We examined the association of occupational exposure to handling cytotoxic drugs at work with risk of birth defects among a cohort of female veterinarians. This study is a follow up survey of 321 female participants (633 pregnancies) who participated in the Health Risks of Australian Veterinarian project. Data on pregnancies and exposure during each pregnancy was obtained by self-administered mailed questionnaire. Female veterinarians handling cytotoxic drugs during their pregnancy had a two-fold increased risk of birth defects in their offspring ). Results were consistent in subgroup analysis of those who graduated during the period of 1961 to 1980  and in those working specifically in small and large animal practice. There was no increased risk in the subgroup that graduated after 1980. Women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis  and had a higher increased risk of birth defects than those who planned their pregnancies in recent graduates and in those who worked specifically in small animal practice . This study suggests that the adverse effects of handling cytotoxic drugs in pregnant women may include an increased risk of birth defects. Pregnancy intention status is an important health behavior and should be considered in prenatal programs. Toxic drugs are defined as having specific health effects  and health toxicity at low doses . Most toOccupational exposure to cytotoxic drugs and related waste also presents a possible risk. The reproductive toxicity of cytotoxic drugs has been reported mainly in female nurses working in clinical oncology settings ,8,9, andThe limited evidence from human epidemiological studies regarding occupational exposure to handling cytotoxic drugs establishes a need to further examine these associations with birth defects. We conducted a follow-up survey of those female veterinarians who have already participated in a large retrospective cohort study titled “Health Risks of Australian Veterinarians (HRAV)” ,19,20,21Study Design: This study was conducted in 2005–2006 and was a follow-up survey of the Health Risks of Australian Veterinarians Study (HRAV) conducted in 2002  [a, 2006) ,19,20,21a, 2006) ,19,20,21Exposure Assessment: Working situation and occupational exposure to handling cytotoxic drugs were assessed in relation to the timeframe of individual pregnancies covering the critical times of vulnerability (3rd–8th week of pregnancy). Respondents answered questions relating to each pregnancy including whether they had worked in veterinary medicine, the job type , clinical role , animal practice type , work hours and handling of cytotoxic drugs used at work . Most of toxic drugs used in veterinary clinical practice in Australia are cytotoxic drugs and the female vets have rarely had occupational exposure to other CMR medicinal products. Information was also obtained regarding lifestyle factors in relation to the timeframe of each pregnancy such as marital status , cigarette smoking (numbers/day), caffeine consumption , alcohol intake (units/week), physical activity (hours/week) and sexual activity (times/week). Data on stress levels directly related to the timeframes of individual pregnancies were collected, with questions about work-related stress and stress in general, social support at work and home, and clinically diagnosed anxiety or depression.Health Risk Assessment: Reproductive history was assessed, for each pregnancy, including whether the pregnancy was planned, the number of months trying to become pregnant (time to pregnancy), duration of pregnancy (in weeks), and complications of pregnancy. Reproductive outcomes were assessed from information on live births, stillbirths, terminations (induced abortions), miscarriage (spontaneous abortions), ectopic pregnancy, birth defects, birth weight, sex of child and plurality. Birth defects were defined as a structural or functional abnormality, present at conception or occur before the end of pregnancy and diagnosed by six years of age. Birth defects were coded by staff at the Western Australian Birth Defects Registry (WABDR) according to the British Paediatric Association (BPA) ICD-9 system and without knowledge of the exposure status of the mother.Cohort Selection: Pregnancy was the unit of observation used in this study. Study entry was restricted to women with past singleton pregnancies who were eligible to be assessed for the outcome of birth defects. We excluded the following pregnancies: those where conception began before graduation from veterinary college (n = 22), twin pregnancies as we only had information on one twin (n = 16); ectopic pregnancies (n = 2), those pregnancies current at the time of the survey (n = 31); pregnancies that ended in miscarriages (n = 115), those women who didn’t work exclusively as clinical practitioners (n = 162); those terminations of pregnancies after 20 weeks of gestation without birth defects (n = 16) and those with missing data or ‘not sure’ reports of birth defects (n = 9). After all these restrictions, out of 1,007 pregnancies (in 412 women), 633 (62.9%) pregnancies in 321 (77.9%) women were included in the analysis.Statistical Analysis: Generalised Estimation Equation (GEE) Modelling by a modified Poisson regression, with robust error variance, was used to estimate relative risk (RRs) and 95% CI for the association between exposure to handling toxic drugs and birth defects [versus a non-exposed group and is a ratio of prevalence rather than incidence. The four adjusted RR models estimated the outcome of all malformations in (a) the total study cohort; (b) a stratified sample of old graduates (1960–1980); (c) a stratified sample of recent graduates (after 1980); (d) a stratified sample of those who worked exclusively in small animal practice. We transpired in 1980 to be able to compare the results from this study with other studies in the literature where the effect of current guidelines on safe handling practices was evaluated before and after 1980s. We also estimated the risk in those who worked in large animal practice, but the crude risk estimate only is presented in the results section due to small numbers and lack of power in full adjustment multivariate analysis. These secondary analyses on stratified samples were undertaken to estimate the risk in even more homogeneous groups and because higher occupational exposures and birth defects were reported in these groups. The following occupational variables were examined as exposures: practice type, handling cytotoxic drugs used at work, years in job and working hours. Occupational exposure to pesticides, anaesthetic gases and x-rays as independent variables were assessed from the first survey and the results for these exposures have previously been reported [ defects ,23. We eraduates 60–1980; a priori considerations as to the importance of the risk factors. Exposure to handling cytotoxic drugs has been evaluated for the response effects of the daily use and weekly use compared to those who were unexposed (rarely or never used). Interaction effects of factors related to birth defects were examined and the only significant interaction was between cytotoxic drugs and work stress, which was included in the model.The final models were adjusted for all exposure variables plus maternal age, smoking, alcohol drinking, marital status, graduation year, work and general stress, and social support from work and home. Inclusion of covariates was based on the magnitudes of regression coefficients and on A total of 633 eligible pregnancies were included in the study of which 59 (9%) had diagnosed birth defects by age six years . CardiovDescriptive characteristics of the study population and working situation are shown in Multivariate regression modelling showed that handling cytotoxic drugs during pregnancy was significantly associated with birth defects among all women  and also in stratified analysis of subgroup of small animal practices   and thosMain findings: We found a 2‒5 fold-increased risks of birth defects for occupational exposure in veterinary practice to cytotoxic drugs on a daily basis during pregnancy. This risk was limited in veterinarians who graduated before 1981 suggesting that current guidelines on safe handling of cytotoxic drugs are being followed more carefully by recent graduates. The results on increased risk on the whole cohort was consistent in those who worked in small and large animal practices. The risk of birth defects was elevated in those with unplanned pregnancies and women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis.Strengths and limitations: This study is a follow-up survey from the HRAV survey and the strengths and limitations of the HRAV study have been discussed in details elsewhere [lsewhere ,18,19. Flsewhere ,25, so eIt is important whether control measures were adequate or protective devices were used during the relevant exposure times. We had no information about the control measures and personal protective equipment (PPE) such as use of hood and glove in regard to handling cytotoxic drug use in this study, but the results from this study on recent graduates suggest that current guidelines on safe handling of cytotoxic drugs are being followed more carefully by recent graduates and this is consistent with many studies assessing this risk after 1980s . We alsoSecond, there is a possible selection bias due to loss of follow up (about 20%) of those who participated in original survey, but didn’t participate in this follow up survey. The results indicate that those who didn’t participate in this follow up survey were older as 77% of participants from this survey graduated after 1980 compared to 72% in the original survey. The results also indicate that those who didn’t work in clinical practice (9%) were less likely to participate in this follow up survey as compared to 15% from the original survey and this non-clinical group was not in the cohort inclusion criteria for this study. We reduced the risk of selection bias by including all abnormalities where the pregnancy was terminated, present at birth and malformations diagnosed by the age of six years. Third, we were unable to analyse the data by specific malformations due to small sample size and the loss of statistical power. Further studies investigating the risk of specific birth defects are needed and require larger sample size.Our study also had several strengths such as; (a) using a specific homogenous occupational group of those who worked in clinical practice with possible intensity in exposure and easier adjustment for covariates and using the comparison group of unexposed pregnant women from those who worked in clinical practice, but unexposed; (b) its sample size represents all types of clinical practice and from all ages in Australia suggesting that our study was generally representative of female veterinarians; (c) allowing the assessment of the exposure during pregnancy including the 3rd–8th weeks of pregnancy; (d) exploring the effect of exposures on potential dose-response relationships using partial quantification of differences according to durations of exposure (per day or per week), but not a more complete quantification that included the average intensities of exposures; (e) performing an explorative stratifying analyses in more homogeneous groups such as small animal practice, large animal practice, recent and old graduates using same comparison groups.The findings from this population-based analysis of no association between risk of birth defects of unknown etiology and advancing maternal age is consistent with another population-based analysis in British Columbia published in Lancet  and alsoInterpretations: Limited research has been conducted to explore the risk of birth defects in offspring of women who are exposed to handling cytotoxic drugs and the majority of these studies have focused on health care workers (nurses and pharmacists). Six studies have investigated this topic [p = 0.05) which is consistent with the results for this study [p = 0.02, eight cases), for malformations in the offspring of nurses handling cytotoxic drugs more frequently during pregnancy and an OR of 2.1  to women who handled cytotoxic drugs less frequently than once a week [is topic ,32,33,34is topic . A case e a week . There we a week . Howevere a week . The incThere were also a high proportion of unplanned pregnancies and its association with exposure to cytotoxic drugs and risk of birth defects indicates a high possibility of harmful occupational exposures during early stages of pregnancy. Consistent with literature ,37 our fConsistent with the animal and human data from previous survey, the results from this study suggest that the adverse effects of handling cytotoxic drugs in pregnant women may include an increased risk of birth defects. The results for recent graduates indicate the safe handling of cytotoxic drugs in the current veterinary practice in Australia. Women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis and had a higher increased risk of birth defects than those who planned their pregnancies in recent graduates and in small animal practice. The findings from this study are important in clinical practice when providers are caring for female veterinarians and other health care workers with similar exposures. Pregnancy intention status is important health behavior and should be considered in prenatal programs.


