous literature Log-poisson models were used to estimate relative risks for stunting employing the methodology of Zou A priori we decided to present stratified categorical analyses by sex, urban/rural residence, household wealth , and WHO World Bank region to assess heterogeneity in estimates. Potential modification of the maternal age association by birth order (firstborn versus birth order 2–5), birth spacing by birth order (birth order 2–5 versus 5+), and birth spacing by maternal age were also assessed. The Wald test for risk-ratio homogeneity was used to assess the statistical significance of the interaction. If significant effect modification was detected, stratified analyses were presented. As robustness check, multivariate linear regression models analyzing HAZ as a continuous outcome are also presented in the Tables S3 and S4 in We then calculated the partial population-attributable risk percentage (PAR%) for teenage pregnancy and birth spacing <24 months by World Bank region for the DHS sample De-identified secondary data was obtained through the Measure DHS website. The project involved no human subjects research.The mean age at first birth across the 153 DHS was 20.4 years with 19% of all births occurring to teenage mothers (<20 years at birth). The DHS with the highest percentage of teenage pregnancies was Bangladesh with 34.8% in 2004, while the lowest was Rwanda in 2005 (6.8%). The median birth spacing interval for the sample was 33 months, with 21.7% of all births occurring less than 24 months from the preceding birth. The DHS with the highest percentage of births with an inter-pregnancy birth interval of less than 24 months was Jordan in 1990 (48.0%), while the lowest was Zimbabwe in 2010 (7.4%).The covariate distribution among the total sample of children 6–59 months is summarized in Table S2 in There were 184,278 firstborn and 439,511 children of birth order 2–5 that contributed to the analysis of maternal age. The association of maternal age with stunting was significantly modified by birth order and as a result stratified analyses are presented . The crude stunting prevalence for firstborn children was >50% for mothers reporting to be under 13 years of age and gradually declined to roughly 20% for mothers 27 years and older  and gradually declined with increased birth interval length up to 60 months (5 years) , Latin America and the Caribbean (5.6%), Sub-Saharan Africa (5.4%), East Asia and Pacific (4.3%) and MENA (3.6%). The larger impact in the first three regions is primarily the result of their high prevalence of teenage motherhood, which is relatively rare in the East Asia and MENA regions. In terms of birth spacing, largest improvements seem possible for the MENA region, where more than one in five children are born within less than 24 months of the preceding birth.A primary concern in the interpretation of DHS analyses is the cross-sectional nature of the data. While reverse causality concerns are often salient in cross-sectional studies, the potential for reverse causation should be minimal in this analysis due to the known temporal ordering of events. Nevertheless, residual or unmeasured confounding is possible. Residual confounding by socioeconomic status may be of particular importance because household asset ownership may not completely capture relative economic standing, especially for households in urban slum areas. More generally, birth timing decisions are the result of a complex set of individual, social, and other contextual factors, whose omission could potentially bias the results presented, so that the estimated associations may not necessarily reflect the true causal effect of interest.The results presented in this study suggest that young maternal age and short birth intervals are risk factors for restricted linear growth, which implies that lowering adolescent fertility and increasing birth intervals has the potential to substantially reduce the number of stunted children, particularly for the South Asian region. Even though birth timing is the result of a complex combination of biological, social, and behavioral factors File S1Contains the following files: Table S1: Survey List. Table S2. Covariate distribution for Maternal Age  and Birth Interval  Datasets. Table S3. Association of Maternal Age with HAZ for Children Aged 6-36. Table S4. Association of Birth Spacing with HAZ for Children Aged 6-36. Figure S4: Geographical Coverage of 61 Sample Countries. Figure S5. Crude stunting prevalence for first born children by maternal age. Figure S6. Crude stunting prevalence for first born children by birth interval.(DOCX)Click here for additional data file.


TMEM16A encodes a CaCC. CaCC pharmacology is restricted to compounds with relatively low potency and poorly defined selectivity. Anthracene‐9‐carboxylic acid (A9C), an inhibitor of various chloride channel types, exhibits complex effects on native CaCCs and cloned TMEM16A channels providing both activation and inhibition. The mechanisms underlying these effects are not fully defined.Calcium‐activated chloride channels (CaCCs) play varied physiological roles and constitute potential therapeutic targets for conditions such as asthma and hypertension. Patch‐clamp electrophysiology in conjunction with concentration jump experiments was employed to define the mode of interaction of A9C with TMEM16A channels.2+, A9C inhibited TMEM16A currents in a voltage‐dependent manner by entering the channel from the outside. A9C activation, revealed in the presence of submaximal intracellular Ca2+ concentrations, was also voltage‐dependent. The electric distance of A9C inhibiting and activating binding site was ~0.6 in each case. Inhibition occurred according to an open‐channel block mechanism. Activation was due to a dramatic leftward shift in the steady‐state activation curve and slowed deactivation kinetics. Extracellular A9C competed with extracellular Cl−, suggesting that A9C binds deep in the channel's pore to exert both inhibiting and activating effects.In the presence of high intracellular CaA9C is an open TMEM16A channel blocker and gating modifier. These effects require A9C to bind to a region within the pore that is accessible from the extracellular side of the membrane. These data will aid the future drug design of compounds that selectively activate or inhibit TMEM16A channels. A9Canthracene‐9‐carboxylic acidCaCCcalcium‐activated chloride channelErevreversal potentialVmmembrane potential2+ concentration ([Ca2+]i) and depolarization of the membrane potential (Vm). Thus, they link Ca2+ signalling with the cell's electrical activity. Our understanding of the physiology and pharmacology of CaCCs has progressed less rapidly than those of other Cl− channel families. This was mainly due to the limited knowledge of CaCC molecular structure and paucity of specific pharmacological