N = 363) of general population from the FinnBrain Birth Cohort Study. sGC exposed infants (N = 12) did not differ from non-exposed infants (N = 351) in their overall probability of disengagement in any single stimulus condition. However, in comparison with non-exposed infants, they did not show the age-typical fear bias and this association remained after controlling for confounding factors such as prematurity, gestational age at birth, birth weight, sex, and maternal postnatal depressive symptoms. Prenatal sGC exposure may alter emotional processing in infants. The atypical emotion processing in turn may be a predictor of emotional problems later in development. Future longitudinal studies are needed in order to evaluate the long-term consequences of sGC exposure for the developing brain.Synthetic glucocorticoids (sGC) are frequently administered to pregnant women at risk for preterm delivery to promote fetal lung maturation. Despite their undeniable beneficial effects in lung maturation, the impact of these hormones on developing brain is less clear. Recent human studies suggest that emotional and behavioral disorders are more common among sGC-exposed vs. non-exposed children, but the literature is sparse and controversial. We investigated if prenatal sGC exposure altered fear bias, a well-established infant attention phenotype, at 8-months. We used eye tracking and an overlap paradigm with control, neutral, happy, and fearful faces, and salient distractors, to evaluate infants’ attention disengagement from faces, and specifically from fearful vs. neutral and happy faces  in a sample ( Maternal stress hormones, glucocorticoids (GC), are critical to normal fetal development, increasing adaptively in concentration over the human pregnancy to ensure fetal maturation and to prepare for birth . GC are According to WHO, around 15 million babies are born preterm every year  . PretermHowever, although a consensus is solid in that the administration of sGCs has decreased neonatal mortality and morbidity, and their benefits outweigh the potential longer-term harms sGC may carry on individuals born preterm , there iIn humans, there is clear evidence that prenatal sGC exposure leads to decreased birth weight, even in term born babies . In addiConversely, some studies have found no association between prenatal sGC and later child outcomes. One randomized controlled trial found no differences in hyperactivity, emotional symptoms, prosocial behavior, conduct, or peer problems between the treated and non-treated children . Two othIn recent years, researchers have been developing new tools to evaluate attention and emotion regulation that do not entail developed speech. One such tool is eye tracking which provides a spatially and temporally accurate method for studying attention and emotional processing in preverbal infants . Eye traIn this study, we investigated whether infants prenatally exposed to sGC differ from non-exposed infants in terms of their attention disengagement probabilities from faces  toward salient distractors . More specifically, we were interested whether the sGC-exposed infants show different “fear bias”  from non-sGC-exposed infants at the age of 8 months, as deviant fear bias may be an intermediate phenotype reflecting aberrant emotion processing. The assessment point for tracking fear bias was set to 8 months as developmentally the phenomenon is well tractable at this particular age, and also individual differences might be detectable at the time of its peak development during the second half of the first year.n = 363 infants from the ongoing FinnBrain Birth Cohort Study (The study sample comprised of rt Study  for whom1. Altogether 129 (3.4%) out of the total 3,808 FinnBrain Cohort mothers received sGC treatment for threatening prematurity. All women were treated in the same tertiary hospital, which implies minor dispersion in diagnostics, reporting and clinical practices. Also, the Finnish Current Care guidelines for preterm delivery  unify the practices. The current practice is to give two doses of 12 mg betamethasone administered intramuscularly 24 h apart.The mothers receiving sGC treatment for threatening prematurity were identified by automated electronic screening of all of the FinnBrain mothers’ hospital records for an indication of sGC treatment. Further indications for sGC administration and information on hospitalization and pregnancy were then collected for this sGC receiving subsample manually from the hospital electronic patient files. Further, the list of identified pregnancies was double-checked from The Finnish Medical Birth Register kept by the National Institute for Health and WelfareN = 14 had another corticosteroid treatment either at GW 14 or at GW 34, and of the sGC treated group one had another corticosteroid (prednisolone) treatment during pregnancy . Of all mothers, N = 60 mothers had gestational diabetes. Sensitivity analyses were conducted by excluding the infants of these mothers .Lastly, the ID list of sGC mother-child-dyads was compared with that of the subsample having attended the 8-month Child Development and Parental Functioning Lab study visit, resulting in 12 mother-child-dyads with sGC administration. The identification of these dyads was all done in retrospect, so that the selection of sGC families within the eye-tracking experiment was not biased. On average, the sGC children were born earlier and weighed less at birth than the rest of the study sample see , factorsRegarding the timing of administration, the earliest phase in pregnancy was GW 27 + 5 days, the latest GW 35 + 1 day. The reasons behind suspected threat of preterm labor varied, with premature contractions accounting for the majority . In the sGC subsample, the earliest delivery took place at 34th GW + 3 days and the latest at 40th GW + 5 days. Seven (58%) out of the 12 children were born full term, i.e., at 37 GW or more.During eye tracking, the infant sat on the parent’s lap at the distance of 50–70 cm from the eye tracker . A sampling frequency of 500 Hz was used. Before every measurement, a five-point calibration procedure, with an audiovisual animation  sequentially presented in five locations on the screen, was used to assure the quality of the measurement. The calibration could be repeated before actual testing and also during measurement when necessary. Small breaks were allowed during measurement if needed. The eye-tracking laboratory was dimly lit and the researcher sat on an independent host computer next to the infant-parent dyad, but was separated by a curtain to avoid interference.The overlap paradigm  was usedBefore each trial, a fixation stimulus was shown to capture the attention of the infant to the center of the screen. Once the infant’s gaze was in the middle of the screen, the trial was presented by the researcher. First, a picture of a face (or a scrambled face control stimulus) was shown in the center of the screen for 1,000 ms. Then, a salient lateral distractor (checkerboard or circles) appeared on either the left or the right side of the face  for 3,000 ms, simultaneously with the face . One triThe trial data, comprising of timestamps for the onset times of central and lateral pictures and the xy coordinates of the participants’ gaze position (500 samples per second) were stored as text files, and analyzed offline using a library of Matlab scripts  . The folFirst, the probabilities of disengagement (DPs) were calculated separately for each stimulus condition . Then, to investigate the differences in infants’ fear bias, a fear bias score was calculated. Following  the “feaMaternal general anxiety and depressive symptoms during pregnancy were assessed at GW 14, 24, and 34 as well as at 3 and 6 months postpartum, using the anxiety subscale of the Symptom Checklist-90 (SCL-90) , and theInformation on maternal health status, infant due date, gestational age at birth, birth weight, and sex were collected from hospital records and the Finnish National Birth Register (see text footnote 1).t-tests. Second, the sGC treatment main effect on infant fear bias was tested in a Multiple hierarchical linear regression model. Here, antenatal sGC treatment (yes/no) was entered on the first step, prematurity , gestational age at birth, weight at birth, and infant sex on the second, and maternal depressive symptoms (EPDS sum) at 3 months postpartum on the third step.All statistical analyses were performed using IBM SPSS 25. First, differences in the eye-tracking measures  were evaluated between the two groups  with Independent samples Moreover, sensitivity analyses were conducted by excluding infants of mothers with either antidepressant (SSRI/SNRI/NDRI) medication or other corticosteroid treatment during pregnancy or maternal gestational diabetes from the analyses. These exclusions did not alter the main results, and the results are therefore reported for the whole sample.in utero and 351 had not. All except one mother were administered with two doses of 12 mg betamethasone 24 h apart. The exception had the two doses within the period of 24 h.The characteristics of the study sample are displayed in No between-groups difference was found regarding maternal age . As expep = 0.041; No major differences were found in maternal anxiety or depressive symptoms during pregnancy or early postpartum , with the exception of EPDS scores being higher among the non-treated mothers 3 months postpartum , intermediate for the neutral and happy faces , and lowest for the fearful faces . All paired comparisons reached p-values <0.001, except for neutral and happy faces p = 0.57. An age-typical fear bias  was observed across the whole sample with infants disengaging their attention less frequently from fearful vs. happy and neutral faces (p < 0.001) as expected.In the overlap paradigm, across the whole sample, the disengagement probabilities (DPs) were highest for the control, scrambled non-face pictures , whereas the non-treated infants did , t(360) = 0.358, p = 0.007, 95% CI.When comparing the infants with and without antenatal sGC treatment exposure, the two groups did not significantly differ in their DPs in the control, neutral, happy, or fearful conditions  after controlling for prematurity (p = 0.33), gestational week (p = 0.35) and weight (p = 0.85) at birth, child sex (p = 0.77) and maternal depressive symptoms at 3 months postpartum (p = 0.05). The model explained 2.2% of the variance in fear bias . See In the linear regression model, antenatal sGC treatment was a significant predictor of fear bias  treatment and emotion processing at 8 months using eye tracking. We aimed to investigate the effects of exposure on a well-established infant phenotype, namely fear bias, soon after its emergence during the second half of the first year. Deviances in the processing of affectively salient cues, and specifically negative information, may represent an intermediate phenotype of later emotion regulation difficulties . We founPrioritized processing of fear or threat is a biologically conserved component of attention due to its clear implication for survival and well-being . A heighIn humans, associations between sGC treatment and later neurodevelopmental, emotional and behavioral problems in offspring have been reported by several studies . AlteredThe evolutionary nature of fear bias posits that it is plastic to environmental factors, enabling changes according to environmental