Maternal overweight and obesity are associated with increased risks of birth-asphyxia-related outcomes, but the mechanisms are unclear. If a change of exposure  over time influences risks, this would be consistent with a causal relationship between maternal BMI and offspring risks. Our objective was to investigate associations between changes in maternal BMI between consecutive pregnancies and risks of birth-asphyxia-related outcomes in the second offspring born at term.This study was a prospective population-based cohort study that included 526,435 second-born term (≥37 wk) infants of mothers with two consecutive live singleton term births in Sweden between January 1992 and December 2012.2) in the first pregnancy.We estimated associations between the difference in maternal BMI between the first and second pregnancy and risks of low Apgar score (0–6) at 5 min, neonatal seizures, and meconium aspiration in the second-born offspring. Odds ratios (ORs) were adjusted for BMI at first pregnancy, maternal height, maternal age at second delivery, smoking, education, mother´s country of birth, inter-pregnancy interval, and year of second delivery. Analyses were also stratified by BMI (<25 versus ≥25 kg/m2), the adjusted OR for a low Apgar score in the offspring of mothers with a BMI change of 4 kg/m2 or more was 1.33 (95% CI 1.12–1.58). The corresponding risks for neonatal seizures and meconium aspiration were 1.42 (95% CI 1.00–2.02) and 1.78 (95% CI 1.19–2.68), respectively. The increased risk of neonatal seizures related to weight gain appeared to be restricted to mothers with BMI < 25 kg/m2 in the first pregnancy. A study limitation was the lack of data on the effects of obstetric interventions and neonatal resuscitation efforts.Risks of low Apgar score, neonatal seizures, and meconium aspiration increased with inter-pregnancy weight gain. Compared with offspring of mothers with stable weight  and birth asphyxia would be further supported if maternal weight gain between pregnancies increases the risks of birth asphyxia in the following pregnancy.Data from the nationwide Swedish Medical Birth Register were used, which included 532,858 second-born infants born at term (≥37 weeks gestation) to mothers having their first and second infants between 1992 and 2012.We estimated the associations between inter-pregnancy weight change and the risks of a low Apgar score (0–6) at 5 min , neonatal seizures , and meconium aspiration .2 change in BMI between pregnancies), infants born to mothers who gained 4 kg/m2 or more between pregnancies had a 33% to 78% increased risk of low Apgar score, neonatal seizures, and meconium aspiration.The risks of a low Apgar score consistently increased with maternal weight gain. Compared with mothers with stable weight (−1 to <1 kg/mA study limitation is that we could not investigate the potential impact of obstetric and neonatal interventions.The risk of birth asphyxia increases with maternal weight gain between pregnancies. Consequently, preventing weight gain between pregnancies could reduce the risk of birth asphyxia and improve infant health. In Sw in 2010 . In the  in 2010 .Maternal overweight and obesity increase the risks of severe neonatal complications, including major malformations, preterm birth, neonatal morbidities, and low Apgar score (0–6) ,8–11. InWe have previously demonstrated a linear relationship between maternal BMI in early pregnancy and the risks of low Apgar scores at 5 and 10 min and birth-asphyxia-related neonatal morbidity in infants born at term . FurtherIn this nationwide Swedish cohort study, we examined whether changes in maternal BMI between first and second pregnancies influenced the risks of birth-asphyxia-related outcomes in the second-born offspring, including low Apgar score (0–6) at 5 min, neonatal seizures, and meconium aspiration.Ethics approval for this study was obtained from the Research Ethics Committee at Karolinska Institutet in Stockholm, Sweden (number 2012/4:9). Informed consent was not required as all data were anonymous.Between January 1992 and December 2012, the nationwide Swedish Medical Birth Register included 533,535 mothers with first and second live singleton term births (≥37 completed weeks). We excluded 165 mothers with no information on inter-pregnancy interval and 512 mothers with no information on mothers’ country of birth. In analyses of low Apgar score in the second infant, we excluded another 6,423 mothers (1.2%) where either the first- or the second-born infant had missing information on Apgar score at 1 or 5 min.The Swedish Medical Birth Register started in 1973 and contains prospectively collected data on more than 98% of all births in Sweden. The quality of data is considered high . Informa2) was calculated for each of the two consecutive pregnancies. At the first antenatal visit, which occurs in the first trimester in 90% of pregnancies [2 , −2 to <−1 kg/m2, −1 to <1 kg/m2 (stable weight), 1 to <2 kg/m2, 2 to <4, and ≥4 kg/m2. A 1-kg/m2 change in BMI corresponds to change of 2.8 kg in a woman of average height (167 cm). Based on BMI in the first pregnancy, mothers were categorized as underweight (BMI < 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), obese grade I (30–34.9 kg/m2), and obese grade II-III (≥35 kg/m2) [Maternal BMI  .The inter-pregnancy interval was calculated as the time difference between the date of birth of the first infant and estimated date of conception of the second infant . Gestational age was estimated primarily based on early second trimester ultrasound, which is offered to all pregnant women and which 95% of women accept . When daWe estimated the risks of severe asphyxia-related outcomes, including low Apgar score, meconium aspiration, and neonatal seizures, at the second birth by change in BMI from the first to the second pregnancy. A low Apgar score was defined as a score between 0 and 6 points at 5 min after birth. A diagnosis of neonatal seizures was based on ICD-9 code 779.0 or ICD-10 code P90, and a diagnosis of meconium aspiration was based on ICD-9 code 770.1 or ICD-10 code P24.0.Rates of low Apgar score, meconium aspiration, and neonatal seizures were calculated as the number of infants with these outcomes per 1,000 births. Logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals for all outcomes. Mothers whose first infant had a low Apgar score, meconium aspiration, or neonatal seizures were excluded from the analysis of the respective outcome in the second pregnancy to avoid bias in case of a tendency to repeat adverse pregnancy outcomes. Inter-pregnancy weight change was categorized as presented above in the regression model, but also treated as a continuous variable. Multivariate models were restricted to second births with complete data on inter-pregnancy weight change and covariates. We adjusted for maternal BMI in the first pregnancy, maternal height, maternal age at second delivery, smoking habits in the second pregnancy, inter-pregnancy interval, mother´s education, mother’s country of birth, and year of second birth, categorized according to 2). Interaction terms were introduced in the multivariate models, and a p-value of less than 0.05 for the interaction term was considered statistically significant.In sensitivity analyses , mothersThe total number of infants with a low Apgar score (0–6 points) at 5 min was 2,824 . Corresponding numbers (rates) for neonatal seizures and meconium aspiration were 658  and 372 , respectively . Rates o2 and 33% increased in offspring of mothers who gained ≥4 kg/m2. Risk of neonatal seizures was increased by more than 40% in offspring of mothers who gained 2 to <4 and ≥4 kg/m2. The risk of meconium aspiration was 78% higher in offspring of mothers who gained ≥4 kg/m2 compared with offspring of mothers with stable weight.Rates of low Apgar score, neonatal seizures, and meconium aspiration increased with inter-pregnancy weight gain . Compare2, respectively) (p = 0.12).We investigated whether the effect of weight change on asphyxia-related outcomes differed between offspring of mothers who were underweight/normal weight and overweight/obese in the first pregnancy (BMI <25 and ≥25 kg/mctively) . In undep = 0.004). In underweight/normal weight mothers, offspring of mothers with a weight gain of ≥4 kg/m2 had a doubled risk of neonatal seizures compared with offspring of mothers with stable BMI.The risk of neonatal seizures increased with weight gain in offspring of mothers who were underweight/normal weight in the first pregnancy, but not in offspring of mothers who were overweight/obese in the first pregnancy  demonstrated a more than doubled risk of meconium aspiration in offspring of underweight/normal weight mothers who gained ≥4 kg/m2. In contrast, in overweight/obese mothers, weight gain was not associated with increased risk of meconium aspiration in offspring. However, the test for interaction was not significant (p = 0.77).Stratifying the analyses by maternal BMI in the first pregnancy  in the second pregnancy  or an inter-pregnancy weight gain of 1 to <2 kg/m2. The proportions of mothers with obesity-related diseases and rates of birth-asphyxia-related outcomes were similar in mothers with and without data on inter-pregnancy weight change  . Also, tt change .The prop2 in the first pregnancy. The observed increments in risks of low Apgar score, neonatal seizures, and meconium aspiration remained essentially the same after exclusion of offspring of mothers with obesity-related diseases.In this population-based cohort study we found that the risks of severe birth-asphyxia-related outcomes in the second offspring born at term increased with inter-pregnancy maternal weight gain. The risk increases were primarily found in offspring of mothers with BMI < 25 kg/mData from epidemiological studies support that maternal