modulators  are activated by rises in the free intracellular CaTMEM16A or anoctamin1 (ANO1) was identified as a CaCC‐encoding genes in 2008  compound  TMEM16A inhibitor that does not interact with anion channels such as CFTR, ClC‐2 and bestrophin 1, has also been identified  was quantified only at a single positive Vm and the effects on current kinetics assessed in the presence of a single concentration of A9C. Another recent study . Furthermore, these studies centre on the effects of extracellular A9C, while the effects of intracellular A9C application were not examined. Thus, we set out to perform a comprehensive analysis of A9C interaction with cloned mouse TMEM16A channels. Understanding the A9C mechanism of action is of considerable importance, particularly as A9C may constitute a novel drug template for the generation of specific TMEM16A channel blockers and activators.Collectively, these existing published papers indicated that A9C acts as both an inhibitor and activator of TMEM16 channels. However, a number of factors limit the comparison and integration of these published results. These include the following: (i) the use of TMEM16 channels cloned from different species or different TMEM16 isoforms and (ii) the use of different experimental conditions (such as [CaThis study employs various configurations of the patch‐clamp technique and a specific protocol designed to isolate A9C‐mediated activation from A9C inhibition. We found that A9C acted as an open channel blocker of cloned TMEM16A channels. A9C‐mediated activation was due to a hyperpolarizing shift of the steady‐state activation curves and slowing of deactivation kinetics. Both effects appeared to involve direct binding of A9C into the pore of TMEM16A channels to a region that is accessible from the extracellular side of the membrane.GenBank NM_178642) subcloned into pcDNA3.1 vector was used in this study  changes in A9C concentration ([A9C]) (‘concentration jumps’) were achieved using a computer‐controlled perfusion system .2, 10 HEPES and 8 CaCl2 to obtain ~300 nM of [Ca2+]i; pH was adjusted to 7.3 with NaOH. The intracellular solutions containing ~600 nM, ~1000 nM and ~12.5 μM [Ca2+]i were obtained by replacing EGTA with equimolar H‐EDTA and by adding 2.1, 3.1 and 7.8 mM CaCl2 respectively. The extracellular solution contained (mM) 150 NaCl, 1 CaCl2, 1 MgCl2, 10 glucose, 10 D‐mannitol and 10 HEPES; pH was adjusted to 7.4 with NaOH. In some experiments, NaCl was reduced to 30 mM, and D‐mannitol proportionally increased to ensure the osmolarity of extracellular solution was unchanged. A9C was dissolved in DMSO ; thus, the final concentration of DMSO was ≤1%. Aliquots of the stock solution were kept at −20° and used within 5 days.The intracellular solution contained (mM) 130 CsCl, 10 EGTA, 1 MgClVm relationships were constructed by measuring currents in response to 1 s Vm steps (test pulses) from −100 to +100 mV in 40 mV increments (unless stated otherwise) after a 1 s Vm step to +70 mV (pre‐pulse). Pulses were elicited every 2 s from a holding Vm of 0 mV. Steady‐state currents were measured at the end of the test pulses. As detailed in the 2+]i and extracellular A9C, the test‐pulse currents reached a peak within the first ~50 ms of the test pulse. These peak currents were also measured and plotted against the Vm of the test pulse. Current density was obtained by dividing the current amplitude for the cell capacitance.Current versus Erev), instantaneous currents were estimated from extrapolation of single exponential fits of the test‐pulse currents to the beginning of each test pulse. These instantaneous current values were plotted as a function of the Vm, and the relative chord conductance was measured between an interval of ±20 m V around the Erev  were normalized to currents measured in the absence of A9C (I0) and plotted against [A9C]. The concentration–response curves obtained were fit with the Hill equation of the form:The relationship between [A9C] and TMEM16A current inhibition was obtained by measuring the currents at the end of 250 ms Ki is the apparent A9C dissociation constant from the inhibitory site and γ is the coefficient of cooperativity (Hill coefficient).where The dose–response curves for activation by A9C were fitted with a modified Hill equation of the form:Ia is the current in the presence of A9C, Amax is the maximal current activation, Kd is the apparent A9C dissociation constant from the activating site and h is the coefficient of cooperativity (Hill coefficient).where Ki or Kd and Vm were fitted with the Woodhull equation  or Kd(0) are the apparent A9C dissociation constants from the inhibitory or activating site at 0 mV, z is the A9C electric valence (−1), δi or δd is the fraction of the Vm sensed by A9C when bound to the inhibitory or activating site, F is Faraday's constant, R is the universal gas constant and T is the absolute temperature.The subscript ‘I, was calculated. The variance, σ2, was computed from the average squared difference of consecutive traces. Background variance and current at 0 mV were subtracted, and the variance–mean plot was fit byFor non‐stationary noise analysis   of stationary currents measured at +70 mV were low‐pass filtered at 10 kHz and sampled at 50 kHz. For each tract of current, the variance and mean were calculated. The variance–mean plots obtained in the absence and presence of various [A9C]ext were fitted simultaneously with Equation TMEM16A channels are almost instantaneously activated by changes in G) versus Vm relationships in the presence of various [Ca2+]i. A 1 s pre‐pulse applied to different Vm (from −100 to +180 mV in 40 mV increments) was followed by a 0.5 s tail pulse to −60 mV. These pulses were elicited every 2 s from a holding Vm of 0 mV. Tail currents were fitted with a single exponential function and the instantaneous tail current amplitude (Itail) estimated from extrapolation of the fit to the beginning of the tail pulse. G was calculated as G = Itail/(Vm− ECl), and normalized G (G/Gmax) was plotted against the Vm of the pre‐pulse. The G versus Vm relationships were fitted with the Boltzmann equation of the following form:The voltage‐dependence of TMEM16A channels was assessed by constructing conductance  environment. Student's two‐tailed t‐test or anova with Bonferroni's post test were used for statistical analysis as appropriate, and P < 0.05 was considered significant. Data are given as mean ± SEM alongside the number of experiments (n).Data were analysed with routines developed by Dr P. Tammaro in the IgorPro , a pre‐pulse of +70 mV was used to open TMEM16A channels followed by a series of test pulses . The steady‐state current at Vm ≤ 60 mV did not change substantially at any [A9C]ext tested.As previously reported  and 8.3 ± 1.4 mV . These values are very close to the expected Erev for Cl− in our recording conditions (~1 mV).To test the possibility that the changes in current amplitude described above were due to alterations in TMEM16A channel ion selectivity, the ext (3000 μM) on non‐transfected cells was assessed. No significant increase in current was observed relative to the small endogenous currents measured in non‐transfected cells in the absence of [A9C]ext  and 3.7 ± 0.7 pA∙pF−1 (n = 6) respectively.To test the possibility that A9C activated endogenous currents in HEK‐293T cells, the effect of [A9C]t Figure A. For exτs) arising from this single‐exponential fit increased as Vm was increased from −100 to +100 mV. For example, in the absence of A9C, τs was 26 ± 2 ms (n = 13) at −100 mV compared with 140 ± 10 ms (n = 13) at +100 mV  current inhibition, observed predominantly at positive Vm.Thus, the first set of experiments indicated that extracellular A9C produced complex effects on TMEM16A currents. The main changes being (i) activation of the peak currents measured at the beginning of the test pulse at negative 2+]i in the inside‐out patch‐clamp configuration. High [Ca2+]i was used to maximally activate TMEM16A channels. Consistent with previous studies . In the absence of A9C, the I−100/I+120 was equal to 0.9 ± 0.1 (n = 16), while I−100/I+100 was 5.3 ± 1.0 (n = 6) and 1.2 ± 0.1 (n = 6) in the presence of 300 μM extracellular and intracellular A9C respectively.To study A9C block in isolation from the A9C activating effects on TMEM16A, currents were measured in the presence of 12.5 μM i and in response to 250 ms steps to various Vm test pulse from a holding Vm of −70 mV. The negative holding Vm was used to prevent channel block before the test pulse was elicited. Figure Vm was stepped to a positive value, an instantaneous current was revealed that did not change in amplitude throughout the duration of the test pulse. In contrast, in the presence of A9C, the current during the test pulse rapidly decreased to a new steady‐state level. The time‐course of this decrease was described by a single‐exponential function characterized by a time constant τB. The extent of the decrease in current was measured for various [A9C]ext and various Vm test pulse and then plotted relative to the current measured in the absence of A9C (I0)  and Ki(0) = 322 ± 13 μM (n = 8). Thus, A9C appeared to block TMEM16A channels according to a Woodhull mechanism, consistent with a single A9C molecule blocking the channel pore.To investigate the precise mechanism by which extracellular A9C inhibits TMEM16A channels, macroscopic whole‐cell currents were recorded in the presence of 12.5 μM ext (n = 5) and 0.04 ± 0.01 at 1000 μM [A9C]ext (n = 5)  to the point when the drug was added. The current activation (Ia) was measured via back‐extrapolation of the transient current spike observed upon drug washout.To study the activating effect of extracellular A9C on TMEM16A currents in isolation from A9C‐mediated inhibition, the following stimulation protocol was used. Whole‐cell currents were measured in response to a constant e Figure A. When Ae Figure . As A9C e Figure . We inteext, and the extent of blockage at each concentration expressed as Ib/I0. The extent of current activation at each [A9C]ext was assessed as Ia/I0. The average activating and inhibitory responses measured at +70 mV are shown in Figure Each cell was exposed to various [A9C]ext on the TMEM16A current is Vm‐dependent, experiments similar to those described above were performed at constant Vm of +10 and +40 mV  = 8370 ± 372 μM (n = 9), δi = 0.68 ± 0.03 (n = 9), Kd(0) = 8945 ± 378 μM (n = 9) and δd = 0.66 ± 0.03 (n = 9).To determine if the activating effect of [A9C]V Figure C. From t2+]i. Figure Ia/I0 in the presence of 3000 μM intracellular A9C during inside‐out patches was 1.3 ± 0.1 (n = 5), while extracellular A9C produced a Ia/I0 of 27 ± 4 (n = 5) in outside‐out patches  located within the membrane‐spanning region of the channel, likely to be the permeation pathway. To test this possibility, the extent of TMEM16A current inhibition and activation were tested in the presence of high (154 mM) or low (34 mM) extracellular Cl− concentrations ([Cl−]ext)  and [Ca2+]i (300 nM). In seven separate experiments, in the presence of low [Cl−]ext, application of 30 μM [A9C]ext led to a fractional inhibition (Ib/I0) of 0.46 ± 0.06 (n = 7). This contrasted with an Ib/I0 of 0.70 ± 0.02 (n = 7) observed in high [Cl−]ext (P < 0.05). The Ia/I0 for activation was 8.2 ± 1.1 (n = 7) and 2.0 ± 0.1 (n = 7) in low and high [Cl−]ext respectively (P < 0.05). Thus, extracellular Cl− antagonizes both the inhibiting and activating effects by a similar extent suggesting that these effects require binding of A9C into the pore of the channel.As outlined in the previous section, the current inhibition and activation induced by extracellular A9C presented a very similar degree of ) Figure . These ei, N and/or Po. As stated above, because A9C‐mediated current activation occurred in a sub‐second timescale, it is reasonable to assume that N would remain unchanged throughout the duration of the experiment. Thus, we examined if extracellular A9C alters the TMEM16A channel i or Po.The next series of experiments aimed to determine the mechanism that underlies the TMEM16A current activation produced by extracellular A9C. As outlined above, a change in current amplitude may be due to a change in 2+]i during a tail pulse to −70 mV . In the presence of 100 and 1000 μM [A9C]ext, i was 0.22 ± 0.01 pA (n = 9) and 0.23 ± 0.02 pA (n = 9) respectively. Thus, extracellular A9C did not affect the single TMEM16A channel current. In the absence of A9C, the Po of TMEM16A was 0.09 ± 0.02 (n = 9) while in the presence of 100 and 1000 μM [A9C]ext, the Po was 0.41 ± 0.06 (n = 9) and 0.62 ± 0.06 (n = 9) respectively. Thus, extracellular A9C increased TMEM16A channel Po at a fixed Vm and [Ca2+]i.Non‐stationary noise analysis was performed in the presence of 300 nM [CaV Figure . In the 2+]i and Vm. To study the effect of A9C on the intrinsic Vm‐dependence of the channel, extracellular A9C (3000 μM) was applied during whole‐cell patch‐clamp in the absence of [Ca2+]i . When extracellular A9C (3000 μM) was applied, the TMEM16A current was inhibited to 7.3 ± 3.8 pA∙pF−1 (n = 5), a value indistinguishable from the small endogenous current present in non‐transfected HEK‐293T cells (6.2 ± 0.5 pA∙pF−1 (n = 5) at +140 mV, not shown). In contrast to the effect of A9C in the presence of 300 nM [Ca2+]i  for mouse TMEM16A. This suggests that the A9C binding site may be conserved among different species. Our study is the first to compare the potency of A9C block of TMEM16A at different [Ca2+]i. The Ki(0) in the presence of 300 nM [Ca2+]i was ~8.4 mM, whereas in 12.5 μM [Ca2+]i, it was ~0.3 mM. This suggests that the conformation of the channel in different [Ca2+]i may affect the inner structure of the pore