needs. According to the stress acceleration hypothesis early-life factors such as adverse caregiving experiences might accelerate the maturation of emotion circuits as an adaptation of the system . Indeed,Importantly, the prevalence of any mental, emotional, and behavioral disorder has been found to be higher in sGC-exposed as compared to non-exposed children . ParentsIf the observed reduction in fear bias in sGC infants supposedly reflects altered maturity of the brain circuits underlying emotional regulation, it is relevant to point out that sGC can induce structural and functional changes in brain regions such as the amygdala or nucleus accumbens. Changes in brain areas important for emotion generation and regulation have been observed in a rodent model that mimics prenatal sGC administration to pregnant women. For example, a rodent model that mimics prenatal sGC administration to pregnant women, presents molecular and anatomical changes in several brain regions sensitive to glucocorticoids and important for emotion attention interactions such as the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens . MoreoveHowever, the literature on prenatal sGC effects in the human brain is scarce. One study has shown that exposure to sGC dexamethasone in the first trimester of gestation is associated with structural changes in the amygdala in humans later in life . Other sImportantly, this study also raises a clinically relevant question of the optimization of the current guidelines for sGC administration due to preterm labor. Only 2–10% of singleton pregnancies assessed due to preterm contractions end up in delivery within the next 7–14 days . UltrasoIn sum, our study shows that prenatal sGC exposure induces alterations in fear processing in 8-month-old infants, which suggests altered emotional development. Further studies are needed to unravel if these changes are associated with alterations in emotional and/or social development later in life. While the functional significance of our findings and their predictive value for later emotional/developmental problems remain subject to further investigation, we may state that prenatal sGC treatment appears to be connected to a well-established feature of infant attention, i.e., fear bias. This bias is typically high during the second half of the first year, and is accompanied with the normative emergence of other fear-related behaviors . As a lilinnea.karlsson@utu.fi.The datasets presented in this article are not readily available because due to Finnish Federal Legislation, the research data cannot be made available online, but data can potentially be shared with Material Transfer Agreement. Requests can be directed to the Board of the FinnBrain Birth Cohort Study. Requests to access the datasets should be directed to LK, The studies involving human participants were reviewed and approved by the Ethics Committee of the Hospital District of Southwest Finland. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.E-LK participated in the planning of the study design, took care of the eye-tracking data collection, analyzed the data, and drafted the first manuscript version. AR drafted the first manuscript version and were involved in data analysis. LK and EE participated in the planning of the study design and revised the manuscript. TH contributed to the building of the eye-tracking paradigm and data managing. NMS participated in the planning of the study design and sample acquisition, conducted sample screening from hospital records, and revising of the manuscript. RK, SN, and NS participated in the revising of the manuscript. HK planned the study design, provided the funding for the study, and revised the manuscript. All authors approved the final version of the manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Birth-preparedness and complication-readiness (BPCR) is the process of planning for normal birth and anticipating the actions needed in case of an emergency. The involvement of husband during pregnancy helps a mother to make timely decisions to avoid delays. Identifying the level of husband involvement in Birth-preparedness and complication-readiness is very important, as husband is the major decision maker in household and health service related issue. However, there is no sufficient data in the Kucha district, which describes the level of husband involvement in Birth-preparedness and complication-readiness. Therefore, this study assessed the level of husband involvement in birth preparedness and complication readiness in Kucha District, Gamo Zone, Ethiopia.Community-based cross-sectional study was conducted on 421 husbands whose wife gave birth within the last 12 months at Kucha District using simple random sampling technique. Data was collected using a pretested interviewer-administered questionnaire by trained data collectors. Binary and multivariable logistic regression with odds ratios along with the 95% confidence interval analysis were employed to find factors associated with the level of husband involvement. A p-value <0.05 with 95% confidence level used to decide statistical significance.Data were collected from 421 study participants. One hundred twenty-seven (30.2%) were involved in birth preparedness and complication readiness plan. Participants who had at least secondary school education AOR = 3.1, CI (1.84–5.23), had at least four antenatal care visits AOR = 4.91, CI (2.36–10.2), and live more than five km from the health care facility AOR = 2.35, CI = 1.40–3.96) were involved in birth preparedness and complication readiness plan.s’ involvement in birth preparedness and complication readiness was low. Husband’s higher educational level, high frequency of antenatal care, and long distance to the health facility were significantly associated with husbands’ involvement in Birth-preparedness and complication-readiness plan. Therefore, advocating for higher frequency of antenatal care and improving educational level are important to increase husbands’ involvement in birth preparedness and complication readiness plan.Husband About 295 000 women died during and following pregnancy and childbirth in 2017. The vast majority of these deaths (94%) occurred in low-resource settings. Sub-Saharan Africa and Southern Asia accounted for approximately 86% (254 000) of the estimated global maternal deaths in 2017. Sub-Saharan Africa alone accounted for roughly two-thirds (196 000) of maternal deaths [More than two in three women (70%) in Ethiopia do not have access to health care . Only 6%A strategy to reduce maternal morbidity and mortality, birth preparedness and complication readiness plan was used as a prioritized intervention in order to reduce home delivery and decrease maternal morbidity and mortality . Birth-pFinding from studies conducted in different African countries show that the majority of pregnant women were not having a birth plan ,9. For eStudy conducted among households targeting husbands with having at least one child of less than one year of age at Mekele town showed that variables like husbands’ awareness of postnatal danger signs, husband’s knowledge in birth preparedness, male involvement in antenatal care (ANC), educational status, economic status, and place of residence were factors associated with husband involvement in BPCR plan .Therefore, the involvement of husband in BPCR during pregnancy, Labor, the postpartum period and its complication helps an expectant mother to make timely decisions to avoid delays that bring about complications that could result in morbidity or mortality and for achieving Sustainable Development Goals. However, little is known about the level of husband involvement in the study area which has different socio-economic and cultural differences with the previous studies. Therefore, this study aimed to assess the level of husband involvement in birth preparedness and complication readiness and associated factors.This study was conducted in Kucha district, Southern Ethiopia, which is located 440 KM away from Addis Ababa and 172 KM away from the capital town of Gamo Zone, Arba Minch. In the district, there are 35 rural and one urban kebele (the lowest administrative unit in Ethiopian government system). In Kucha district there were eight health centers, 39 health posts, and 15 private clinics. This study was conducted from March 15/2018 to April 15/2018.A Community based cross-sectional study was conducted.All husbands whose wife gave birth in the last 12 months in the selected kebeles of the district and live for more than six months in the district were included in the study. Those who were critically ill during the data collection period and husbands who were not living with their wives were excluded from the study.n = (Zα/2)2 × p (1 − p)/d2) [The sample size for this study was determined using single population proportion formula (− p)/d2)  with the− p)/d2) . The finSimple random sampling technique was used to select the study subjects, the district has 36 kebeles and 7 kebeles were selected by lottery method, and then the calculated sample size was allocated proportionally to each kebele with consideration of the estimated number of husbands per each kebele. The sampling frame containing a list of all married women, who gave birth in the last 12months, was obtained from a family folder of health posts. In each health post there is a family folder that includes information about births, number of children, etc. we obtained the list of women who gave birth in the last one year before data collection period. Accordingly we allocate sample for each kebele  based on the available data of women who gave both in the last one year. Unique identifier number was given for each households. Finally, from the list, women who gave birth in the last 12 months were selected randomly using computer generated technique and their husbands interviewed in a private place around their home. Those husbands who were not available at first visit were revisited for the second times and those who were not available were revisited for the third times.Gammotho) and back-translated to English by language experts to check for its original meaning. The questionnaire was pre-tested on 5% of the total sample in Kucha town which was not included in the main data collection.The data collection tool was initially adapted from the survey tools used for maternal and neonatal health program which was developed by Johns Hopkins program for international education in gynecology and obstetrics (JHPIEGO) . AdditioThe data collected by trained data collectors using face-to-face interview method of data collection. A total of eleven diploma holders’ clinical nurses and four health officers were recruited for the data collection and supervision of data collection process respectively. Both data collectors & supervisors were given a day-long intensive training on the data collection techniques, research purposes and research ethics.The questionnaire was pre-tested on 5% of sample size in Kucha town which was not selected for the final study. Based on the pretest, the logical sequence, as well as skip patterns of the questions was modified. Moreover, the time needed to complete an interview and the total number of days needed for data collection was estimated. Appropriate training for data collectors and supervisors was given which includes but not limited to the data collection process and the contents of the