BMI and changes in maternal BMI influence the risks of maternal complications, preterm delivery, and infant mortality –11,17–23The pathophysiology underlying the associations between maternal overweight/obesity and birth-asphyxia-related outcomes in offspring is likely to be complex and multifactorial. Obesity in pregnant women is accompanied by inflammation in maternal and placental tissues, impaired microvascular function, oxidative stress, and marked insulin resistance ,25, chanFetal macrosomia is the most prevalent complication in pregnancies with maternal obesity . There i2 in the first pregnancy. The same pattern has also been demonstrated for complications during pregnancy [2 in the second pregnancy, risks of low Apgar score and neonatal seizures were more than doubled in offspring of mothers who gained ≥4 kg/m2 between pregnancies  between BMI and fat mass in early pregnancy [The primary strengths of our study are the population-based design, including a large number of births, and the prospectively recorded data on exposures and outcomes. The large cohort enabled us to investigate the impact of a range of inter-pregnancy weight change categories on the risks of neonatal outcomes related to birth asphyxia. The prospectively collected data limited the risks of selection and information bias. We were also able to analyze these risks stratified by maternal BMI in the first pregnancy and to adjust for several potential confounders. We used maternal BMI as a proxy for maternal fat mass. This assumption is justified as there is a strong correlation Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


According to traditional Chinese medicine (TCM) theory, Yang and Qi are driving forces of biological activities in the human body. Based on the crucial role of the mitochondrion in energy metabolism, we propose an extended view of Yang and Qi in the context of mitochondrion-driven cellular and body function. It is of interest that the clinical manifestations of Yang/Qi deficiencies in TCM resemble those of chronic fatigue syndrome in Western medicine, which is pathologically associated with mitochondrial dysfunction. By virtue of their ability to enhance mitochondrial function and its regulation, Yang- and Qi-invigorating tonic herbs, such as Cistanches Herba and Schisandrae Fructus, may therefore prove to be beneficial in the treatment of chronic fatigue syndrome with Yang deficiency. Traditional Chinese medicine (TCM) views the human body as an organic entity, consisting of an assembly of various organs that function in a mutually interdependent manner . “Yin/YaTCM theory states that the interaction between Yin and Yang generates Qi. Qi refers to the refined and nutritive substances flowing in the body as well as the functional status of organs and tissues. Within this framework, the complete deprivation of Qi signifies death in TCM . To provOver the past decades, the mitochondrion has been considered to be a central coordinator of life and death in cells by virtue of its regulatory role in both bioenergetics and programmed cell death . Accordi2. Both NADH and FADH2 then donate their high energy electrons to the mitochondrial electron transport chain that generates a proton gradient across the mitochondrial inner membrane. By utilizing the electrochemical potential energy stored in this proton gradient, ATP synthase synthesizes ATP from ADP. ATP, a molecule with high phosphoryl transfer potential , energizes a number of endergonic reactions in the cell, particularly those supporting vital activities. During the mitochondrial electron transport process, reactive oxygen species (ROS) are unavoidably produced from the leakage of electrons, particularly from complexes I and III. The excessive production of ROS from mitochondria, under conditions of high respiratory activity and/or in the presence of threats to homeostasis, results in an increase in oxidative stress. Under conditions of severe oxidative stress, mitochondrial permeability transition pores open, with the subsequent nonspecific release of proapoptotic factors , leading to caspase-dependent and caspase-independent cell death [The mitochondrion is the “power house” of the cell, where the aerobic metabolism of fuel molecules takes place. In aerobic metabolism, acetyl-CoA, which is formed from glucose via glycolysis and oxidative decarboxylation of pyruvate, enters the Krebs cycle occurring in the mitochondrial matrix. Acetyl CoA is ultimately oxidized to carbon dioxide, with the concomitant production of the high energy reducing equivalents, NADH and FADHll death . With rePrimordial Qi, which is the primary driving force of human life in the context of TCM, can be functionally related to the pumping action of the heart that maintains the circulation of the blood throughout the body . RecentlPrimordial Qi (Yang) interacts with pectoral Qi (Yin) to form the normal Qi, which is comprised of nutritive Qi and defensive Qi. Nutritive Qi is responsible for nourishing visceral organs. In this regard, nutritive Qi may be related to the efficiency of tissues/cells to generate energy from nutrients, that is, the efficiency of mitochondria to generate ATP using fuel molecules . This po1H nuclear mass resonance spectrometry and partial least squares discriminant analysis in patients suffering from Yang deficiency syndrome revealed that blood lipid parameters, the ratio of low density lipoproteins to very low density lipoproteins, lactic acid, and sugars, which are fuel molecules or metabolites of energy metabolism, were found to be unbalanced and/or abnormal [Given the causal relationship between Yang and Qi, we adopted the term “Yang/Qi” in the subsequent discussion on chronic fatigue syndrome (CFS). According to TCM theory, Yang/Qi is the driving force of biological activities in the human body. Deficiencies in Yang/Qi display a high prevalence in the “fatigue syndrome” in humans . While Yabnormal , indicatInterestingly, CFS in Western medicine partially resembles the Yang/Qi deficiency-induced fatigue syndrome in TCM . Unlike A growing body of evidence has suggested the involvement of mitochondrial dysfunction in the pathogenesis of CFS with Yang/Qi deficiency. In this connection, physical exercise, which was shown to improve oxidative capacity of skeletal muscle in patients with mitochondrial myopathy , is bein in vitro and in rat hearts ex vivo. Cistanches Herba was found to increase the ATP-GC in H9c2 cardiomyocytes and in rat hearts, with the extent of stimulation being most potent among all tested Yang-invigorating herbs. Among Qi-invigorating herbs, Schisandrae Fructus has been shown to confer cellular/tissue protection against oxidative stress in rodent brain, heart, liver, and skin tissues via the enhancement of mitochondrial antioxidant status [In the realm of TCM, a pathological condition is caused by an imbalance of Yin/Yang status in the body. A prescription with tonic herb(s) can help to restore the balance of Yin and Yang and achieve a healthy condition. Tonic herbs are generally classified into four categories on the basis of their health-promoting actions, namely, “Yang-invigorating,” “Qi-invigorating,” “Yin-nourishing,” and “blood-enriching” herbs . The “Qit status . In thisCistanches Herba, one of the “Yang-invigorating” tonic herbs, was found to enhance mitochondrial respiration, as indicated by a significant increase in ATP-GC and mitochondrial state 3 respiration in H9c2 cells and in isolated rat heart mitochondria . Cistanc Schisandra chinensis, is a Qi-invigorating herb. Schisandrae Fructus possesses five tastes, namely, sweet, sour, bitter, astringent, and salty, which, according to “Five-Element Theory,” correspond to five visceral organs  in TCM [ in vitro [ in vivo [Schisandrae Fructus , the fruit of) in TCM . Accordi) in TCM . Over th) in TCM , 43. Amo) in TCM . A huge in vitro  and in v in vivo  experime in vivo . Conceiv in vivo . As prop in vivo . The Sch in vivo . These f in vivo , 45, but in vivo .Based on the crucial role of mitochondria in energy metabolism, we propose an extended view of Yang and Qi in the context of mitochondrion-driven cellular and body function. Yang and Qi likely connote mitochondrion-driven biological processes in the human body. The manifestation of Yang/Qi deficiencies in TCM is in common with CFS of Yang deficient type, for which a huge body of clinical evidence has accumulated linking mitochondrial dysfunction to CFS. By virtue of their ability to enhance mitochondrial function and its regulation, Yang- and/or Qi-invigorating herbs, such as Cistanches Herba and Schisandrae Fructus, respectively, may prove useful for the treatment of CFS with Yang deficiency. Moreover, the astringent and immunomodulatory actions of Fructus Schisandrae may also be beneficial to CFS patients with Yin deficient symptoms such as increased sweating, dry mouth, and immune dysfunction. Future clinical studies on Cistanches Herba and Schisandrae Fructus or their combination in CFS patients, particularly those with Yang deficiency, are therefore warranted.


Cytokines are pleiotropic mediators that play a major role in inducing and orchestrating the inflammatory and the immune response. They play a major role in the response to damage or infections. In some pathological condition abnormal regulation of the production of cytokines leads to pathological events and subsequent damage to target tissues. Dissecting the role of each single mediator in the plethora of cytokines and in the complex networks has been one of the aims of biomedical research that has led to relevant applications in rheumatic diseases. In the presentation we will briefly review the evidence leading to the identification of the role of some cytokines  as key mediators and therapeutic targets in pediatric rheumatic diseases.None declared.