and, consequently, the A9C binding site.At physiological pH, A9C is a negatively charged molecule that is known to block the permeation pathway of many Cl, et al.  reportedy et al.  estimateet al., et al., Vm. This is consistent with a model in which the inhibitory A9C binding site is accessible from the extracellular side and is situated within a region that spans the electric field of the membrane. According to this model, A9C applied from the intracellular side is expected to have no or very little effect on TMEM16A currents. This is because hyperpolarized Vm would not favour entry of intracellular A9C into the channel pore. Indeed, our data show that TMEM16A inhibition by extracellular A9C is enhanced in low [Cl−]ext, a phenomenon that is consistent with the idea that A9C enters the pore in a competitive manner with permeant anions. However, when applied to the intracellular side of the membrane, A9C produced a small inhibition of the TMEM16A current at positive Vm. A possible explanation for these results is that intracellular A9C reached the inhibitory site by crossing the membrane bilayer and then blocking TMEM16A channels from the extracellular side of the membrane. This is plausible considering that A9C contains a hydrophobic region of three aromatic rings, which could enable the drug to cross the membrane lipid bilayer  and others  to reach its inhibitory site. This finding is consistent with reported values of ~60 and ~54% for native Xenopus laevis CaCCs  and in the absence of A9C, pulses to negative Vm elicited instantaneous currents followed by exponential current decays. These exponential current decays reflected the channel's conformational changes leading to channel closure. However, in the presence of A9C and at negative Vm, the instantaneous tail currents were described by the sum of two exponential functions. The initial rapid phase presumably represents dissociation of A9C from the inhibiting site, while the slower current decay may represent long lasting A9C‐mediated conformational changes. The relationship between the time‐course of current decay and Vm shifted progressively leftwards as [A9C]ext was increased. This is consistent with the leftward shift in the steady‐state activation curves and the observed changes in channel Po at a fixed Vm determined via non‐stationary noise analysis.In the presence of a physiological ext. The number of experiments was 13 in each case.Figure S2 Relationship between τB‐1 and [A9C]ext measured at various Vm, as indicated. The continuous lines are the best fit of the data with Suppl. Eqn.5.Table S1 Parameters (kon and koff) obtained from the fit of the relationship between τB‐1 and [A9C]ext measured at various Vm with Suppl. Eqn.5. Ki was calculated as koff/kon.Supporting info itemClick here for additional data file.


Compare respiratory health in children born extremely preterm (EP) or with extremely low birthweight (ELBW) nearly one decade apart, hypothesizing that better perinatal management has led to better outcome.1999–2000) and matched term-controls were assessed with comprehensive lung function tests and standardized questionnaires. Outcome was compared with data obtained at 10 years of age from all (n = 35) subjects born at GA <29 weeks or birthweight <1001 gram within a part of the same region in 1991–92 (EP1991–1992) and their matched term-controls.Fifty-seven (93%) of 61 eligible 11-year old children born in Western Norway in 1999–2000 with gestational age (GA) <28 weeks or birthweight <1000 gram (EP1999–2000 had significantly reduced forced expiratory flow in 1 second (FEV1), FEV1 to forced vital capacity (FEV1/FVC) and forced expiratory flow between 25–75% of FVC (FEF25–75), with z-scores respectively -0.34, -0.50 and -0.61 below those of the term-control group, and more bronchial hyperresponsiveness to methacholine , whereas other outcomes did not differ. Low birthweight z-scores, but not neonatal bronchopulmonary dysplasia (BPD) or low GA, predicted poor outcome. For children with neonatal BPD, important lung-function variables were better in EP1999–2000 compared to EP1991–1992. In regression models, improvements were related to more use of antenatal corticosteroids and surfactant treatment in the EP1999–2000.EPSmall airway obstruction and bronchial hyperresponsiveness were still present in children born preterm in 1999–2000, but outcome was better than for children born similarly preterm in 1991–92, particularly after neonatal BPD. The findings suggest that better neonatal management not only improves survival, but also long-term pulmonary outcome. Since the 1990s most infants born extremely preterm or with extremely low birthweight (hereafter referred to as EP-born) in high-income countries have survived to discharge . Birth aNeonatal pulmonary autopsy data suggest that EP birth may lead to severe bronchoalveolar abnormalities, but structural data from later life are scarce . However1999–2000) and to compare the findings with those of children born similarly preterm in 1991–1992 (EP1991–1992). We hypothesized that changes in perinatal care during the 1990s were associated with respiratory improvements [Better NICU management benefits all infants born preterm, but it also facilitates survival of more immature and vulnerable individuals who may be at particular risk of severe long-term morbidity , 15. Theovements , 17.Detailed descriptions are provided in 1999–2000 included all NICU admitted infants born in 1999–2000 with gestational age (GA) <28 weeks or birth weight (BW) <1000 gram within Western Norway Health Authority, which serves a population of approximately 1.1 million. It was a regional selection of a national cohort [1999–2000 data were compared with data obtained at 10 years of age from all (n = 35) subjects born with GA <29 weeks or BW <1001 gram within a part of the same region (population 615 000) in 1991–92 and treated at the NICU in Bergen (EP1991–1992). EP1991–1992 data have been published previously in a different context [The EP context , 16 and th percentile for GA according to Norwegian growth curves [®) (31) to natural surfactant (Curosurf®)  questionnaire . Small fh curves . Z-scoreh curves , 20. BPDrosurf®)  The studies were approved by the regional committee on medical research ethics in Western Norway Health Authority (REC West), and parents of all participants gave written consent.1991–1992. The children were seen on two separate days at the University Hospitals in Bergen or Stavanger according to place of birth. Spirometry, static lung volumes and pulmonary diffusing capacity for carbon monoxide (DLCO/KCO) were measured with Vmax equipment , applying standard quality criteria [KCO reported as raw data. Fractional exhaled nitric oxide (FeNO) was measured with Exhalyzer CLD-88 , according to ATS/ERS recommendations [NO) and bronchial flux of NO (nl/sec) (Jaw NO) were calculated