questionnaire. The overall activity of data collection was supervised and coordinated by the supervisors. After data collection, the collected data were checked for its completeness by the principal investigator. Before and after data entry, data were checked for any missing and inconsistencies.Data were entered into EpiData version 4.4 software and then exported to IBM SPSS version 24.0 statistical product and service solution (SPSS) for analysis. Then, the data were cleaned to check for errors, and missed values. Descriptive statistics using frequencies, percentages, mean and standard deviations were used to describe findings. Binary logistics regression was done primarily to check which variables had an association with the dependent variable. Multiple logistic regression analysis was conducted to identify the independent predictors of husband involvement in planning birth preparedness and complication readiness. Those variables that had a significant association in binary analysis were selected for multivariable analysis. Both crude and adjusted odds ratios (AOR) with the respective 95% confidence intervals (CI) was reported and interpreted.Men involved in birth preparedness and complication readiness practice: men who are involved in at least in two Birth preparedness plan  .Good knowledge about pregnancy danger signs: husband who spontaneously mentioned at least two danger signs of pregnancy. Poor knowledge about pregnancy danger signs: husband who did not spontaneously mention two danger signs of pregnancy . The keyBirth-preparedness and complication-readiness (BPCRP): is the process of planning for anticipating actions which will be needed in case of emergency, encourages women and households to make arrangements to give normal birth by reducing delays in reaching care once a problem arises ,6.Before the study conducted, ethical clearance obtained from the ethical review committee of Arba Minch University, College of Medicine and Health Sciences institutional review board (IRB). Written informed consent obtained using standard disclosure procedures. Individual identifiers were removed to maintain the anonymity and confidentiality of the information. Interview was conducted in a private place where the audio and visual privacy were maintained.A total of 421 husbands were participated in this study with a 100% response rate. The mean age of the respondents was 34.11±5.5 years. Around half, 48.9% of them had age range of 30 to 39 years old. Regarding their ethnicity, the majority (72.7%) were Gamo and 102(24.2%) of them were government employees .Three out of four study participants didn’t arrange transportation for their wives. Thirty five percent of the participants travel more than five kilometer to reach the health facilities. Only 10(2.4%) of study participant’s wife made decision by themselves to seek health care services .Almost all of the study participants were aware of that severe headache and blurring of vision was one of the danger sign during pregnancy. Three out of four (72.4%) study participants were aware that leakage of amniotic fluid as a sign of obstetrics danger signs. Nine out of ten (92.1%) had a good level of knowledge about the danger signs during pregnancy .Less than one-third of husbands, 127(30.2%) were involved in planning birth preparedness and complication readiness .In the bivariate analysis, significant association was observed between husband involvement in birth preparedness and complication readiness and the educational levels of husband, the educational level of wife, knowledge on danger sign of pregnancy, frequency of ANC visits, if delivery was assisted, if arrangement for transportation to the health facility were made and distance to reach health facility.After adjusting for the effect of confounding variables using multivariable logistic regression, educational level of husbands, number of ANC visits, arrangement for transportation and distance to health facility were associated with husband involvement in birth preparedness and complication readiness.Husbands who had secondary and higher education were 3.1 times more likely AOR = 3.1, CI (1.84–5.23) to be involved in birth preparedness and complication readiness plan than those who had primary and below educational level. Husbands whose wife attended four and more ANC visits were 4.91 times more likely AOR = 4.91, CI (2.36–10.2) to be involved in birth preparedness complication readiness plan than those their counterparts. Families who lived far from a health care facility with a distance greater than 5km were 2.35 times more likely AOR = 2.35, CI = 1.403–3.96) involved in birth preparedness and complication readiness plan than those who live in less than 5 km distance from health facilities. Husbands who have arranged for means of transportation previously were 2.9 times more likely AOR = 2.9, CI (1.62–5.2) to be involved in planning birth preparedness and complication readiness than their counterparts .The main finding of this study is that only one-third of husbands were involved in planning a birth preparedness and complication readiness. Husband educational status, number of antenatal care visits and living more than 5 KM from health care facility were significantly associated with husband involvement in birth preparedness and complication readiness.The level of husband involvement in birth preparedness and complication readiness was 30.2% 95% CI: 25.8–34.6%). This is lower than studies conducted in rural Bangladesh, Endarta district, Ambo town and Wolaita Sodo town ,19,20,25.8–34.6%.In this study, husbands’ educational level was one of the significant factors in promoting husband involvement in birth preparedness and complication readiness, Husbands who attend secondary and higher level of the school were involved in birth preparedness and complication readiness plan than those who attend primary school and below. This finding is supported by the study from northern Nigeria and Ambo Ethiopia ,19 whichThe frequency of ANC visits was a significant predictor for husband involvement in birth preparedness and complication readiness plan. Husbands whose wife had four and more ANC visits were more involved in birth preparedness and complication readiness plan than their counterparts. This finding is similar to a study conducted in Wolaita Sodo town, Southern Ethiopia . This fiDistance to the health care facility was one of the significant factors affecting husband involvement in BPCR plan. Husbands who live far from a health care facility with a distance greater than 5 km were more involved. This finding is consistent with the studies conducted in Wolaita Sodo town . It is lThis study might be exposed for recall bias due to the reason that information was collected retrospectively. However, to minimize the recall bias we reduce the duration of last birth to one year. The other limitation as the study is cross sectional it is not possible to establish a cause effect relationship between the independent variables and outcome variable. Even though it is based on the reference of previous research, the measurement of involvement in birth preparedness and complication readiness and the level of knowledge it was difficult to compare with some studies.Husband’s involvement in BPCR is low in the study region of Ethiopia. Husband’s level of education, the number of ANC visits, distance to the health facility and pre-arrangement of transportation were significant factors associated with the husband’s involvement in BPCR.Therefore, investing on antenatal care visits is crucial including the frequency of the care as it increases exposure with health-related messages including birth preparedness and complication readiness plan. The more information women get from health care provider the more likely to they are to convince their husband to be involved in the health care decisions. Improving education level of men in the community is important to improve the involvement of them in the BPCR plan.


Studies suggest that exposure to ambient air pollution during pregnancy may be associated with increased risks of birth defects (BDs), but conclusions have been inconsistent. This study describes the ethnic distribution of major BDs and examines the relationship between air pollution and BDs among different ethnic groups in Liuzhou city, China.Surveillance data of infants born in 114 registered hospitals in Liuzhou in 2019 were analyzed to determine the epidemiology of BDs across five major ethnic groups.Concentrations of six air pollutants  were obtained from the Liuzhou Environmental Protection Bureau. Logistic regression was used to examine the associations between ambient air pollution exposure and risk of BDs.10  and CO  in second and third month of pregnancy. SO2 was also significantly associated with BDs in the second month before the pregnancy  and third month of pregnancy . Congenital heart disease, polydactyl, cleft lip and/or palate were also significantly associated with PM10, SO2 and CO exposures. However, no significant association was found between birth defects and O3, PM2.5 and NO2 exposures (P > 0.05).Among 32,549 infants, 635 infants had BDs, yielding a prevalence of 19.5 per 1000 perinatal infants. Dong ethnic group had the highest prevalence of BDs (2.59%), followed by Yao (2.57%), Miao (2.35%), Zhuang (2.07%), and Han (1.75%). Relative to the Han ethnic group, infants from Zhuang, Miao, Yao and Dong groups had lower risks of congenital heart disease, polydactyly, and hypospadias. The Zhuang ethnic group had higher risks of severe thalassemia, cleft lip and/or palate, and syndactyls. Overall BDs were positively correlated with air pollutants PMThis study provides a comprehensive description of ethnic differences in BDs in Southwest China and broadens the evidence of the association between air pollution exposure during gestation and BDs.The online version contains supplementary material available at 10.1186/s12887-021-02687-z. Birth defects (BDs) are functional, structural, or metabolic abnormalities that occur before birth, usually as a result of chromosomal abnormalities, congenital malformations, genetic and metabolic disorders, and functional abnormalities . They arChina is the most populous country in the world, with one of the highest incidences of documented BDs. In China, the estimated prevalence of BDs is approximately 4 to 6% . In receNumerous studies have shown that ambient air pollutants have a direct negative impact on the birth outcomes of pregnant women , 7. Expo10 during the whole pregnancy, early pregnancy and middle pregnancy was correlated with the occurrence of patent ductus arteriosus, a congenital heart malformation. However, the previous study did not consider the influence of ethnic factors on BDs [10 exposure and fetal cardiovascular malformation [10 and patent ductus arteriosus during weeks three to seven of pregnancy [2 had a greater effect on the prophase of pregnancy, while PM10 had an effect in late third trimester [2 exposure was related to coarctation of the aorta and tetralogy of fallot, two congenital heart defects [10 and SO2 have no association with BDs [However, studies on the relationship between ambient air pollution and BDs are inconsistent, and the timing of BD susceptibility during pregnancy as a result of ambient air pollution is unclear. A study in the United States showed that exposure to NO2 in early pregnancy increases the risk of