Prematurity is an issue related to increasing the neonatal morbidity and mortality and smoking pregnant women cause the risk of low birth weight and prematurity increase, compared to non-smoking ones.This study investigates second-hand smoke (SHS) exposure’s effects over pregnant women on gestational age and birth weight.In this descriptive-analytic study, 205 women referred to both public and private hospitals in the third trimester were questioned about second-hand smoke (SHS) exposure during pregnancy. In addition to birth weight and gestational age, other variables including mother’s education and job and sex of the newborns were also assessed.Of all 205 women, 43 (20.97%) women exposed to SHS during pregnancy and 162 (79.02%) women did not. In SHS exposure group, 11 infant (25.6%) and in non- SHS exposure group, 17 infant (10.5%), were born prematurely (< 37 weeks) (P = 0.01). Also birth weight of newborn in non-SHS exposure group was 118 gram more than other group but the differences were not significant (P = 0.09).Our findings showed that the secondhand smoke (SHS) exposure of pregnant women may be significantly associated with early preterm delivery. There are many identifiable causes of preterm birth such as multi parity, placental dysfunction, bicornuate uterus, preeclampsia, low socioeconomic status, maternal under nutrition, anemia, inadequate prenatal care, obstetric complications, teenage pregnancies, short interval of pregnancy, maternal size and maternal smoking . CigaretThe goal of our study is to examine the association of pregnant women and secondhand smoke exposure (or passive smoking), during the first and second trimester of pregnancy, with birth weight and gestational age.In this descriptive-analytic study, 205 women between 16 and 40 old years were questioned about secondhand smoke (SHS) exposure during their pregnancy. Pregnant women, referred to Sadoghi (public) and Mojibian (Private) hospitals in the third trimester from January till July, 2009 participated in the study. Non-random simple method was used as sampling procedure. Based on statistical calculations (α = 0.05), sample size consisted of 205 people. t-test, Man-Whitney and Chi-square test data analysis have shown the significant level of P < 0.05 in the present study.As recorded in the neonate’s medical records, Low birth weight-less than 2,500 g at birth- was defined as a neonate and live born infants, delivered before 37 weeks from the 1st day of the last menstrual period (LMP), were termed premature. In addition to birth weight and gestational age assessment, other variables including mother’s education, mother’s job and sex of newborn were also evaluated. After data collection, through SPSS 16 software and using independent The mean age of women was 25.93 years (SD = 5.14 y/o); 86.9% of them reported having a high school degree and below and 13.1% possessing a bachelor degree.Also 13 women (6.3%) were workers and others were house wives . The meaThe results of our study showed an adverse effect of SHS exposure on gestational age and birth weight at the time of delivery. This is consistent with the results of previous studies, in which the researchers found that maternal exposure to SHS was associated with prematurity and low birth weight , 28-32. In our study the mean birth weight of newborn in non-SHS exposure group was 118 g more than SHS exposure group P = 0.09). This finding is similar to some studies which found that maternal exposure to SHS was not associated with low birth weight , 36, 37.. This fiAs shown in Although we didn’t study SHS exposure rate, there are sufficient evidences from many studies in this regard. There is a significant negative association with exposure rate and gestational age and birth weight , 34, 42.


The wide range and complex combinations of factors that cause birth defects impede the development of primary prevention strategies targeted at high-risk subpopulations.Latent class analysis (LCA) was conducted to identify mutually exclusive profiles of factors associated with birth defects among women between 15 and 49 years of age using data from a large, population-based, cross-sectional study conducted in Shaanxi Province, western China, between August and October, 2013. The odds ratios (ORs) and 95% confidence intervals (CIs) of associated factors and the latent profiles of indicators of birth defects and congenital heart defects were computed using a logistic regression model.Five discrete subpopulations of participants were identified as follows: No folic acid supplementation in the periconceptional period ; low maternal education level + unhealthy lifestyle ; low maternal education level + unhealthy lifestyle + disease ; unhealthy maternal lifestyle + advanced age ; and multi-risk factor exposure . Compared with the reference subgroup, the other subgroups consistently had a significantly increased risk of birth defects . For congenital heart defects, the ORs and 95% CIs were all higher, and the magnitude of OR differences ranged from 1.59 to 16.15.A comprehensive intervention strategy targeting maternal exposure to multiple risk factors is expected to show the strongest results in preventing birth defects. Birth defects affect 3% of all babies, cause 2.7 million neonatal deaths, and result in approximately 3.2 million birth defect-related disabilities every year. They have a significant effect on individuals, families, health-care systems and societies . Birth dSince 2010, WHO has been encouraging countries to develop primary prevention and health promotion strategies for birth defects and to raise awareness of their effects , 12. HowPrevious studies have suggested that maternal factors from multiple domains are associated with birth defects. While advanced maternal age ; maternaThe co-occurrence patterns of associated factors must be examined because this information could aid in the development of intervention strategies that are relevant to the prevention of birth defects among women of childbearing age. In designing health promotion strategies, it is important to understand the many factors that women are simultaneously experiencing and that are unlikely to occur in an entirely uniform manner in the population. For example, if most women with poor dietary intake are also smoking and experiencing stress, narrow intervention strategies specifically targeting nutrition-related behavior changes  may not be effective in helping these women. However, using the same intervention strategy related to all modifiable risk factors in the entire population is neither efficient nor cost effective, particularly in China, which has limited per capita financial and temporal resources . Indeed,Latent class analysis (LCA) is conceptually similar to cluster analysis, which is based on a measurement model much like factor analysis, and is one useful approach to address these needs in the field. LCA is a data-driven approach positing that there are underlying homogeneous, mutually exclusive subgroups or latent classes existing within a heterogeneous population, but a true subgroup membership of individuals who share similar characteristics is unknown and can only be inferred through a measurement model of a set of observed categorical indicators. Therefore, instead of subgrouping every possible factor combination, LCA helps to address the complexity of birth defects-related factor patterning and to capture the most parsimonious, meaningful key patterns of factors, while accounting for measurement error .LCA is increasingly being applied to identify memberships of study populations based on modeling multidimensional factors, including weight-related health behaviors , socioecA population-based, cross-sectional survey was conducted between August and October, 2013. The subjects were Chinese women of childbearing age (15 to 49 years) living in Shaanxi, a major province in western China with a population of 40 million that is undergoing rapid economic change. The inclusion criteria for the women were a pregnancy that ended between August 2011 and August 2013 and a birth that occurred at a gestational age of ≥28 weeks. Women were excluded if they were pregnant during the time of the survey or had a serious illness, such as cancer or cardiovascular disease. A stratified, multistage, random sampling method was used to obtain the sample. Women were recruited from 10 urban districts and 20 rural counties that were randomly selected according to the proportion of urban to rural residents and the fertility level in Shaanxi Province. In urban areas, 3 subdistricts were randomly selected from each sampled district, 6 communities were randomly selected from each sampled subdistrict and the urban women were selected from each sampled community. In rural areas, for each sampled county, 6 townships were randomly selected, and 6 villages were randomly selected from the sampled townships. Finally, the rural women were randomly selected from the sampled villages. To gain a larger sample size and detect more birth defects in the population, we assumed that the prevalence of birth defects in Shaanxi Province was 1% when estimating sample size, while the reported prevalence of birth defects is 1.4% according to the results of a population-based, cross-sectional survey conducted in 128 townships in 16 counties/districts in Shaanxi Province between 2008 and 2009. A sample size of 30,000 was estimated assuming a prevalence of birth defects of 1%, a relative error of 20%, a 2.0 designing deficiency, two-tailed α = 0.05, and an expected response rate of 90%. The proportion of urban to rural residents in the sample was determined to be approximately 50%, which was close to the proportion of urban to rural population in Shaanxi Province.All women were interviewed in person by trained interviewers who used a standard questionnaire comprising four sections. The first part was designed to collect information on maternal sociodemographic characteristics, including age, ethnicity, education, marital status, address of residence, and occupation at the time of the survey. The second part was primarily about the outcomes of each woman’s most recent pregnancy, which was identified as the woman’s most recent live birth or stillbirth at a gestational age of ≥28 weeks, to confirm birth defects. Birth defects were classified according to the International Classification of Diseases Clinical Modification Codes, tenth edition, (ICD-10) as congenital malformations, deformations, and chromosomal abnormalities(Codes Q00–Q99). First, we asked participants who reported birth defects to provide their medical records. Second, for participants who either did not report birth defects or reported them but did not provide their medical records, we used one of two measures to identify cases. Either we checked the surveillance system of birth defects at the corresponding hospital where that participant had delivered her baby or the interviewers performed physical examinations of the infants to detect apparent structural defects and took pictures that would be reviewed and diagnosed by experts. Third, we obtained data on the women’s reproductive history by asking about their previous pregnancy outcomes, including induced abortions, miscarriages, stillbirths, preterm deliveries and any birth defects associated with previous pregnancies. Fourth, we focused on maternal exposure to periconceptional risk factors associated with birth defects during the most recent pregnancy, which covered the following topics: lifestyle, illnesses, periconceptional stress, exposure to harmful factors in the periconceptional environment, family history of diseases and periconceptional folic acid supplementation. Periconceptional was defined as the period from 3 months prior to pregnancy through pregnancy. Information on lifestyle included alcohol use (drinking Chinese wine or beer at a frequency of more than once per week); smoking (smoking cigarettes continuously or cumulatively for three months or more); passive smoking (defined as family members who smoked cigarettes while living together with the women); and drinking strong tea and/or coffee (at a frequency of more than once per day). Maternal diseases were defined as colds; fevers; and pregnancy complications, including pregnancy-induced hypertension and diabetes mellitus. Information about maternal stress during the periconceptional period was obtained by asking three questions: “Have you experienced serious life crisis events, such as marital discord, bereavement, unemployment or major diseases?”, “Have you experienced domestic violence?” or “Have you experienced low spirits, irritability, or any suicidal thoughts?”