using three different flows  [Spira Electra, Finland), providing baseline FEV1 ≥65% predicted [1, or until the maximum dose of 11.5 μmol methacholine. Dose-response slope (DRS) was calculated as the ratio of maximum percentage decline in FEV1 from baseline to cumulative administered dose of methacholine (%/μmol) [1 before (baseline) and 10–15 minutes after administering 0.1 mg/10 kg salbutamol (Ventoline) from a metered dose inhaler via a spacer (Volumatic); an increase ≥12% was considered positive response [The two birth-cohorts were examined at 10–11 years of age in 2001–2002 and 2010–2012, respectively, using the same type of equipment and the same examination program, except that nitric oxide was not studied in EPcriteria , 22 withcriteria , 24, excndations . Alveola ml/sec) . Methachredicted , 28. The(%/μmol) . Reversi1999–2000, multiple backward regression models were constructed in order to address potential associations between neonatal data and selected background data (listed in the Results chapter) vs. current FEV1. Independent variables were included if the correlation with the dependent variable was > 0.3 and the bivariate correlation with other independent variables was < 0.7. Interaction terms were used to test if effects (differences in lung function between EP-born and matched term-controls) differed between EP-born subgroups; i.e. BPD vs. non BPD, GA-categories (GA ≤25 vs. 26–27 vs. ≥28 weeks) and birth-cohort (1991–1992 vs. 1999–2000). The interaction terms were tested for influence from selected neonatal factors that varied between the two preterm born cohorts  was used for computations.Non-paired groups were compared using independent sample t-tests, Mann-Whitney U-test, Fishers exact 2-sided mid-p value  or odds 1999–2000, 61 eligible EP-born were discharged alive, two could not be traced and two were excluded due to cerebral palsy, leaving 57 (93%) participants, all but three Caucasians. In EP1991–1992, all 35 eligible EP-born survivors participated, all Caucasians. On average, respectively 1.6 and 1.3 term-born subjects were approached to recruit a full 1:1 control group for the two inclusion periods. In EP1999–2000, uneven drop-outs eventually caused a numeric gender difference; i.e., 49% EP-born vs. 46% controls were female (p = 0.85).In EP1999–2000) vs. 74% (EP1991–92) (p = 0.57). Due to slight differences in the inclusion criteria, mean BW was lower and the proportion born SGA was higher in EP1999–2000. Eleven subjects (19%) were included solely by BW (i.e. GA ≥28 weeks) in EP1999–2000 (mean GA (range) 29.2 (28–31) weeks), and two solely by BW (i.e. GA ≥29 weeks) in EP1991–92 (GA 30 and 31 weeks). The number of participants born at GA ≤27 weeks was 46/57 (81%) and 21/35 (60%), respectively. For subjects with BPD in EP1999–2000 compared to EP1991–1992, mean GA and BW did not differ, but days on ventilator were fewer, a higher proportion had received prenatal corticosteroids and surfactant treatment and fewer had artificial closure of persistent ductus arteriosus (surgery or indomethacin).For subjects admitted to the NICU, survival rates were 81%  and use of asthma medication tended to be rarer in EP1999–2000 than in EP1991–92 and not significantly different from term-controls, contrasting EP1991–92. Wheeze was unrelated to airflow-limitation, with one report of current wheeze in the overall 15 subjects with z-FEV1 below -1.64, which is the lower limit of normal [At follow-up, EPf normal .1991–1992 have been published previously [1999–2000, data are presented in Tables 1, FEV1/FVC and FEF25–75, higher airway resistance (Raw), and higher DRS from the methacholine challenge than term-controls. DRS was negatively and similarly associated with z-FEV1 (p<0.001) in the EP- and term-born groups . Static lung volumes , FeNO and DLCO did not differ significantly between the EP-born and term-born groups. Nine subjects  had ≥12% increase in FEV1 on the salbutamol reversibility test . Mean FEV1 change before vs. after salbutamol did not differ between those born EP and at term, and responses were negatively associated with z-FEV1 (p<0.001) in both groups .Data on EPeviously , 16, andThere was no effect of neonatal BPD vs. no BPD on any of the assessed lung function variables (non-significant interaction-terms). Lung function variables that differed between the EP- and term-born groups were analyzed also by GA-category, and the deficits were numerically most pronounced for the GA-category ≥28 weeks, although interaction terms were non-significant .1999–2000, BW z-score was the only significant predictor of z-FEV1 at 11 years  in a regression model including the following perinatal variables: GA, BW z-scores, days on ventilator, days on oxygen treatment, use of antenatal and postnatal corticosteroids, surfactant treatment and BPD vs. no-BPD. Applying the same model on the EP1991–1992, BW z-scores similarly predicted z-FEV1  in a final model; however, including also days of oxygen  and antenatal corticosteroids  . Maternal smoking in pregnancy was not associated with z-FEV1 at age 11. Regressing the background variables asthma ever, asthma medication last 12 months, wheeze last 12 months, atopy and maternal smoking in pregnancy on z-FEV1 at age 11, revealed no significant associations for either EP or term-born in any birth-cohort.For EP1, z-FVC and z-FEF25–75 and RV/TLC for the group with BPD born in 1999–2000 compared to the group with BPD born in 1991–1992 (tests of interaction). Adjusting these interaction terms for differences between the study periods regarding GA, BW, days on ventilator and PDA management did not influence conclusions, whereas the effect disappeared for z-FEV1 when surfactant and/or antenatal corticosteroids were included in the model. Differences between EP-born without BPD and their matched term-controls did not differ between two inclusion periods.Paired differences between EP-born and matched term-controls for the inclusion periods 1991–1992 and 1999–2000 are given in This study showed that respiratory outcomes in mid-childhood were encouraging in children born at extremely low GAs or BWs in 1999–2000. Still, the preterm born participants had more small-airway obstruction and bronchial hyperresponsiveness than matched term-controls, but static lung volumes, diffusing capacity and exhaled nitric oxide did not differ. Outcome data were in most respects unrelated to BPD, and those born most immature did surprisingly well. Compared to children born similarly preterm in the same region in 1991–1992, lung function data were generally better, and particularly for those with neonatal BPD, where significant improvements had occurred for important variables.2) [The major strengths of this study were the population-based design with almost complete attendance, and recruitment of matched control groups that followed a strict algorithm