congenital abnormalities in newborns . Additios on BDs . A case ormation . Stricklregnancy . In a porimester . Vrijhei defects . Howeverwith BDs . Some stwith BDs . Furtherwith BDs , 20, Yanwith BDs , 22 and with BDs . There aLiuzhou is located in southwestern China and is the main gathering place for ethnic minorities in Guangxi province, China. Ethnic minorities account for 37.2% of the population of Guangxi Province . By the Using the ambient air pollution monitoring network and the BDs monitoring system, we investigated all infants born in ethnic minority areas of Liuzhou between January 2019 and December 2019 to study whether air pollution was associated with an increased risk of BDs. We also calculated the mean daily gestational concentrations of environmental pollutants during 3 months before pregnancy and the first trimester of pregnancy. This study also examines differences in the prevalence of BDs among five major ethnic groups and provides a reference for the prevention of birth defects in minority areas.Research data were extracted from the birth defect monitoring sub-module in the Liuzhou Maternal and Child Health Information Management System between January 2019 and December 2019. This includes records from perinatal babies, including live birth, stillbirth and infant death within 7 days, reported by 114 midwifery agencies in Liuzhou for a total of 32,549 births. The data excluded twin and multiple births. Among this cohort, there were 635 cases of BDs. All data was derived under the supervision of the health administration, and this study was approved by the Institutional Review Board of Liuzhou Maternal and Child Health Hospital.https://zhibao3.mchscn.org/) and the Maternal and Child Health System of Liuzhou City. Using the “Birth Defects Registration Card” and “Quarterly Report on Number of Perinatal Births” from the Maternal and Child Health System of Liuzhou City, relevant data were collected, including maternal status, birth status, birth defect diagnosis and family history. Maternal data included ethnicity, age, education, family income, date of last menstrual period, residential address, registration address and parity. Infant data included date of birth, sex, gestational age, fetal number, weight, and outcome .Additional perinatal and maternal data were derived from the China Maternal and Child Health Monitoring Data Direct Reporting System  and Chinese National Criteria of BDs . We inveIn order to ensure the accuracy of the report, a physician at each registered hospital was required to complete a quarterly form, in addition to the Birth Defects Registration Card. Each quarterly table contained 3 months of data, including ethnicity, date of last menstrual period, parity, education, family income, date of birth, gestational age, weight, number of births, whether labor was inducted after diagnosis of a birth defect, diagnostic basis, diagnosis of malformation, and birth defect diagnosis for each birth occurring in the hospital. Birth defect registration cards and quarterly tables were reviewed and audited by maternal and child health hospitals and health administrative departments. Quality control measures were monitored regularly in respective hospitals, quarterly at the county level and every two years at the municipal or provincial level. The quality requirements for BDs monitoring data included: 100% completion rate of form, form items error rate less than 1%, input error rate less than 1%, and a rate of missed birth defects less than 1%.The ambient air pollution data used in this study came from the weather information data collected by the Liuzhou Environmental Protection Bureau between January 2018 and December 2019, which includes six state-controlled air automatic monitoring points in Liuzhou , two district control stations , and six city and county control stations  . The average annual secondary concentration limits of PM2.5, PM10, SO2 and NO2 are 35 μg/m2.5, PM10, SO2, CO, NO2 and O3 on the dates between last menstrual period and date of delivery were determined based on maternal residential address. Monthly concentrations for the 3 months prior to pregnancy and the first trimester of pregnancy were estimated for each participant [Maternal ambient air exposure was determined through block kriging, a statistical technique which predicts average exposure concentrations based on spatial variation. The daily concentrations of PMticipant , 34.Potential covariates considered from the birth defects registration cards included maternal age , family income , highest education levels , birth weights , number of pregnancies , total previous live births , and gender of infant . We also adjusted for additional maternal covariates according to the existing literature and the study population characteristics. We collected variables suspected as potential confounders from the China Maternal and Child Health Monitoring Data Direct Reporting System. These potential confounders included premature rupture of membrane, syphilis, ethnicity, hyperthyroidism, gestational diabetes, preeclampsia, gestational hypertension, HIV, hypothyroidism, infection, medication and in vitro fertilization-embryo transfer. Maternal smoking and alcohol use during pregnancy were not controlled for because < 0.3% of the mothers reported smoking or drinking alcohol.Chi-square test was performed to examine the differences in social demographics between infants with BDs and infants without BDs. Prevalence rates of overall BDs and each specific BD were also examined. Distributions of air pollutant concentrations were presented by quartile and interquartile range (IQR) averaged over three months preconception and during the first trimester of pregnancy. Logistic regression was used to assess the association of air pollution exposure on BDs. BDs were the dependent variable, and the individual exposure concentration of air pollutants during three months prior to pregnancy and the first trimester of pregnancy were the independent variables. Important covariates were controlled, in order to explore the influence of exposure concentration and exposure time on BDs. To assess the role of ambient air pollutant exposure at different stages of pregnancy, we constructed exposure variables for the 3 months before pregnancy and the first trimester of pregnancy. We studied both the impact of a single pollutant on BDs and the combined effects of multiple air pollutants. Corresponding odds ratio (OR) and 95% confidence interval (95% CI) were calculated for birth defects and air pollutant exposure at different stages of pregnancy. In order to evaluate the robustness of the estimated effects, we performed sensitivity analyses measuring the associations between ambient air pollution and birth defects in Han and Zhuang ethnic groups . Statistical test significance level is 0.05 (two-tailed). Data processing and statistical analysis were performed using SAS 9.4  statistical software package.p < 0.01). There were no statistically significant differences between infants with and without BDs for family income and number of pregnancies (p > 0.05).Table Table BD diagnoses in the five major ethnic groups is presented in Table Individual ambient air pollution exposure levels at different gestational time points are shown in Table 3 increase in concentration during two months prior to pregnancy  and the third month of pregnancy . CO also had a significant association with BDs for every 1 mg /m3 increase in concentration in the second  and third months of pregnancy . However, no significant association was found between birth defects and O3, PM2.5 and NO2 (P > 0.05). We observed similar associations in sensitivity analyses in Han and Zhuang, ethnic groups, respectively.Table 10, SO2 and CO. The sensitive period of these three birth defects caused by air pollution is consistent with that of total birth defects  of pollutants and congenital heart disease.Additional file 2: Supplemental Table 2. Correlation between monthly concentration (ug/m3) of pollutants and polydactyly.Additional file 3: Supplemental Table 3. Correlation between monthly concentration (ug/m3) of pollutants and cleft lip and/or cleft palate.


Several studies on tourism have examined the effects of vacation and travel on individuals' wellbeing. However, relatively little is known about the underlying psychological factors and mechanisms. Therefore, this study aimed to investigate the effects of a winter vacation on individuals' wellbeing. A total of 507 participants (255 men and 252 women) completed three questionnaires at three different time points. The questionnaires comprised psychological scales and items to seek demographic information so that the changes in their wellbeing could be assessed. The results revealed that people who traveled had higher subjective wellbeing than those who did not. Moreover, out of the four elements of the recovery experience, mastery was the only one influenced subsequent subjective wellbeing. The findings suggest that it is crucial to take vacations and to savor recovery experiences while off work. In particular, experiencing new and challenging events during a vacation was the most significant predictor of vacationers' subsequent wellbeing. Our results clarify what type of vacation is most effective for wellbeing. The results can help tourism practitioners manage their customers' experiences better during their vacations, and these efforts will arguably contribute not only to the wellbeing of vacationers but also to future company growth. Wellbeing is one of the buzzwords of the decade and is omnipresent in almost all discourses related to daily human routines  with a happiness index as an economic situation indicator. The proposal illustrates the belief that a vision that emphasizes an increase in humans' happiness and the sustainability expansion of economic activities is necessary for human welfare in a country . In an organizational setting, relaxation occurs when employees are allowed time off from work-related tasks, freeing them from the need to expend physical or mental effort  and examined factors that affect the said changes. We conducted multiple surveys before and after a winter vacation to achieve these aims. We expected to obtain some intriguing implications for what kind of vacation is more beneficial for people's wellbeing. The long-term success, sustainability, and competitiveness of tourism will undoubtedly depend on how it contributes to improving the QOL of all stakeholders  and age groups to participate. Respondents answered questionnaires according to instructions on the computer screen.Participants completed the questionnaire at three time points: the first survey was conducted at the end of December 2017 (Time 1: before the vacation); the second survey was conducted immediately after the end of the winter vacation in early January 2018 (Time 2: immediately following the vacation); and the third survey was conducted in early February, 1 month after the second survey (Time 3: 1 month after the vacation).Questionnaires were randomly distributed to the sample registered with the research company. They were controlled to stratify across ages  and to be equally portioned. The purpose was to ensure that age and gender effects did not occur as much as possible. At the same time, to prevent bias in the responses of the target population, we aimed to collect 500 responses in the end. There were 1,100 