. As long as there was one “yes” answer, the woman would be defined as having experienced stress during the periconceptional period. Harmful environmental factors were defined as either the women’s residence during the most recent pregnancy being less than 3 kilometers, with the content of pollutants varying significantly as the distance changed, from industrial production sites that may discharge pollutants, such as coal mines, paper mills, cement plants, and coal-fired power plants, or exposure to any radioactive examination or chemical pesticide, including insecticides, herbicides and rodenticides, during the periconceptional period. A family history of diseases that might be related to birth defects was also evaluated, including incidences of birth defects and Keshan disease . Women were asked to report their use of periconceptional nutritional supplements, including folic acid and other micronutrients.The analyses reported here were confined to women with single births because multiple births increase the risk of birth defects , 35. OnlAll factors associated with birth defects were coded as dichotomous indicators . Although many factors in this study were dichotomous by nature, several continuous measures of factors were converted into dichotomous factors by logical or previously established cut-offs. Maternal education level and age at the time of the interview were dichotomized by cut-offs 9 and 30 years, respectively, which were selected based on the conditions of most reproductive-aged women having a low education level and being of a young age reported in previous studies , 36. We 2 (G-squared test statistic), the Bayesian information criterion (BIC) and the Akaike information criterion (AIC), with lower values indicating a better model fit [We used LCA to define groups of women with similar factor profiles across the 9 indicators associated with birth defects. Latent class models with 2 or more classes were fitted to items measuring different aspects of the women’s factor profiles. The estimation was performed using the maximum likelihood with expectation-maximization algorithm. Criteria used to select the final LCA model included the Godel fit . Howeverodel fit . In thisAfter the most parsimonious latent class model was determined, the odds ratios (ORs) with their 95% confidence intervals (CIs) were used to estimate the strength of the associations between factor profiles and either birth defects or congenital heart defects using the classify-analyze approach. To compare the results of exploring the causes of diseases using traditional multivariable analysis, the ORs and 95% CIs of all indicators of birth defects and congenital heart defects were computed using a logistic regression model, in which all indicators described in All LCA models were fitted using Mplus , while SPSS 20.0 software  was used for the logistic regressions. A P value of <0.05 was considered statistically significant using a 2-tailed test.The study was conducted in accordance with the Declaration of Helsinki and was approved by the Human Research Ethics Committee of the Xi'an Jiaotong University Health Science Center (No. 2012008). Written informed consent was obtained from all participants after the nature of the study had been explained. Participants who were 15 to 17 years old during the study period and had therefore not reached the minimum legal marriageable age of 20 for females and 22 for males in China also provided oral informed consent for themselves, and their mothers-in-law provided written consent on behalf of these participants. There was no need to obtain informed consent from the next of kin, caretakers, or guardians on behalf of the minors/children enrolled in our study because all information about the infants was obtained from their mothers.In total, 30,027 women were interviewed, and 29,608 (98.60%) singleton births were included in this study. Among them, 61 women were excluded for incomplete or missing data regarding the factors associated with birth defects, and 29,547 observations were used for the final analysis. The demographic characteristics are shown in The prevalence of birth defects was 1.80% , and congenital heart defects were the most common type of birth defect, with a prevalence of 0.58% . As shown in As shown in 2 and AIC values of the 2 through 6 class models; however, based on the interpretability and the lowest BIC , we determined that the 5-class model best described the different indicators associated with birth defects in this study.For the 5-class solution, conditional item-response probabilities are shown in The lower section of In a large population-based sample of reproductive-aged women from Shaanxi Province in western China, where the prevalence of birth defects is 1.80% , and the prevalence of the most common type  is 0.58% , five distinct latent subgroups ; Low maternal education level + unhealthy lifestyle (39.75%); Low maternal education level + unhealthy lifestyle + disease (23.71%); Unhealthy maternal lifestyle + advanced age (4.71%); Multi-risk factor exposure (10.45%) that adequately accounted for variations in the co-occurrence patterns of 9 associated indicators in terms of birth defects were identified using LCA. Each subgroup exhibited a unique latent profile of associated indicators. Compared with the study of associated indicators in isolation, these profiles evaluated individuals more holistically and suggested the manner in which multiple factors were organized within individuals. Memberships in these subgroups were significantly associated with birth defects and congenital heart defects, which were measured separately in logistic regression models for further analysis, and the results showed that the association with the latent subgroup characterized by multiple factors was stronger than that with the other latent subgroups. Therefore, these findings provide new insights into the health needs of this population and refine our understanding of the intersection of birth defect-related factors so that we can develop successful intervention programs tailored for and targeted at high-risk population subgroups characterized by the corresponding factor profiles illustrated in this analysis.The prevalence of birth defects in our study sample was 1.80%, which was slightly higher than the prevalence of 1.43% reported in a population-based survey conducted between 2009 and 2010 . An upwaMultivariable logistic regression analyses showed that low maternal education level, maternal diseases, no folic acid supplementation in the periconceptional period, exposure to harmful environmental factors and periconceptional stress were significantly associated with a higher risk of birth defects, which is consistent with the findings of other studies –23, 36. When we used “No folic acid supplementation in the periconceptional period” membership as the reference, we found that class 2 ; class 3 ; class 4 ; and class 5  were all consistently significantly associated with an increased risk of birth defects or congenital heart defects. Not surprisingly, the observation that this result differed from that of only three indicators significantly associated with congenital heart defects in multivariable logistic regression analyses demonstrated the utility of LCA in understanding the complex relationships among factors and outcomes, such as those observed in the current analyses.It is interesting that the effects of different indicator profiles on congenital heart defects appear to be stronger than the effects on any birth defects, and the magnitude of OR differences ranged from 1.59 to 16.15. This might be because different types of birth defects are caused by different determinants. For example, advanced maternal age is more highly associated with numerical chromosomal aberrations, such as trisomy 21 (Down syndrome) , and folAlthough the findings from multivariable logistic regression analyses were helpful in understanding how multiple factors are associated with birth defects and highlighted that overall associated factors should be the focus of prevention efforts, they provided little information on how we should design future intervention strategies or whom we should target. These findings simply imply that the most appropriate, effective preventive approach for reducing the risk of birth defects would be to try to reduce the number of associated indicators for all women, regardless of how an individual’s entire spectrum of associated indicators interact to predict negative outcomes or which associated indicators are present in an individual’s life. By contrast, the five meaningful latent profiles derived by LCA provided a complete picture of the intersection of associated indicators and birth defects among these reproductive-aged women in terms of both the number of indicators present in each factor profile subgroup and which associated factors dominated the profile, meaning that they will fit well into a holistic/ecological framework for the development of intervention strategies.Specifically, the item-response probability of folic acid supplementation in the periconceptional period was significantly smaller for all latent classes, indicating that “No folic acid supplementation in the periconceptional period” is very common among women of childbearing age in the Shaanxi Province. Despite the fact that WHO has recommended folic acid supplementation to prevent neural tube defects and that the provincial government has provided folic acid tablets free of charge since 2009, our results still suggest that more health declarations or intervention strategies for improving folic acid supplementation in the periconceptional period should be provided in Shaanxi Province. However, promoting such strategies with the aim of reducing the risk of birth defects may only be efficient and practical for members of the “reference” subgroup, which was predicted to represent 20.91% of the sample, because this subgroup was solely characterized by the indicator “No folic acid supplementation in the periconceptional period”; other latent classes were characterized by more than one indicator. The largest subgroup of women, comprising 39.75% of the sample, was class 2. This class was defined by a high probability of reporting an education level of ≤9 years and an unhealthy lifestyle, and a lower probability of reporting other factors; therefore, a more straightforward approach to providing periconceptional health education for promoting healthy lifestyles, such as avoiding passive smoking, may be appropriate for these women. Nearly a quarter of the sample comprised class 3 individuals, who were highly likely to experience diseases based on the class 2 factor profile. Members of this class may benefit most from the prevention or seasonable treatment of diseases that do not focus solely on improvements lifestyle , 49, or Despite the interesting implications of these findings, several limitations of our study are important to address. First, because our participants were Chinese women of childbearing age(15 to 49 years), from Shaanxi Province in western China, these findings may be limited in terms of their generalization to other ethnic or racial populations. Second, the generalizability of our study may also be influenced by the indicators used in LCA because the number, prevalence and profiles of classes may differ if other associated indicators  are considered in concert with the indicators that we focused on in the present study. Third, although dichotomizing associated factors are commonly used in LCA and may be helpful in interpreting and communicating the findings, this may result in some loss of information from categorizing the data in this way. However, most associated factors used in this study were categorical by nature except for maternal age and education level, while in some cases, receiver operating characteristic curves or latent profile analysis may aid in addressing such issues , 51. FouThis study also had several strengths. Compared with the data from hospital-based birth defect surveillance, the large, population-based sample used in this analysis provided more factors associated with birth defects, such as lifestyles, nutritional factors, environmental risk exposures, maternal illnesses, and genetic factors, to more accurately determine the prevalence of birth defects in a population and to inform the development and evaluation of prevention strategies , 55. ThiUsing LCA, we identified five latent subgroups characterized by the intersection of multiple recognized causes and determinants of birth defects among Chinese women of childbearing age (15 to 49 years) from Shaanxi Province in western China. More than 80 percent of women of childbearing age in Shaanxi Province do not receive folic acid supplementation during the periconceptional period and exposure to multiple risk factors associated with birth defects and congenital heart defects is high among these women, although the factors were co-occurring in different profiles. The combined effects of maternal exposure to multiple risk factors raises the risk of birth defects and congenital heart defects among offspring, and this risk is significantly higher than the simple summation of the risks from single factors. A comprehensive intervention strategy targeting maternal exposure to multiple risk factors will contribute to the primary prevention of birth defects, particularly for high-risk subgroups, which are expected to show the strongest response.