based on the ‘next-born-subject’ principle, minimizing risks of selection bias. An age difference of approximately one year at follow-up between the two birth-cohorts was adjusted for by reference equations or by statistical models. Potential bias introduced by a two-center design was limited by statistical analyses performed according to the matched preterm versus term-born structure. The algorithm for inclusion was based on a combined use of GA and BW, initially preferred in 1991–1992 to ensure inclusion of all children perceived to be extremely immature at birth. We continued this approach in 1999–2000, although changing the GA criterion from <29 weeks to <28 weeks. Due to the inclusion criteria the data may not be generalizable to subjects born extremely preterm in general. A diagnosis of BPD must reflect oxygen treatment algorithms, which to some extent is subject to department policy. In this study, the same senior neonatologists operated the same algorithms for oxygen supplementation in both inclusion periods, making systematic changes unlikely. The study could not discriminate moderate from severe BPD since oxygen treatment at 36 weeks GA was provided through low flow nasal cannulas without recording the exact fraction of inspired oxygen  in the range of 75% predicted and significant methacholine hyperresponsiveness indicate that small airway airflow limitation and bronchial abnormalities were still present. Those born most immature did surprisingly well, in that lung function variables did not differ significantly from those of the term-controls. Moreover, the presence of neonatal BPD was not significantly associated with outcome, contrasting some [highest GA-category; i.e. basically SGA infants with GA ≥28 weeks who were included on the basis of BW <1000 gram, in whom significant airway obstruction and remarkably high bronchial hyperresponsiveness were observed. In adjusted regression models, BW z-score was the only remaining neonatal variable associated with FEV1 at age 11. Thus, within the frames of todays advanced NICU management, the paradigm that neonatal BPD or extreme immaturity is inevitably linked to poor long-term pulmonary outcome may need to be revised. However, statements regarding causal pathways for novel findings are bound to be speculations within the frames of a study of this kind.The lung function abnormalities in the 11 year old children born preterm in 1999–2000 were minor. FEVing some , 32, and1 in the EP-born and term-control group, further reducing the group differences. Few subjects had salbutamol responses considered clinically significant (≥12% from baseline) [Interestingly, administration of salbutamol increased all airflow variables to within 0.5 z-score of zero; i.e. clearly within normal limits. Salbutamol responses were negatively and similarly associated with FEVaseline) , and on Pulmonary abnormalities after EP birth may clinically mimic pediatric asthma, and studies have reported increased respiratory symptoms and more hospital admissions, particularly during the first few years of life –35. In t1 for preterm born children with neonatal BPD (defined by need of oxygen treatment at 28 days of age) in recent compared to earlier studies [1 and z-FEF25–75 in preterm compared to term-born children. The Australian study [1 and z-FVC than those born in 1991–92. In light of the possibility that more children at risk of unfavorable outcome may have survived in the most recent cohort, this may be interpreted as a positive development. These findings are in line with ours, although we found this positive development particularly evident in the group with neonatal BPD. The EPICure study had more extreme inclusion criteria, with mean GA at birth almost two weeks lower (24.9) and BW approximately 100 gram lower (750 gram) than the EP1999–2000 cohort of our study, and also a higher rate of neonatal BPD; i.e. 70% compared to 50%. They found no differences between preterm and term-born participants regarding FRC, TLC and alveolar volume, which is comparable to our findings, but elevated RV/TLC and some impairments in DLCO and DLCO/VA; differences that we did not see as clearly in our EP1999–2000 cohort but resembling our findings at ten years of age in the EP1991–1992 cohort [Some authors have expressed optimism regarding long-term pulmonary outcomes in children who were born EP more recently , 36. Kot studies , 32, and studies , 32. Botan study  compared2 cohort . One may1 and other important lung function variables from 1991–1992 to 1999–2000. This was particularly evident for the group of children with neonatal BPD, who presumably had the most turbulent neonatal history. The interaction terms used to assess these improvements were robust for adjustment for most perinatal variables, except that use of antenatal corticosteroids and surfactant eliminated the improvements in z-FEV1. Thus, statistical modeling of the dataset suggested that more extensive use of these modalities may partly explain the observed improvement with time. However, a limitation that applies to studies of this kind is that a variety of known and unknown influences of possible significance for outcome cannot be accounted for in the applied regression models. Thus, more and larger studies are required to resolve this issue.There were significant improvements for z-FEVstrengthens the notion that outcome did in fact improve for the average infant born preterm during the 1990s.The inclusion algorithms varied slightly between the two preterm-born cohorts. Despite this, the two groups had fairly similar BWs and GAs, although with more SGA children included in 1999–2000. More SGA children and more extreme criteria as regards GA in 1999–2000 should theoretically lead to worse outcomes, whereas the opposite was in fact observed. Thus, one may argue that this without neonatal BPD [with BPD, i.e. the infants with the most turbulent neonatal history.The field of neonatal intensive care is in constant change, and it has been suggested that pushing the limits of viability might have masked improvements in outcome , althougatal BPD . The preEleven year old children born at extremely low GAs or BWs in 1999–2000 had more small-airway obstruction and bronchial hyperresponsiveness than matched term-controls, but lung volumes and diffusing capacity were similar. Outcome was mostly unrelated to BPD, and those born most immature did surprisingly well. Compared to a group born similarly preterm in the same region nearly one decade earlier, lung function was generally better, particularly after neonatal BPD. The findings indicate that infants born preterm in this millennium may have better pulmonary prognosis than previously assumed, and that BPD or extreme immaturity may not necessarily be linked to poor lung function in mid-childhood.S1 File(DOC)Click here for additional data file.