respondents in the first survey, 838 (76.18%) in the second survey, and 507 (46.09%) in the third survey. In this research, we targeted those who responded to all surveys. Thus, the total number of participants was 507 Japanese individuals from the general population (255 men and 252 women).Questionnaires consisted of items seeking demographic information  and details on how the respondents spent their winter vacation . We also sought information on travel expenses by entering the actual cost . In addition to the items mentioned above, we used the following psychological measures.strongly disagree to 5 = strongly agree).Respondents' recovery experiences during the winter vacation were assessed using the Recovery Experience Scale  to 7 (strongly agree).Life satisfaction refers to an overall evaluation of the quality of one's life .SD = 13.40; range = 20–69 years). Most respondents had completed higher education .The sample was divided into two based on gender, with an average age of 45.03 years , education , household income , life satisfaction , psychological detachment , relaxation , mastery , and control .Means, standard deviations, and correlations between the variables are presented in To verify the effects of the winter vacations on wellbeing, we divided participants into those who traveled abroad or domestically. Additionally, during the New Year holidays in Japan, many people return home to visit friends and relatives, although they may stay in different types of accommodations. Therefore, we added homecoming as a typical holiday behavior during the study period. Moreover, we created one group that included people who did not travel anywhere. The survey was conducted such that the above four groups had almost the same number of people.The respondents were divided into four groups based on their travel: 89 were assigned to the foreign travel group, 156 to the domestic travel group, 115 to the homecoming group, and 147 to the staying-home group.2[3] = 0.38, ns.), education , and household income  revealed no significant differences between the groups. Thus, subsequent analyses were conducted without considering the influence of the above demographic factors.Before conducting analyses using these groups, we accounted for any difference in each group's demographic characteristics. The chi-square tests on gender  was higher than that of those who did not travel  = 3.29, d = 0.29, p < 01; Time 2: t (505) = 2.93, d = 0.26, p < 01; Time 3: t (505) = 2.51, d = 0.22, p < 05).Before comparing the four groups, we conducted a pre-analysis comparison of the groups that traveled  and the groups that did not . Independent samples F  = 5.16, p < 0.01; F  = 9.79, p < 0.01; F  = 0.90, ns.; To compare the groups in more detail, we performed a 4 × 3 Group  × Time  repeated-measures analysis of variance (ANOVA) for the subjective happiness of vacationers. For the total PERMA-profiler score, significant main effects of the group were observed for group [Mforeign = 88.92, SDforeign = 24.00; Mdomestic = 86.28, SDdomestic = 21.10) were significantly higher (p < 0.05) than those of the staying-home group . Regarding the effects of time, the scores of the groups at Time 1 were significantly higher (p < 0.01) than those of the groups at Times 2 and 3  on foreign travel and ¥804.22 (SD = 1100.55) on domestic travel on average. Concerning the relationship with annual income, 50% of the respondents spent approximately 2.33% of their annual income on travel during winter.Subsequently, we examined the relationship between travel expenses and wellbeing. We included only participants who traveled in this analysis because the analysis was based on the amount spent on the travel. Participants reported spending ¥3,206.55 , Time 2 , and Time 3 . Thus, Hypothesis 1b was not supported.Further, after controlling for household income, we calculated partial correlations to examine the relationships between the influence of consumption expenditure and travel. We controlled for annual income because participants with higher annual incomes could spend larger money on travel. However, there were no significant relationships with wellbeing at Time 1  to confirm the constructs of the Recovery experiences scale  were significantly correlated with one another . TherefoF  = 13.18, p < 0.01, F  = 22.88, p < 0.01; F  = 8.72, p < 0.01; F  = 39.28, p < 0.01; F  = 1.30, ns; The results revealed that the multivariate main effects of group were significant [Wilks's Λ = 0.721, Hierarchical regression analyses were conducted to examine the relationship between independent variables and vacationers' wellbeing 1 month after winter vacation (Wellbeing Time 3). To detect the effect of recovery experience on wellbeing, we controlled for demographic factors. In the first step, demographic factors  were included. The second step added the sociodemographic characteristics of the respondents . In the third step, life satisfaction was added. Finally, in the fourth step, we added the four sub-factor scores  of the recovery experience .In the final regression model, the nine included variables explained a significant proportion of the variance in the dependent variable . Age, hoWe conducted surveys at different time points to identify the changes in wellbeing before and after a winter vacation. The primary objective was to capture and examine the factors that create a more effective vacation based on the experiences during the participants' winter vacation.Our ANOVA revealed significant main effects for both group and time regarding the effects of travel during vacations. The differences between the groups were clarified. People who traveled during vacation exhibited higher wellbeing than those who stayed home. This result indicates that getting away from daily life during long holidays and experiencing something out of the ordinary improved vacationers' wellbeing.Subsequently, we divided the survey participants into four groups based on the type of travel to examine the difference in wellbeing and recovery experience. The results suggested that foreign and domestic travelers' wellbeing was higher than those who stayed home. Concurrently, the three recovery experiences other than control were also higher in the last two groups. These results may indicate the superior effects of investing money in wellbeing experiences, as noted in previous studies , activities that people cannot experience in everyday life, and those that also pose some degree of difficulty may be preferable. Tourism service providers should consider providing various activities for their customers. In this way, vacationers could select and make decisions about their behavior during their vacation, leading to control experiences. While there is no doubt that many tourist destinations already offer various activities and relaxing environments, tourism organizations and businesses can attract even more tourists from specific groups by designing more relevant products and promoting them by highlighting sought-after features.In summary, while several scholars have shown vacations as profitable opportunities, we demonstrated that the perceived experiences were essential in determining subsequent wellbeing after the vacations. The results showed that people who traveled during winter vacation had higher subjective wellbeing than those who did not. We confirmed that mastery experiences that provide challenges and learning opportunities are valid within diverse vacation experiences. These results elucidate the question of what kind of vacation is more effective. This study also suggested that tourism practitioners could better manage their customers' experience during their vacations, and these efforts will arguably contribute not only to the wellbeing of vacationers but also to the tourism industry.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by College of Contemporary Psychology, Rikkyo University. The patients/participants provided their written informed consent to participate in this study.AK analyzed data and wrote the first draft of the manuscript. TO supervised the project and critically reviewed the manuscript. Both authors contributed to manuscript revision, read, and approved the submitted version.This research was supported by the Private University Research Branding Project  and JSPS KAKENHI Grant No. JP20H04444.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


I:Cr was similar, but with nonlinear trend suggesting I:Cr up to 200 μg/g associated with increasing birthweight . Birthweight was 2.0 centiles  higher with UIC ≥ 150 μg/g, but not for I:Cr. UIC ≥ 150 μg/L was associated with lower risk of SGA , but not with I:Cr. Conclusions: The main risk of bias was adjustment for confounding, with variation in urine sample collection and exposure definition. There were modest-sized associations between some measures of iodine status, birth weight, birth weight centile, and SGA. In pregnancy, we recommend that future studies report standardised measures of birth weight that take account of gestational age, such as birth weight centile and SGA. Whilst associations were modest-sized, we recommend maintaining iodine sufficiency in the population, especially for women of childbearing age on restricted diets low in iodide.Background & aims: Iodine is important for thyroid function during pregnancy to support fetal growth, but studies of maternal iodine status and birth outcomes are conflicting. We aimed to quantify the association between iodine status and birth outcomes, including potential threshold effects using nonlinear dose–response curves. Methods: We systematically searched Medline and Embase to 10 October 2022 for relevant cohort studies. We conducted random-effects meta-analyses of urinary iodine concentration (UIC), iodine:creatinine ratio (I:Cr), and iodide intake for associations with birth weight, birth weight centile, small for gestational age (SGA), preterm delivery, and other birth outcomes. Study quality was assessed using the Newcastle-Ottawa scale. Results: Meta-analyses were conducted on 23 cohorts with 42269 participants. Birth weight was similar between UIC ≥ 150 μg/L and <150 μg/L (difference = 30 g, 95% CI −22 to 83,  Iodine has an important role in normal thyroid function, with demands for iodine increasing during pregnancy to support fetal growth as well as compensating for increased renal clearance ,2. SeverDespite salt iodisation programmes available across many regions, the populations of over 50 countries are still considered to be affected by iodine deficiency . HoweverDairy and seafood are the main dietary sources of dietary iodine, excluding supplements and fortified foods such as iodised salt. With recent increases in diets that restrict intake of these foods, particularly in women of childbearing age, the iodine status of populations previously considered sufficient are moving more towards mild deficiency ,8. WhilsTwo recent systematic reviews of observational studies of iodine and birth outcomes drew differing conclusions ,10. SincWe conducted a systematic literature review of cohort studies that included relevant information on both maternal iodine status and birth outcomes. We searched MEDLINE and EMBASE databases through OVID, up to 10 October 2022 using a PICO structure, with a cohort study search filter, synonyms relating to pregnancy, iodine status, and specific birth outcomes, with adjacency terms and allowing for alternative