Background: In recent years, the study of birth intervals has been a main determinant of the levels of fertility in the populations, as it is associated with rates of fertility and population growth. Objective: The purpose of this study was to firstly apply survival analysis for modeling of first birth interval and secondly to explore its determinants.Materials and Methods: In a cross sectional study, the fertility history of 858 women was collected in rural areas of Shiraz (southern Iran) in 2008. We used the survival analysis such as cox regression and alternative parametric models to evaluate the prognostic factors of first birth interval.Results: Among the explanatory variables of interest, age at marriage, level of women's education, and menstrual status had highly significant effects on the duration of birth interval after marriage (p<0.01).Conclusion: It is concluded that the suitable parametric models would be a useful tool for fitting to first birth interval, the fact that has been less paid attention to in researches. The study of the dynamics of timing and spacing of births is important for several reasons, including an understanding of completed family size as well as maternal and child mortality . Modelinet al demonstrated in their study of human reproduction, measurement of fecund ability has got an important place. Among the various types of fertility data used for the purpose, data on first birth interval have an upper hand over all other types of birth interval due to certain reasons. First, being the earliest and first event of the married life of a female, it hardly suffers from recall lapse; second, it is free from the period of post-partum amenorrhea (ppa) associated with a live birth. Other birth intervals are heavily affected by the erratic fluctuations of this period  was reviewed . The peoLive birth in the first delivery was the success event and a stillborn fetus or abortion (5% in this data set) was considered as censored. The event time was defined as the interval between marriage and a live birth or censoring (years). The explanatory variables were age at marriage, age at first pregnancy, age at menarche, education level of women, education level of husbands, family income, and menstrual cycle. Data were obtained from a university approved project and all ethical consideration has been met. Statistical analysisBecause the study was included the censored data, the survival analysis methods was carried out. Log rank test was used to compare the survival between different groups. The Cox proportional hazards model, a popular mathematical model, was used to determine the effects of various factors on the first birth interval. This model is usually written in terms of the hazard model formula. In cox model, we can exponent ate the coefficients to obtain hazard ratio to calculate the factor change in the hazard rate associated with the changes of variable. The hazard ratio greater than one increases the hazard rate of duration of live birth. The hazard ratio less than one decrease the hazard rate of duration of live birth. The statistical significance of the coefficient indicates whether these changes in expected duration will be statistically significant or not. Moreover, we evaluated the two parametric survival models , because the cox model is a semi-parametric model. A major advantage of the parametric survival model on the Cox model is that a description of the hazard rate of live birth over time can be plotted. Also, the parametric models tend to give more precise estimates of coefficients. In parametric models, we measure the direct effect of the explanatory variables on the survival time instead of hazard. This characteristic allows for an easier interpretation of the results because the parameters measure the effect of the correspondent covariate on the mean first birth interval. The effect size for parametric model is the time ratio. For each covariate, a time ratio value greater than one can be interpreted as individual experiences the event at a later timing. Conversely, a time ratio value of less than one implies that individuals will experience the event of interest faster. The statistical software used for modeling is Stata/SE, version 10 and R software used for plotting of graph.Of 654 women, 621 (95%) had experienced first live birth, and the others (5%) were censored (right censored). The mean and median of the first live birth interval for women experiencing the event were 2.6 and 2.1 years, respectively. The mean age at marriage was 18.3±3.8 years. Proportion of women not having live birth before 1, 2, 3, 4, 5 years after marriage is 0.55, 0.23, 0.11, 0.07 and 0.05 percent. The Generalized Gamma and log-logistic are more preferable when hazard rises to a peak before decreasing. By using the Log rank test, age at marriage of women had significant effects on the duration of birth interval after marriage (p=0.002). The median length of live birth interval after marriage decreases with the increase age at marriage. Menstrual status had significant effects on the duration of birth interval after marriage (p<0.001). In women that had irregular menstrual cycle, the median length of live birth interval after marriage was longer. We used the parametric models and Cox model after adjustment of other covariates. We find age at marriage of women, menstrual status and education level of women affect live birth interval after marriage. The results of the survival regression analysis are summarized in Based on the Generalized Gamma model, women with primary and secondary education had faster transition to first live birth compared to those without any formal education  and by cox model, the hazard rate of live birth of women with primary and secondary education is 33% more than those without any formal education . Based on the Generalized Gamma model, women with regular menses had faster transition to first live birth compared to those with irregular menses  and by the Cox model, the hazard rate of live birth of women with regular menses is 68% more than those with irregular menses . Moreover, the results are showed that the standard errors with parametric models are lower than the Cox model.The timing of the first birth is known to be a critical factor in completed family size. First childbirth has a direct relationship with number of factors such as couples’ educational and occupational status, age at marriage, etc. . Few stuAs our results indicated, age at marriage, women's education and menstrual status were significant prognostic factors of transition to the first live birth. The result showed that women who married at a relatively later time had a significantly shorter timing to first birth. Age at first marriage is an important variable in most fertility studies since it indicates the beginning of a woman’s exposure to sexual intercourse and hence to the risk of childbearing , 21-23. In the present study, women with primary and secondary education have faster transition to first live birth. Women's education is considered to be an essential component of reproductive behavior. When women spend a longer time at school, this is likely to significantly affect both age at marriage and the duration between marriage and the first birth. Our results agree with the findings of other studies , 9-10. IAccording to the results of this study, the parametric survival model is more suitable to analysis this type data to several reason. 1) The hazard function shape showed that using parametric models are appropriate. 2)


This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth.There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm  impairments and the Parent Report of Children's Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses.Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls . Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% . LMPT infants were at twice the risk for neurodevelopmental disability . Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge.Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth. School-aged children born late and moderately preterm are at significantly increased risk for adverse neurodevelopmental outcomes compared with term-born peers.Large prospective population-based studies of outcomes in infancy are needed.Two-year-old children born late and moderately preterm are at double the risk for neurodevelopmental disability compared with term-born peers.Risk factors for cognitive impairment include male sex, socio-economic disadvantage, non-white ethnic origin, preeclampsia and not receiving breast milk at discharge.+0 weeks) have increased significantly in recent decades, largely due to an increase in late (34+0–36+6 weeks) and moderately preterm (32+0–33+6 weeks) deliveries.16Preterm birth rates  within a geographically defined region of the East Midlands (UK) were invited to participate in the Late And Moderately preterm Birth Study (LAMBS). This examined births at four maternity centres, a midwifery-led birthing unit and home births during this period. A random sample of babies born at term (37+0–42+6 weeks) was also recruited during the same time period and in the same geographical region. Eligible term births were selected based on random sampling of dates and times of birth of babies in the same area during the previous year. In addition, mothers of all term-born multiples were invited to participate. Infants with major congenital anomalies were excluded from the present analyses.From September 2009 through December 2010 the mothers of all babies born LMPT (32The study was approved by Derbyshire NHS Research Ethics Committee (Ref 09/H0401/25). Research midwives obtained informed consent from mothers during their postnatal stay; home visits were arranged for mothers discharged shortly after delivery. Mothers participated in a semi-structured interview after birth and obstetric and neonatal data were collected from mothers’ and infants’ medical records at discharge. Follow-up questionnaires were completed at 2 years corrected age.Mothers were asked about demographic characteristics including ethnicity and language. To quantify socio-economic status (SES), a composite SES-Index score was computed using five proxy variables that measured mothers’ occupation, education, social support, income and wealth. Total SES-Index scores (range 0–12) were used to define three socio-economic risk categories: low (scores 0–2), moderate (scores 3–5) and high (scores ≥6) (see the online supplementary appendix).Obstetric data collected included maternal chronic health conditions, smoking and recreational drug use during pregnancy, preeclampsia, maternal infection during pregnancy, pre-labour rupture of membranes, antenatal corticosteroids, induction of labour, mode of delivery, raised C-reactive protein (CRP) during delivery and antenatal umbilical Doppler studies. Neonatal data items included sex, gestation, birth weight, small for gestational age .Parents were asked whether their child had non-febrile seizures over the past year and whether s/he was currently taking anticonvulsant medication. Parents were also asked whether their child had a diagnosis of cerebral palsy (CP) and were asked to rate their child's vision, hearing and gross motor function (irrespective of CP); forced-choice answers corresponding with criteria for classifying health status following preterm birth2 test) and means (t test) as appropriate. Neurodevelopmental outcomes were compared between term and LMPT infants both crude and with adjustment for major confounders  using sandwich estimators to account for clustering of outcomes within multiple births. Sampling weights were used to account for the over-sampling of multiple births among the term group. For binary outcomes, differences between groups were quantified using relative risks obtained using Poisson regression. For continuous outcomes, the mean difference (95% CI) between groups was estimated using linear regression models. PARCA-R scores were converted to z scores using the mean (SD) of the term-born reference group to compare effect sizes across scales. Given the high prevalence of cognitive problems, univariable predictors of cognitive impairment were analysed using Poisson regression. A multivariable model was then constructed to identify independent risk factors using sandwich estimators to account for clustering of outcomes within multiple births. Backwards selection was used with all variables in the univariable analyses entered into the model and dropping