Birth defects are a leading cause of neonatal and infant mortality, and several studies have indicated an increase in the prevalence of birth defects; more recent investigations have suggested that the trends of some defects are increasing in rapidly industrialized areas. This study estimates the prevalence rate and types of birth defects in Korea.This study used medical insurance benefit data of 403,250 infants aged less than one year from the National Health Insurance Corporation from seven metropolitan areas in Korea for 2009 and 2010.The prevalence rate of birth defects was 548.3 per 10,000 births (95 % CI: 541.1–555.6), 306.8 among boys and 241.5 among girls. Anomalies of the circulatory system  were the most common , followed by defects of the genitourinary tract  (particularly obstructive genitourinary and undescended testis), musculoskeletal system , digestive system , and central nervous system .Relatively higher rates of some birth defects were found in the metropolitan areas. The high differences of birth prevalences for septal heart defects and undescended testis are probably due in part to progress in clinical management and more frequent prenatal diagnosis. Environmental exposure might play a critical role in the development of some birth defects. In attempting to describe the prevalence and spatio-temporal variations of birth defects in Korea, establishment of a registry system of birth defects and environmental surveillance are needed. The prevalence of birth defects has continued to increase and has also led to a significant proportion of infant and childhood mortality, whereas the infectious causes are decreasing due to the extensive and successful use of prevention and control programs , 2. ApprIt has been reported that the cause of 60 % of congenital birth defects is unknown and primary prevention is impossible, and approximately 20 % of congenital cases are caused by genetic disorders . In addiIn the last few decades, early research investigating the trends of birth defects has shown variation to the temporal changes in the prevalence of birth defects. The prevalence of several birth defects has increased over time, including, for example, heart defects, obstructive genitourinary defects, Down syndrome, and gastroschisis –12. NeurOver the past 40 years, Korea has transformed itself into a vibrant capitalist economy with a rapid rate of urbanization, aggravating the environmental degradation. At the same time, it is likely that the pattern of birth defects is changing with time. Despite the fact that the overall prevalence of birth defects in Korea is lower or similar to that of most developed countries, the increase in the prevalence of some categories of birth defects still poses a major public health concern. Although several studies have examined the characteristics of birth defects, few studies have been conducted in Korea. The objectives of this study are to estimate the current prevalence and types of birth defects in Korea and to describe the prevalence of selected birth defects.The study protocol was approved by the institutional review board (IRB) of the University of Inha School of Medicine before the start of the study. We have participated in the health monitoring program for newborn babies supported by the Ministry of Environment, Korea. The Ministry of Environment asked the Korea National Health Insurance Corporation (NHIC) to allow us access to the insurance claims database. This study used the insurance claims database for 2009–2010 and estimated the prevalence of birth defects using data from seven metropolitan areas . The need for consent was waived by the IRB, because we only use NHIC database without private individual information. NHIC collects information on the insurance society, type of medical care institution, episodes of hospital admission, birthday, day of first visit, days of visits, diseases code, total expenses, and other individual characteristics. Target population for analysis comprised 403,250 infants aged less than one year. Analysis of the medical insurance claims database of birth defects diagnosed during the first year after birth was performed to obtain information on the study subjects. Data on the same birth defect in the same patient from various organizations were assembled and reviewed. The possibility of multiple occurrences of birth defects in the same patient was considered. An infant or a fetus with more than one anomaly was counted once only based on the primary diagnosis. A total of 46,679 infants were selected for referring to birth defects code or subcode. When these results were further refined based on the reconfirmation of diagnoses, rule out diagnoses, disease name and exclusion of inappropriate cases, 35,697 study subjects from patients born from 2009 to 2010 were selected for final analysis. Birth defects were classified according to International Classification of Diseases, Tenth version (ICD-10). Cases of minor anomalies  treated as outpatients were excluded from further analysis. The birth defects code from Q00 to Q99 included 27,645 cases, and analysis of 69 major birth defects, which were used in some European Surveillance of Congenital Anomalies (EUROCAT) studies, reduced the number of subjects to 22, 111.In addition, the prevalence of birth defects for 2009–2010 was compared with that of a similar study conducted 16 years previously . In thisp < 0.05.Birth defect prevalence was calculated by dividing the numerator  by the relevant denominator . The prevalence was expressed as the number of cases per 10,000 live births. The Poisson distribution was used to calculate 95 % confidence interval of birth defects prevalence. Statistical analyses were performed using Stata version 11.2, and alpha was set at The number of live births in the study areas was 403,250 from 2009–2010, with 196,532 in 2009 and 206,718 in 2010. Table Four cases of anencephaly , 311 cases of spina bifida , 28 cases of encephalocele , 122 cases of microcephaly , 53 cases of holoprosencephaly , and 133 cases of congenital hydrocephalus  were registered with associated prevalence rates at birth of 8.1 per 10,000 births (95 % CI: 7.2–9.0) for males and 7.6 per 10,000 births (95 % CI: 6.7–8.5) for females.It was found that 140 cases of the defects were recorded in boys  and 101 cases in girls . The most common were microtia , congenital cataract , and congenital glaucoma . One girl had anophthalmos, while five cases of absence of iris , 18 cases of microphthalmos , and 16 cases of congenital absence of auricle  were reported.Congenital anomalies of the circulatory system affected more infants born  in the study area than any other type of birth defects: 4,761 in boys  and 5,007 in girls . The three most common types of heart malformations were atrial septal defect , ventricular septal defect , and patent ductus arteriosus .The study found 403 cases of cleft palate without cleft lip , 164 in boys  and 239 in girls ; 330 with cleft lip with or without cleft palate , 198 in boys  and 132 in girls ; and 17 with choanal atresia , 11 in boys  and six in girls .It was found that 536 cases of the defects were diagnosed in boys  and 458 in girls . Hirschsprung’s disease , anorectal atresia/stenosis , and small intestine atresia/stenosis  were mainly reported.There were 5,250 reported cases of congenital anomalies of the urogenital