spellings where appropriate. The key words included synonyms relating to pregnancy, maternity, and birth (study population); iodide, iodine, and urinary biomarkers of iodine (exposure); and birthweight, fetal growth, head circumference, preterm, and spontaneous abortion (outcomes). The complete search strategies are detailed in We included preferred reporting items for systematic reviews and meta-analyses (PRISMA) and followed guidelines for conducting meta-analysis of observational studies in epidemiology (MOOSE) throughout the review. The review protocol was published on PROSPERO (registration number CRD42016043748) prior to starting the study.Eligible studies were cohorts, case-control studies nested within cohorts, and case-cohort studies, with exposure measured during pregnancy. Relevant exposures were urinary iodine concentration (UIC), urinary iodine excretion or iodine to creatinine ratio (I:Cr), and iodide intake. Relevant outcomes were pre-specified as those related to fetal loss, preterm birth, and birth size. Low birth weight and macrosomia were taken as birth weight <2.5 kg and >4 kg, respectively.Birth weight centile was based on standardized birth weight adjusting for at least gestational age, using the study-specific definitions, and transforming z-scores to centiles where necessary. Small for gestational age (SGA) was defined as birth weight <10th centile and large for gestational age (LGA) >90th centile. Spontaneous abortion was defined as fetal loss ≤24 weeks gestation and stillbirth as fetal loss >24 weeks gestation. Preterm delivery was taken as spontaneous preterm birth <37 weeks, or any preterm delivery <37 weeks if this information was not available.Titles and abstracts were screened by two independent reviewers  using Screenatron and Disputatron , with diWe assessed methodological quality of studies using the Newcastle–Ottawa scale for cohort studies . StudiesData from each study were synthesised by meta-analysis, comparing dichotomous exposures of UIC < 150 μg/L with ≥150 μg/L based on the WHO criteria  and I:CrLinear and nonlinear dose-response trends in relative risks for binary outcomes  were derived using Greenland and Longnecker’s method ,19. The To compare dichotomised exposures, adjusted means were first combined using common (fixed) effect meta-analysis where necessary, then differences pooled using random-effects meta-analysis. Linear trends in continuous outcomes  were estimated using multivariate random-effects meta-analysis ,22 and p2) [Between-study heterogeneity was expressed as the range of study estimates, and as a percentage of total variation (I2) ,25. Pote2) .Two hundred and forty-seven unique references were identified by the literature search. Of these, 53 were identified as potentially relevant after screening of titles and abstracts (with 89% agreement between reviewers) and 26 were identified as relevant following reading of the full texts (with 80% agreement between reviewers). These publications reported on 24 cohorts containing 42,503 participants  11,12,1,44,45.Eighteen cohorts reported UIC exposure, seven used I:Cr, three dietary intake and one total intake including dietary and supplemental sources. Eleven (46%) studies were from higher income countries, 14 (58%) were from iodine-deficient populations with median UIC < 150 μg/L, including six (25%) with median UIC < 100 μg/L. Study characteristics are presented in Study quality was assessed in duplicate for six papers (25%) with 89% agreement between reviewers across all items, and the remainder extracted by one reviewer. Overall study quality was generally good, with results based on established birth cohorts using objective measures of exposures and outcomes. The main differences in risk of potential bias derived from adjustment for confounding .p = 0.3, n = 13, I2 = 89%), nor of a linear trend . Between-study heterogeneity was high, but there was no evidence of nonlinearity   a–c.p = 0.2, n = 5, I2 = 0%), nor linear trend . However, there was evidence of nonlinearity , with an association between I:Cr and increasing birth weight evident up to around 200 μg/g , but some evidence of nonlinearity   .For the binary outcomes of low birth weight (<2.5 kg) and macrosomia (>4 kg) there was no evidence of any association with UIC  and too p = 0.02, n = 4, I2 = 0%), with no evidence of a linear dose-response trend , and no evidence of nonlinearity  , nor evidence of a linear trend . There was also no evidence of nonlinearity   a–c. Ther, n = 4) e–f.p = 0.01, n = 13, I2 = 0%), but with no evidence of a linear trend . There was no evidence of nonlinearity   or as a linear trend . However, there was evidence of nonlinearity, with the lowest risk around 150 μg/g and higher risks associated with both lower and higher I:Cr . There were sufficient studies of iodide intake and SGA only to investigate linear trend, where there was no evidence of an association   a–c. Ther2 = 35%) .There were too few studies reporting LGA to conduct any meta-analyses for this outcome.p = 0.6, n = 5, I2 = 0%), as a linear trend , or any evidence of nonlinearity   . There wp = 0.9, n = 5, I2 = 78%), as a linear trend , or any evidence of nonlinearity  , as a linear trend , or any evidence of nonlinearity   . Neither, n = 3) . There wp = 0.2, n = 12, I2 = 47%), or as a linear trend . There was also no evidence of nonlinearity in the trend   or as a linear trend . There was also no evidence of nonlinearity    a–c. Simi, n = 4) d–f. TherI2 = 0%) .p = 0.3, n = 3, I2 = 94%), albeit with large between-study heterogeneity  and linear trends (p = 0.02), and some differences between Newcastle-Ottawa comparability scores   .Our systematic review and series of meta-analyses have included nearly four times as many studies as the most recent reviews, involving analysis of iodine and birth outcomes for more than five times as many participants ,10. In aThere was evidence of children born to mothers with UIC > 150 μg/L having higher birth weight centile, and lower risk of SGA, but the association between these outcomes and I:Cr was less clear. We also found evidence of an association between higher I:Cr and higher birth weight, up to a threshold of around 200 μg/g, but not for UIC. The potential size of the associations identified was relatively modest compared to other established modifiable risk factors for lower birth weight and SGA, such as smoking ,47,48, aResults were broadly consistent across studies collecting urine samples earlier in pregnancy and those collecting later, and across different populations defined by median UIC and geographical region, with adjustment for confounding making little difference too.Our results are consistent with the most recent review, which found insufficient evidence of an association UIC and low birth weight, but adds to this previous work with findings on birth weight centile and SGA. Furthermore, we identified nonlinearity in some of the dose-response curves and differences between subgroups, none of which would have been apparent without the additional information provided by the more recent cohorts. For example, we saw threshold effects in the associations between I:Cr and birth weight and between iodide intake and birth weight, and noted a potential u-shaped association between I:Cr and SGA.We have included results from studies reporting iodine exposure as both UIC and I:Cr, with the latter identifying stronger associations with birth outcomes. I:Cr may hold some advantage for epidemiological studies in pregnancy, because UIC cannot adequately estimate iodine status of individuals because of day-to-day variation in iodine status and urine dilution. Results from our review support this, with less between-study heterogeneity with I:Cr, and clearer associations despite the smaller number of studies. However, in addition to maternal kidney function, creatinine excretion may also vary with age, physical activity levels, and body mass index, which themselves may be associated with fetal growth .One well-conducted case-control study nested with the Finnish Medical Birth Register using serum iodide as a measure of iodine status was excluded as outside our pre-defined list of exposures in our protocol . The autTaking risk of bias into account, we interpret results for preterm delivery cautiously, because of potential reverse causality, with the decision to deliver influenced by fetal growth up to that point. Otherwise, our assessment of study quality mostly differed by choice of covariate adjustment. Standardised measures of birth weight, such as birth weight centile and SGA controlled for important potential confounding, led to broadly reduced between-study heterogeneity in our results, and potentially provide more informative outcomes for obstetricians and paediatricians.Our review was partly limited by the available data. As with all observational studies, residual confounding within each study is a potential source of bias, with covariate adjustments differing between studies. Self-reported intake is also prone to measurement error, which can bias associations in either direction. In addition, not all studies reported all birth outcomes or all measures of iodine status. Whilst there was no evidence of small study effects such as publication bias for the more widely reported outcomes of birth weight and preterm delivery, there is more opportunity for publication bias in the less frequently reported outcomes, which we could not assess for small study effects using Egger’s test because of insufficient data.Very few randomised controlled trials of iodine supplementation or fortification have been conducted outside severely iodine-deficient settings , so we hMost studies reviewed measured iodine status in spot urines for pragmatic reasons. These are prone to greater variability than 24-h urine collections, so subsequent results are inevitably less precise. Furthermore, the timing of the urine collections was averaged within each study for subgroup comparisons, potentially masking some within-study variation.Our review is strengthened by the large number of well-conducted birth cohorts that have recently published on this topic allowing greater precision in our results and allowing us to identify potential threshold effects and differences between pre-defined subgroups. We have also been able to explore urine dilution-adjusted results using I:Cr, with novel findings, as well as including self-reported iodide intake. We have conducted a comprehensive review, in terms of the range of different measures of iodine status and birth outcomes that give an overall picture of the association between maternal iodine status and birth outcomes.In conclusion, we have found evidence of modest associations between some measures of iodine status, birth weight, birth weight centiles standardised for gestational age. In pregnancy, we recommend reporting iodine status accounting for urine dilution variability using I:Cr as well as the more usual UIC, because of inconsistency in findings between the two measures. Any future studies should also report standardised measures of birth weight for more accurate comparison of outcomes. Whilst the associations are small and not found in all outcomes, they are potentially still important at a population level, and we recommend consideration of methods to maintain iodine sufficiency in the population, especially for women of childbearing age on restricted diets.