out the least significant variable until all had p<0.05; all of the dropped variables were then entered in turn into this preliminary model and included if p<0.05.Baseline socio-demographic characteristics were compared between the term and LMPT groups using percentages  LMPT infants and 765 (62%) controls . The chaThe characteristics of non-responders have been described previously.LMPT children were at significantly increased risk for neuromotor/sensory impairment , while rates among female LMPT infants and controls were similar (1.4% vs 1.6%). The male disadvantage in neurodevelopmental outcomes is well documented in preterm cohorts and the interaction between sex and gestation may explain much of the disadvantage observed here among our LMPT population. As expected, socio-demographic factors were also markers of adverse outcomes; the additive impact of socio-economic factors on long-term outcomes has previously been reported in this population.43Preeclampsia was also identified as an independent risk factor and has been associated with long-term cognitive and behavioural sequelae in general population samples,It was noted that lack of continuing provision of breast milk at discharge was associated with moderate/severe cognitive impairment. Among extremely preterm infants this has been identified as an independent risk factor for autism and psychiatric disorders.49The present study addresses the growing need for large, population-based investigations of outcomes following LMPT birth. Data were collected from a birth cohort spanning a wide geographical region of the East Midlands of England and the prospective nature enabled an investigation of risk factors for adverse outcomes including neonatal, antenatal and maternal lifestyle factors. Neurodevelopmental outcomes were classified using standard criteria for defining health status at 2 yearsThe major limitation of this study was the response rate at 2 years and the selective dropout of mothers with greater socio-demographic risk. This may have resulted in an underestimation of the true prevalence of adverse outcomes; however, the factors affecting non-response were the same in both groups and thus the relative risks reported are likely to be reflective of the total population. The size of this study necessitated the use of parent questionnaires as outcome measures. Although these may be considered less preferable than developmental tests, well-validated tools were used where possible. In particular, the use of parent reports may have resulted in underestimation of the true prevalence of CP as this may be diagnosed later in childhood, particularly for infants with mild neuromotor signs. Longer term follow-up is needed to determine their prognostic value for later functional outcomes. Despite the sizeable cohort recruited, the study was powered to detect a difference in cognitive impairment between two groups (LMPT vs term). As such, we were unable to assess the statistical significance of group differences in neuromotor and sensory impairments and there was insufficient statistical power to explore a dose–response relationship with gestation age at birth.Prematurity remains one of the major causes of infant mortality and lifelong morbidity worldwide. We have demonstrated that babies born at 32–36 weeks of gestation are at double the risk for neurodevelopmental disability at 2 years of age, with the vast majority of identified impairments in the cognitive domain. Given the size of the LMPT population, even the small increases in impaired outcomes observed in the present study may have significant long-term public health implications.


Effects of antiretroviral therapy (ART) on birth outcomes remain controversial.To assess the impact of antenatal exposure to ART on the occurrence of preterm birth (PTB) and low birth weight (LBW).A cross-sectional study conducted at the Essos Hospital Center in Yaounde from 2008 to 2011 among HIV vertically exposed infants with two distinct maternal antiretroviral experiences: monotherapy group  and the combination ART group (cART). Mothers already receiving cART before pregnancy were ineligible. In both groups, events of PTB (<37 weeks) and LBW  were analyzed using univariate and multivariate logistic regression; with p<0.05 considered statistically significant.3. Median duration of ART at onset of delivery was 13 [IQR: 10–17] weeks. In the cART-group, 64.9% (312/481) of mothers were exposed to Zidovudine/Lamuvidine/Nevirapine and only 2% (9/481) were on protease inhibitor-based regimens. Events of PTB were not significantly higher in the cART-group compared to the ZDV-group , while onsets of LBW were significantly found in the cART-group compared to ZDV-group . Other factors  were not associated with PTB.Of the 760 infants, 481 were born from cART-exposed mothers against 279 from maternal-ZDV. Median maternal CD4 count was 378 [interquartile range (IQR): 253–535] cells/mmcART, initiated during pregnancy, would be an independent factor of LBW. In the era of option B+ , further studies would guide towards measures limiting onsets of LBW. During the last decade, efforts in preventing mother-to-child transmission (PMTCT) of HIV have significantly reduced new HIV pediatric infections worldwide. Of note, antiretroviral drugs, and especially combination antiretroviral therapy (cART), have minimized the risks of HIV vertical transmission  to almost zero in developed countries –3. FurthIn spite of the great achievements with PMTCT interventions, the safety of cART on birth outcomes remains questionable. Indeed, there are conflicting evidences on the increasing rate of preterm birth (PTB) and/or of low birth weight (LBW) following prenatal antiretroviral exposure , 7. ThouCameroon is a SSA country experiencing a generalized HIV epidemiology with almost a doubled rate among women 5.9%) [.9% [5]. 3 was prescribed from 28 weeks of pregnancy up to delivery from 2008 to 2009, and later on from 14 weeks up to delivery from 2009–2011; meanwhile pregnant women with CD4 cell count ≤350/mm3 were eligible for lifelong cART consisting of Zidovudine (ZDV), Lamivudine (3TC) and Nevirapine (NVP) at any moment during pregnancy  among PMTCT-enrolled mother-child pairs at the Essos Hospital Centre (EHC), a referral hospital belonging to the National Social Insurance Fund in Yaoundé, Cameroon. The study-reporting period ranged from 2008 through 2011.The EHC is an Approved Treatment Centre for ART in Cameroon, offering all services for infants and adults within the health district area of Djoungolo, in Yaounde. The EHC also serves as a reference center for PMTCT program in the health district, with regular updates in the implementation of PMTCT guidelines according national policies. Briefly, PMTCT program was launched at the EHC in 2008 and involved 25 health facilities, whereby HIV-infected pregnant women received are referred to the EHC for free CD4 cell count and MTCT prophylaxis. All HIV-infected antenatal care (ANC) attendees are monitored by Obstetricians assisted by Midwives based on mother age, gestational age, parity, absolute lymphocytes CD4 cell count, antiretroviral regimen and duration on ART. Gestational age was assessed based on the last menstrual period associated with fundal height and ultrasonography whenever necessary. HIV-infected ANC attendees are advised to deliver in any facility of the Djoungolo health district network; to ease referral of HIV vertically exposed newborns at the EHC within ten days following birth. At registration, neonatal parameters are collected from the maternal medical records: date of birth, gender, term at delivery, and birth weight.Practically, about 30 to 40 new women are registered for antenatal care on a daily basis, ARV drugs were dispensed on a monthly basis during pregnancy to ensure adherence and therapeutic monitoring, and about 20 HIV-exposed newborns are enrolled in the PMTCT-cascade care on a monthly basis.Data from HIV-infected mothers and their babies routinely monitored in the PMTCT program were abstracted from the register for the period of 2008 through 2011 . HIV-infPrimary outcomes were PTB and LBW. Preterm was defined as babies born alive before 37 weeks of pregnancy. LBW was defined as a birth weight <2,500g regardless of gestational age.Dependent variables were low birth weight and prematurity. Independent variables were: gestational term at ART initiation, moment of ART initiation, type of antiretroviral regimen, number of CD4 T cells, maternal age and parity. Chi-square and Student tests were used to analyze qualitative and quantitative variables respectively. Univariate and multivariate regression were used for covariates with PTB and LBW. Due to the limited number of independent variables (n = 4), there were all considered in multivariate analysis. Statistical analyses were performed using Stata / IC12.0 Software , with p-value ≤0.05 considered statistically significant.Ethical approval was obtained from the Institutional Review Board of the National Social Insurance Fund Hospital. At enrollment for PMTCT intervention, a verbal informed consent was obtained from each mother on the possible use data and reported in the medical file. Data were processed using unique identifiers for purpose of confidentiality, and the data were encrypted for protected.3, [IQR: 435–679], p = <0.001), as shown in In the total of 760 mother-baby pairs, 481 mothers initiated cART during ANC and 279 received ZDV-monotherapy . These tAmong mothers exposed to cART during pregnancy, 98% (472/481) were on non-nucleoside reverse-transciptase inhibitor (NNRTI)-based regimens and 2% (9/481) on protease inhibitor (PI)-based regimens. Median duration of antiretroviral exposition was lower in the ZDV-monotherapy group (12 weeks [IQR: 8–15]) as compared to the cART group (14 [IQR: 10–19]); p<0.01.Overall, the prevalence of PTB was 8.8%, 95% confidence interval (CI): 6.9–11.1, without a significant difference between cART and ZDV-monotherapy groups .Of note, HIV-infected mothers exposed to cART had not more premature babies than those exposed to ZDV-monotherapy neither in univariate  nor in multivariate analysis  .The prevalence of LBW was 10.0% (95% CI: 7.9–12.4), with a significantly higher rate in babies exposed to cART compared to those exposed to monotherapy . Similarly, LBW was associated significantly associated with mothers receiving cART  compared to those on monotherapy.According to maternal age during pregnancy, mothers aged less than 21 years had a higher likelihood for LBW compared to mothers aged 21 to 35 years (OR: 2.2 [1.1–4.4]). Following adjustment in multivariable analysis, cART remained as an independent factor associated to LBW (adjusted OR: 1.8 [1.1–3.2] p = 0.03) .Understanding factors associated with poor birth outcomes in HIV vertically exposed babies is of paramount importance in setting-up approaches to limit such events and their potential impaired effects , 9. In tBy reporting a non-significant burden of PTB with cART, our data are inconsistent with previous findings from other African or Asian settings in newborns, while PTB (15% to 30% in previous studies) was reported to be associated with cART compared to monotherapy used mainly for PMTCT purpose , 14. OnsThe rate of LBW from our findings <20%) differ considerably from data reported in Cote d’Ivoire and in India , 11, 12,% differ Interestingly, statistical adjustment for maternal age and parity confirmed the association of cART with LBW, but not with prematurity, stresses the need for collaborative interaction between gynecologists, obstetricians and pediatricians to overcome the onset of LBW in RLS –10, 23.Beside LBW and PTB, there are other factors known to potentially affect fetal growth  , 25. FurTaking into account the overall benefit of cART in the context of PMTCT option B+ our findings support the safety of currently used ART during pregnancy, as previously postulated from the dream cohort .In an era of scaling-up in PMTCT option B+ implementation in the entire sub-Saharan Africa, there is need to closely monitor the birth outcomes from pregnant women receiving lifelong, with a wider data safety and monitoring to address potential confounders , 31, 32.Conclusively, ANC with exposure to cART may be associated to LBW, especially when the mother is less than 21 years. Additional studies should further explore onsets of PTB and other safety features on cART while scaling-up PMTCT.S1 Data(TXT)Click here for additional data file.S1 Text(DOC)Click here for additional data file.


To investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP).st, 2008. Information on four indices of fetal growth: ponderal index, head circumference/ abdominal circumference ratio, cephalization index and birth weight/ placenta weight ratio was collected. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). All measurements were evaluated as gestational age and sex specific z-scores and in z-score percentile groups, adjusted for potential confounders, and stratified on gestational age groups .We identified all live-born singletons born in Denmark between 1995 and 2003 and followed them from 1 year of age until December 31We identified 503,784 singleton births, of which 983 were confirmed cases of CP. Head/ abdominal circumference ratio  and cephalization index  were associated with the risk of CP irrespective of gestational age. Birth weight-placental weight ratio was also associated with CP in the entire cohort . Ponderal index had a u-shaped association with CP, where both children with low and high ponderal index were at higher risk of CP.CP is associated with disproportions between birth weight, birth length, placental weight and head circumference suggesting pre and perinatal conditions contribute to fetal growth restriction in children with CP. Congenital cerebral palsy (CP) is the most common physical developmental disability in children occurring with a birth prevalence of 2 per 1000 live births.Disproportionate or “asymmetric” fetal growth has been defined by abnormal ratios of anthropometric measurements at birth for a given gestational age. Cox el al have defFetal growth abnormalities, which may include both symmetric or asymmetric growth, may be induced by a wide variety of antenatal factors including potential risk factors for CP such as placental abnormalities–9, parenThis study was approved by the Danish Data Protection Agency 2010-41-4543 on December 14th, 2011, Research Ethic Committee and University of California, Los Angeles Institutional Review Board. Informed Consent was waived because information involving the subjects was recorded in such a manner that the subject could not be identified directly or through identifiers linked to the subject by the investigator.www.dst.dk.In Denmark’s comprehensive registration systems, all residents in Denmark are assigned a unique personal identification number at birth, which enables linkage of individual information among all Danish national registries. The Danvalidated CP if they were alive after the first year of life and included in the Danish National Cerebral Palsy Register. The Danish National Cerebral Palsy Register is a population-based registry that contains a record of individuals with validated CP diagnosis based on the non-CP population were calculated for all these measurements and ratios and used in the analysis.Characteristics of children in our cohort stratified by CP vs non-CP were analyzed as proportions, means ± standard deviations (SD). All children were followed from one year of age until a reported diagnosis of CP in the Danish National Cerebral Palsy Register, death, emigration, or December 31, 2008, whichever occurred first, as a function of exposure to anthropometric measurements measured at birth  and indices of growth proportionality . Exposures were evaluated both as continuous z-scores and in groups of percentile z-score , >75–90, >90). We additionally examined these associations in strata of gestational age . Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazard regression models using PROC PHREG in SAS version 9.2 and Schoenfeld Residuals against log  were used . All statistical analyses were conducted with SAS version 9.2.We identified 503,784 singleton newborns that survived or did not emigrate prior to 1 year of age (date of birth+365). Among these, there were 983 confirmed cases of CP. The characteristics of the subjects are presented in Median z-scores for cephalization index and head-abdominal circumference ratio were higher in CP infants, while median z-scores were lower in CP infants vs. non-CP infants for all other measures . In fullThe association with CP for different percentile levels of z-score for birth weight, birth length, abdominal circumference and placental weight showed similar results . Low z-sth percentile) of head circumference also showed a trend toward an association with higher risk of CP, but this “U-shaped” association was only significant for children born at 37–38 or 41+ weeks.The associations of head circumference z-scores with CP according to percentile level  and accoth percentile) and high (above the 90th percentile) z-scores for this index are positively associated with CP. This U-shaped trend was shown in term and post-term gestational age strata  for both indices were also associated with higher risk of CP  had a 44% increased risk of CP .Ponderal index is an index of leanness of the newborn. Asymmetric fetal growth, characterized by a low ponderal index, presumably reflects fetal malnutrition and has The scientific literature concerning the association of ponderal index with CP is conflicting. In 1992, Blair and Stanley reported that 23% of the children with CP have a low ponderal index. SubsequeHead Circumference was observed to be positively associated with CP when low, as well as when high confirming findings previously reported by Blair and Stanley.. In addiBirth weight/ placenta weight ratio has been used as an indicator of placental function, 37. OurThe strength of the study is the fact that CP was ascertained by the strict inclusion criteria of the Danish National Cerebral Palsy Registry and the large size of the cohort including a large number CP cases. An additional strength is that data on measurements at birth were collected from the Danish National Birth Registry, which records measurements on all births in Denmark. Therefore, underreporting or selection bias is unlikely to occur since medical care is free of charge for residents in Denmark.Our study is limited by the amount of missing data for maternal smoking and parental education. We used multiple imputation methods to fill in missing values, but because of the large number of missing values, imputation may have led to some loss of precision in the estimates and bias to the null. However, sensitivity analysis using patients with complete data showed similar results. Additionally, although we used education as a marker of socio-economic status, there may still be residual confounding by socio-economic status that is not represented with this variable. Other unknown confounders may also be present and contribute to residual confounding. By conditioning on gestational age we may induce collider stratification bias if we doOur study was restricted to children who were born and then survived and did not emigrate from Denmark prior to the age of 1 year; Danish emigration rates are low and unlikely to be a source of selection bias. Another limitation of our study is the potential lack of generalizability to Non-Caucasians due to the lack of racial-ethnic diversity of the Danish population. Based on our study data we cannot pinpoint the timing or underlying cause of insult or the timing of initiation of disproportionate growth associated with CP, since the events (insult and resulting growth changes) could arise at various points in pregnancy. In addition, the study is limited by the absence of imaging or other information that would permit further characterization of the nature of the problems underlying aberrant anthropometric measurements. The biology of growth, body and brain development is highly complex and incompletely understood. Further studies based on longitudinal recording of fetal growth are needed to determine if measurements of asymmetric growth could have predictive value in determining CP outcomes. Given this lack of knowledge, a proper analytical strategy cannot be well identified. Conditioning on intermediate variables may not only block the causal path we take an interest in, but may also produce,-stratifiIn conclusion we observed that risk of CP was associated with reduced fetal growth measured in different dimensions; smaller anthropometric measures overall as well as lower weight for length, lower weight for placental weight, lower weight relative to head size.. In some instances, greater fetal growth  was associated with CP also. These results support the concept that CP is a condition arising from pre and perinatal conditions that, in some cases, contribute to disproportionate fetal growth, perhaps even early in fetal life.S1 Fig(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S7 Table(DOC)Click here for additional data file.