system, resulting in the prevalence of 104.6 per 10,000 in boys (95 % CI: 101.4–107.8) and 25.6 in girls (95 % CI: 24.1–27.2). The most common anomalies were obstructive genitourinary defect , congenital hydronephrosis , undescended testis , and hypospadias .Structural limb anomalies include dysplasia, reduction defects and duplication defects with supernumerary limb elements. Of the 4,261 cases , congenital hip dislocation , polydactyly , craniosynostosis , and syndactyly  were most prevalent.102 boys  and 87 girls  had Down syndrome, the most commonly reported congenital autosomal anomaly. Three boys and four girls had Turner syndrome, while seven boys had Kleinfelter syndrome.In 1993–1994, the overall prevalence of birth defects per 10,000 infants less than one year was 368.3 (95 % CI: 364.9–371.8), and cardiovascular anomalies were the most common defects followed by musculoskeletal and gastrointestinal anomalies [The overall prevalence of birth defects in our study area in 2009–2010 was 548.3 per 10,000, which is higher compared to the rates of Korea published three years previously . In this10 (particulate matter 10) [10 and carbon monoxide found that an increased risk of ventricular septal defect was due to maternal exposure to carbon monoxide and patent ductus arteriosus due to exposure to PM10 [The elevated prevalence of heart defects including atrial septal defect and ventricular septal defect in the study is probably due to change in diagnostic method: routine use of echocardiography on newborns may have resulted in the identification of large numbers of defects. Progress in clinical management and more frequent prenatal diagnosis may have increased the prevalence of congenital heart defects, as also suggested by Khoshnood . These rtter 10) . Likewis to PM10 , 26.The birth prevalence of undescended testis varies widely (1.4–31.7). The study found very high rates of undescended testis  in accordance with data from Canada  but in sharp contrast to the low rate of France  . On the In England, the prevalence of undescended testis increased by more than 60 % between the 1950s and 1980s, and the reported prevalence of hypospadias is 0.1–0.8 per 10,000 male births , 29. A sIn particular, the prevalence of hypospadias and undescended testis in the study areas showed remarkably higher prevalence rates compared to the study conducted 16 years ago Table . The tenHirschprung’s disease , the most common congenital gut motility disorder, is relatively easy to diagnose, thus, the relatively higher prevalence compared to North England   is probaWith regard to nervous system defects, particularly spina bifida , the prevalence rate was comparable to that of Japan  but higher than found in the United States  . The reaThe prevalence rate for Down syndrome  was particularly low in the study areas; however, other population-based studies had reported higher than this figure in Finland , France , and Japan  [The existence of etiological heterogeneity for the birth defects has been described elsewhere in the literature . A numbeHowever, the results in this study must be interpreted in the context of some limitations. The study cannot avoid the methodological limitation of insurance based data analysis. Diagnostic criteria, coding and the timing for follow-up of outpatients might vary in the hospitals, and further validation of the diagnosis was difficult with the insurance database analysis due to lack of detailed records. For example, some newborns with birth defects might have died before entering the hospital, although the number of such patients should be rare. In addition, ICD-9 codes were used to specify birth defects for years 1993–1994, while ICD-10 was used to classify birth defects for 2009–2010. Two versions of disease classification differ substantially. The change to the tenth revision resulted in more detailed classification, with about 8,000 categories compared with about 5,000 categories in the ninth revision. The relatively large difference of some birth defects reported between 1993–1994 and 2009–2010 may be due to the switch from ICD-9 to ICD-10. This study used a comparable category of codes for 26 selected defects according to the ninth and tenth revisions. However, there may be an important underlying variation to case ascertainment and diagnostic criteria (inclusion or exclusion of minor cases) which may have given higher reported rates in some birth defects. A study found the comparability ratio of 0.9064 between ICD-10 and ICD-9 while explaining congenital anomalies and chromosomal abnormalities as a cause of death in the United States . NonetheRelatively higher rates of some birth defects were found in the metropolitan areas. The high difference of birth prevalences for septal heart defects and undescended testis are probably due in part to progress in clinical management and more frequent prenatal diagnosis. Environmental exposure might play a critical role in the development of some birth defects. In attempting to describe the prevalence and spatio-temporal variations of birth defects in Korea, establishment of a registry system of birth defects and environmental surveillance are needed.


Birth is a challenging and perhaps painful process for primates that have large heads relative to their body size. This includes our own species, but for humans, the pelvic changes resulting from the origin of bipedalism 5–7 million years ago restructured the pelvis, altered the birth mechanism and further limited the size of the birth canal. Additional challenges to the birth process occurred with dramatically increased brain size starting about 2 million years ago .The bipedal birth canal is ‘twisted’ in the middle with the inlet and outlet perpendicular. In between these two planes is the midplane, which usually presents the smallest diameter. The changing shape typically involves rotations of the infant in order to pass through the three pelvic planes to emerge with the occiput anterior (OA), facing away from the mother. These challenges place a selective advantage on having assistance for guiding the baby out, clearing the face and nose and dealing with a wrapped umbilical cord. Worldwide it is rare for women to give birth alone. Western medical perspectives on childbirth view it as sufficiently risky that it must take place in a clinical setting.Two evolutionary legacies that impact childbirth today are the potential for obstructed labor and the selective premium on having assistance at birth. Obstructed labor accounts for 12%  and withMost nonhuman primates give birth with the occiput posterior, allowing the mother to easily guide the infant up toward her chest. With the anatomical changes that accompanied bipedalism, humans typically emerge OA. Simply having another person present to guide the infant out reduces the risks associated with OA deliveries .For most of history and in many parts of the world today, the most common delivery position is upright in a squatting or standing position. This widens the birth canal and enables gravity to work with contractions to expel the baby. Replacing the lithotomy position with supported squatting incorporates a beneficial practice from the past into contemporary birth.A desire for social and emotional support during birth reflects the evolutionary context in which humans have given birth for at least the history of our species . In many