Better biomarkers need to be developed to efficiently stratify pregnant women with the most common autoimmune diseases.A prospectively study of pregnant women with systemic lupus erythematosus (SLE), antiphospholipid syndrome, or non-criteria obstetric antiphospholipid syndrome was conducted to describe the characteristics of women followed in a referral unit and to derive a predictive tool for adverse pregnancy outcome (APO). Demographic characteristics, treatments, SLE activity, and flares were recorded. Laboratory data included a complete blood cell count, protein-to-creatinine urinary ratio (Pr/Cr ratio), complement, anti dsDNA, anti-SSA/Ro, anti-SSB/La, and antiphospholipid antibodies status. A stepwise regression was used to identify baseline characteristics available before pregnancy and during the 1st trimester that were most predictive of APO and to create the predictive model. A total of 217 pregnancies were included. One or more APO occurred in 45 (20.7%) women. A baseline model including non-Caucasian ethnicity , smoking , pregestational hypertension , and pregestational corticosteroids treatment OR 2.98; 95% CI [1.30–6.87]) yielded an AUC of 0.78 . Among first-trimester parameters, only Pr/Cr ratio improved the model fit, but the predictive performance was not significantly improved (AUC of 0.78 vs. 0.81;  Most autoimmune diseases are no longer an absolute contraindication for pregnancy. Advances in management of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have provided a better quality of life of women at childbearing age and a consequent increase in the pregnancy rate among these women . A groupThe reported risk factors for adverse pregnancy outcomes (PO) include presence of lupus anticoagulant (LAC), antihypertensive use, physician global assessment score greater than 1, and low platelet count . ConsideSome studies have attempted to identify predictive variables, obtaining models with limited predictive capacity and diverse results ,19,20. WThis is an observational cohort study based on a prospectively collected database of pregnant women with autoimmune diseases followed in a high-risk obstetric unit of a tertiary hospital between 2010 and 2019. Pregnant women diagnosed with SLE, APS, or NC-OAPS were included. Each pregnancy of the included patients was registered and analyzed as an independent episode. The diagnosis of SLE was established according to the criteria of the latest update of the American College of Rheumatology/EUropean League Against Rheumatology (ACR/EULAR) . The diaThe study protocol was approved by the local Ethics Committee (HCB/2020/0184), and all participants signed informed consent. All women were treated according to a specific protocol that included the schedule of visits, ultrasounds, and laboratory tests. Patients with aPL received treatment according to the latest recommendations ,24,25.Demographic characteristics, previous obstetric outcomes and episodes of thrombosis, pre-pregnancy arterial hypertension, mode of conception, presence of other autoimmune diseases, and treatments were recorded. Regarding SLE activity, SLE flare during pregnancy or puerperium was defined as onset or worsening of signs/symptoms of SLE in any organ or system attributed to the activity of the disease and that conditioned a change in the treatment . In addiLaboratory data included in each trimester of gestation a complete blood cell count, protein-to-creatinine urinary ratio (Pr/Cr ratio), C3, C4, and anti-dsDNA antibodies. Status of anti-SSA/Ro (anti-Ro) and anti-SSB/La (anti-La) antibodies were registered. Regarding aPL, anticardiolipin antibodies (aCL), anti-B2-glycoprotein I antibodies (anti-β2GPI), and LAC that tested positive at least twice on two or more consecutive occasions at least 12 weeks apart with titers >40 GPL/MPL (99th centile) and/or >40 AU, respectively, were recorded as criteria aPL positivity. Persistent aPL at low titers and those with medium-high aPL titers or LAC but not persistently positive (only one positive determination) were classified as non-criteria aPL positivity. Pregnancy and adverse pregnancy outcomes were recorded. APO were defined as follows: (a) fetal death > 10 weeks of gestation not explainable by chromosomal abnormalities, anatomical malformations, or congenital infections; (b) neonatal death before hospital discharge due to complications of prematurity and/or placental insufficiency; (c) preterm birth < 37 weeks due to placental insufficiency, gestational hypertension, or preeclampsia; (d) small for gestational age newborn (<percentile 5) in the absence of anatomical malformations or genetic alterations; and (e) preeclampsia during gestation or puerperium. n = 21) were imputed from maternal age and second-trimester values by expectation-maximization (EM) method assuming a normal distribution and checking for the randomness of missing values by Little’s statistic. The MVA-package of IBM SPSS 23.0 was used. The statistical significance of differences in continuous data was calculated using the Student’s t-test or the Mann–Whitney U-test for normally and not-normally distributed data, respectively. The categorical data was analyzed using Fisher’s exact test. Multivariable analysis was performed by selecting variables with p < 0.1 in the univariate analysis as potential predictors of APO. Logistic regression was applied to assess the OR and 95% CIs of APO for all potential predictors. A stepwise regression was then used (p < 0.05 for the forward and p < 0.10 for the backward steps) to identify baseline characteristics available before pregnancy that were most predictive of APO and to create the predictive model. All the models were runed by penalized maximum likelihood method, which is more robust in samples with rare events. From individual risks, receiver-operating characteristics (ROC) curves were plotted. The area under the receiver-operating characteristics curve (AUC) was used to assess the discrimination of the logistic model obtained. The same procedure was applied to identify and generate a model with variables available during the 1st trimester of pregnancy to assess if the addition of some variable to the pregestational model might improve the predictive ability. The data were collected and entered into a database for analysis using the STATA software . The distribution of data was evaluated using the Shapiro–Wilk normality test. Missing values in the first trimester protein-to-creatinine urinary ratio , smoking , and pre-gestational hypertension  were significantly more prevalent in the APO group. Regarding laboratory parameters, hypocomplementemia (low C3 or C4)  and Pr/Cr ratio in the 1st trimester  and 3rd trimester  were significantly associated to APO. Regarding treatments, only the use of corticosteroids treatment at the beginning of pregnancy was significantly more prevalent in APO group . However, mean corticosteroids dose was similar between APO and non-APO group . No association was found with the other treatments, namely LDA, LMWH, and hydroxychloroquine. In this cohort, almost 70% of women were treated with low dose of aspirin, 40% with low-molecular-weight heparin (any dose), and almost 60% with hydroxychloroquine. Regarding SLE activity, only SLEPDAI score was significantly higher in the APO group. Kidney involvement was the only SLE organ involvement significantly associated to APO. Surprisingly, in our cohort, aPL positivity  of any type was not associated to APO. As expected, APO group had more caesarean sections and SLE flares. No differences were found regarding maternal age, body mass index, mode of conception and previous APO, or thrombosis episodes between study groups. Among the baseline epidemiological characteristics, non-Caucasian ethnicity  ; p = 0.021) significantly improved the model fit . However, the predictive performance was not significantly improved . A baseline model including non-Caucasian ethnicity , smoking , pregestational hypertension , and pregestational corticosteroids treatment  yielded an AUC of 0.78 . Among the potential first-trimester laboratory predictors, only Pr/Cr ratio  was associated to APO even though it was not finally included in the model. Similarly, Pr/Cr ratio at the 1st and 3rd trimesters was associated to APO, which might reflect some degree of kidney involvement, a marker of worse prognosis in women with SLE ,30. HoweAnother finding to remark is the absence of association between any APO and the positivity of any of antiphospholipid antibodies regardless of whether they met the diagnostic criteria for APS or not. These results differ from other studies, in which lupus anticoagulant positivity was the main predictor of adverse pregnancy outcome in women with aPL ,19. GAPPIt is worth mentioning the inclusion of women with NC-OAPS, who have been routinely excluded from studies despite representing approximately one-quarter of the pregnant women with aPL positivity referred to high-risk units. The inclusion of this group in our model enhances the external validity. In our cohort, 21% of women with NC-OAPS presented an APO, which agrees with data from previous studies and confirms that women with such autoimmune diseases still present worse perinatal results. Regarding study limitations, sample size is small due to the relatively low prevalence of AID in pregnant women. When the number of events is small, model overfitting can be a problem. An overfitted model tends to demonstrate poor predictive accuracy when applied to new data, but this small-events problem may also undermine external validation. Although we applied frequentist shrinkage methods to alleviate overfitting , we acknowledge that the small number of events in our cohorts may still result in an underpowered validation. It also worth mentioning that each one of the pregnancies from the recruited women were included and analyzed as independent events. However, only twenty-nine women presented two episodes or pregnancies. No women with more than two pregnancies were included. However, advances in management of AID have provided a better quality of life with a consequent increase in the number of pregnancies among these patients, a tendency that will continue to grow in the upcoming years.To conclude, until new and better APO biomarkers are developed, a model including ethnicity, smoking status, pre-gestational hypertension, and corticosteroids treatment at the beginning of pregnancy could efficiently stratify pregnant women with the most common autoimmune diseases according to their risk for subsequently presenting an adverse pregnancy outcome.


BMJ Open 2021;11:e046322. doi: 10.1136/bmjopen-2020-046322Kananura RM. Mediation role of low birth weight on the factors associated with newborn mortality and the moderation role of institutional delivery in the association of low birth weight with newborn mortality in a resource-poor setting. This article was previously published with an error.There was a mistake in calculating the indirect effect of the Perinatal Mortality (PM) factors that are mediated through Low Birth Weight (LBW).Based on tables 1 and 2 results, the indirect effects are calculated as:Total effects are calculated as:where, Based on the two equations, LBW mediated +47% of rural resident mothers, +54% of adolescent mothers, +15% of mothers with previous experience of new-born or pregnancy loss, +100% of multiple births and −45% of mothers with partners.


Extraction of coal through mountaintop removal mining (MTR) alters many dimensions of the landscape. Explosive blasts, exposed rock, and coal washing have the potential to pollute air and water. Previous research suggests that infants born to mothers living in areas with MTR have a higher prevalence of birth defects. In this cross-sectional study, we further examine the relationship between MTR activity and several types of birth defects. Maternal exposure to MTR was assessed using remote sensing data from Skytruth, which captures MTR activity in the Central Appalachian region of the United States. Active MTR area was quantified within a five-kilometer buffer surrounding geocoded maternal address captured on birth records for live births to Appalachian Kentucky mothers between 1997 and 2003 . We assigned high, medium, and low exposure based on the tertile of total MTR area within 5-km, and births with no MTR within this buffer were assigned zero exposure. The presence or absence of a birth defect grouped into six major organ systems was identified using birth records alone. Finally, we applied conditional multiple imputation for variables with missing values before conducting separate multivariable log-binomial regression models for each birth defect group. Prevalence ratio (PR) estimates were adjusted for individual level covariates from birth records. The prevalence of gastro-intestinal defects was significantly higher in birth records with high and low active MTR exposure compared to records with no exposure. . This study supports some of the existing findings of previous ecological studies. Research addressing the relationship between gastro-intestinal birth defects and MTR coal mining is warranted but should carefully consider temporal dimensions of exposure. From 19[2 about .5% of CeMountaintop removal coal mining alters the landscape by reducing its topographical complexity, affecting water quality, stream and river flooding, and other physical dimensions of the landscape . To expoPrevious research has shown that the extraction of mineral resources, like coal, is associated with negative health outcomes in humans –10. CongLaboratory and environmental studies of MTR suggest that exposure can occur through contaminated water and air , 16. In A previous study of fugitive dust and fumes from MTR mining found that levels of contaminants generated by blasting can be sampled up to 2000 ft (610 meters) away from the blast site, but coal transportation and water runoff may also be a factor . Still, Ahern et al. hypothesized that a higher prevalence of birth defects would be present in MTR mining counties compared to other coal mining counties and non-mining counties . Their rAhern et al. found that birth defect prevalence rate ratios (PRR) were significantly higher in MTR areas compared to non-mining areas  after controlling for covariates. Six of the seven birth defect groups studied were significantly higher in MTR areas. The PRR remained elevated even after adjusting for socio-economic status (SES), and the spatial analysis suggested that the impacts of mountaintop mining extended beyond the immediate site of mining operations. However, Ahern et al. were limited in their use of a county-level exposure assessment. Notably, counties were classified as MTR coal-mining counties irrespective of the number or size of MTR sites or whether the site was historical or active over the study period.The present study sought to investigate the relationship between MTR coal mining exposure and birth defects using a finer spatial resolution than in previous literature to assess maternal exposure to MTR. Using a cross-sectional study design, we examined maternal addresses from birth certificates relative to precise satellite data of MTR activity to assess the relationship between congenital anomalies and residential proximity to MTR mining at birth in Appalachian Kentucky.The Medical Institutional Review Board (IRB) at the University of Kentucky and the Kentucky Cabinet for Health and Family Services (CHFS) IRB approved this study protocol .The Kentucky Department for Public Health, Office of Vital Statistics, provided individual outcome and covariate data from birth records, which included all live births to Kentucky residents from January 1, 1997, to December 31, 2003, using birth certificate formatting of the 1989 revision to U.S. standard live birth certificate. The study period of 1997 to 2003 was chosen because it precedes Kentucky’s adoption of a new standard in 2004, to increase comparability of births within the dataset, and to increase comparability with previous studies. Requested records identified maternal residential address, congenital anomalies, and covariate data.Among all live births between 1997 and 2003 , 24,849 (6.6%) self-reported maternal addresses could not be geocoded, and 255,444 (67.9%) were not Appalachian . FurtheSkyTruth.org, a non-profit that tracks resource extraction using remote sensing data. This data set includes several GIS layers representing active MTR mining sites in the Appalachian region by year. It possesses both high temporal and spatial scale and is made available freely and openly by its original creators to facilitate future research [Mountain-top removal coal mining polygons were sourced from a dataset produced by research . Their tresearch .2) were first excluded from further processes due to the improbability of being a viable surface mining area [ArcGIS  software was used to determine exposure to active MTR. MTR mining polygons with an area <40 acres  code centroid, depending on the strength of the match. Geocoding match scores (or level of agreement) less than 93% were unsuccessfully matched, and 93.3% of all addresses geocoded to the ZIP code or better. The spatial join tool computed the total area of active MTR within a 5-kilometer (km) buffer surrounding the matched location. At least one previous study of birth outcomes uses a similar measure of exposure . This prThe final exposure variable was categorized into low, medium, and high MTR exposure based on tertiles of active MTR area within 5-km of maternal residence. Births where maternal residence was not within 5-km of active MTR were given a 0 (no exposure). Births in the low tertile of exposure had up to 0.32 square km of active MTR within the 5-km buffer, medium >0.32 to 1.17 square km, and high >1.17 square km. We categorized the exposure variable after examining the non-normal distribution of active MTR area near maternal residence and the considerable proportion of births in the population with zero exposure.Birth records included twenty-two congenital anomalies grouped into six major organ systems. The central nervous system group included anencephaly, spina bifida, hydrocephaly, and macrocephaly; circulatory/respiratory group: heart malformations; gastro-intestinal group: omphalocele/ gastroschisis and tracheoesophageal fistula; urogenital group: genital malformation and renal agenesis; musculoskeletal group cleft lip, clubfoot, diaphragmatic hernia, and polydactyly, syndactyly, and adactyly; and chromosomal group: Down syndrome. All groups also include nonspecific categories. This approach was also taken by Ahern et al . For eacIndividual-level covariates originated from birth record demographic variables. Categorical definitions were based on meaningful qualitative cut points identified through literature. Infant covariates included male or female sex, gestational age at delivery , and birth weight . Maternal covariates included education , age at delivery , any diabetes comorbidity (including Type II), cigarette use, parity (previous births), plurality , and Kotelchuck index of prenatal care  .All birth defect groups were dependent variables in separate multivariable log-binomial regression models used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Covariates included in the final statistical models were based on previous literature. All final models included maternal education , age of We found only gastro-intestinal defects to be more prevalent among births with MTR exposure during unadjusted analysis. After adjusting for maternal education, age, tobacco use, diabetes comorbidity, Kotelchuck index, plurality, and sex of the infant in the log-binomial regression model, the relationship between MTR exposure and gastro-intestinal defects remained statistically significant. The prevalence of gastro-intestinal defects was 88% higher in birth records with low exposure to active MTR within 5-km of residence compared to records with no exposure . The prevalence of gastro-intestinal defects was 99% higher in birth records with high exposure compared to records with no exposure .Since mothers 25 years of age and younger are more likely to have a baby with gastroschisis compared to older mothers, we examined whether age modified the relationship between MTR exposure and prevalence of gastro-intestinal defects , 37. In We observed that gastro-intestinal birth defects were associated with maternal residential proximity to MTR mining. Before or after controlling for individual-level covariates, no other birth defect group was associated with MTR activity. We did not find that differences in covariates between the exposed and unexposed populations contributed to significant birth defect prevalence differences, as estimates changed little when literature-based covariates were incorporated into the model. Our results show an increase in the prevalence of gastro-intestinal defects in births with geocoded maternal residence within 5-km of active MTR in Appalachian Kentucky counties. After quantifying the amount of active MTR area within the 5-km buffer, birth records with the lowest and highest exposure had increased prevalence of gastro-intestinal defects compared to records with no exposure. While not significant, the prevalence in the medium exposure group still trended in the same direction. A preliminary analysis using a binary indicator of MTR exposure (home address within 1 km of active MTR sites) showed a similar increase in the prevalence of gastro-intestinal defects.Although we only examine a subset of Central Appalachian counties located in the state of Kentucky, the United States’ Appalachian region consists of 13 states and 423 counties that span from New York to Georgia . The homTwo previous studies examined the relationship between MTR surface mining and adverse birth outcomes in this region , 39. AheStill, our more precise exposure assessment should reduce possible differential misclassification bias. While Lamm et al. rejected the Ahern et al. hypothesis, both studies shared a county-level exposure assessment, which might obscure the true relationship between MTR mining and birth defects. In our study, individuals from the same county could have different assessed exposures but still share a birth hospital. Our approach was like that of Buttling et al., where satellite images of surface mining and maternal street address and ZIP code were used to quantify mining area within a 5-km buffer of maternal residence . The useOur study also improves on existing literature by recognizing the potential for exposure during the pre-conception period (12 weeks prior to estimated LMP), as some trace elements and heavy metals  bioaccumulate, can cross the placental barrier, and are associated with stillbirth, impairments in the development of the central nervous system, and maternal complications . Our stuHowever, previous literature is inconclusive regarding the distance MTR-derived agents might travel. Exposure pathways, duration, and quantity may be heterogeneous within the study population due to variation in mining practices, geography, coal transportation, chemical treatment, and weather, as seen in Kurth et al. . Our quaAs our study relied on birth records alone to identify maternal information and birth outcomes, self-reported tobacco use and residential address may be inaccurate due to recall or interviewer bias. Similarly, spelling, address truncation, and other address errors can impact the accuracy of geocoding and thus exposure assessment. Spatially non-random differences in the success of geocoding have been demonstrated previously , and geoDifferences in maternal characteristics may impact rates of termination, such as access to adequate prenatal care or socio-economic status, age, race/ ethnicity, urban vs rural residence, and previous pregnancy , 49. We Bell and Belanger identified the residential mobility of the mother as a key determinant of environmental exposures during pregnancy . HoweverAs we could only access live birth records, we did not capture all congenital anomalies within the population. Watkins et al. demonstrated that the sensitivity of birth certificates in reporting birth defects is overall low and varies by type due to ease of detection at birth , and preWe observed a slightly lower but similar prevalence of birth defects among live births compared to Ahern et al. and Lamm et al , 39. TheStudies using birth defects registries have estimated the prevalence of any birth defect at about 3% in Kentucky and the U.S. . ConsistDespite these limitations, our study builds upon previous research by quantifying active MTR exposure for all birth records individually and at a finer spatial scale compared to the county-level assessments in previous literature examining the relationship between MTR and birth defects.This study found that MTR near maternal residence reported at birth was associated with the presence of gastro-intestinal birth defects in infants born to women in Appalachian Kentucky between 1997 and 2003. Taking into consideration the amount of active MTR surface mining land within a 5-km buffer of maternal residence during the year of majority exposure during pregnancy, we found that the prevalence of gastro-intestinal defects was significantly higher in birth records with high and low active MTR exposure compared to records with no exposure. This finding agrees and contrasts with previous research that demonstrated evidence of an association between several additional birth defects in MTR mining areas. Based on our study’s results, additional research addressing the relationship between gastro-intestinal birth defects and MTR coal mining is warranted. Additional research is needed at this spatial scale of exposure with better adjustments for data heterogeneity, such as hospital of birth, maternal residential history, occupational characteristics of household members, a more robust source of birth defect cases, and the inclusion of electively terminated pregnancies. Furthermore, research is needed to better characterize the type and amount of environmental contamination encountered by communities in close proximity to active MTR sites since prior studies have not conclusively examined this issue.S1 Text(PDF)Click here for additional data file.