The response of the phenological events of individual species to climate change is not isolated, but is connected through interaction with other species at the same or adjacent trophic level. Using long-term phenological data observed since 1976 in Korea, whose temperature has risen more steeply than the average global temperature, this study conducted phenological analysis . The phenological shift of the producer group (plants) was found to be negative in all researched species, which means that it blooms quickly over the years. The regression slope of consumers (primary consumers and secondary consumers) was generally posi-tive which means that the phenological events of these species tended to be later during the study period. The inter-regional deviation of phenological events was not large for any plant except for plum tree and Black locust. In addition, regional variations in high trophic levels of secondary consumers tended to be greater than that of producers and primary consumers. Among the studied species, plum was the most sensitive to temperature, and when the temperature rose by 1 °C, the flowering time of plum decreased by 7.20 days. As a result of checking the day differences in the phenological events of the interacting species, the phenological events of species were reversed, and butterflies have appeared earlier than plum, Korean forsythia, and Korean rosebay since 1990. Using long-term data from Korea, this study investigated differences in phenological reactions among trophic groups. There is a possibility of a phenological mismatch between trophic groups in the future if global warming continues due to differences in sensitivity to climate and phenological shifts between trophic levels. Between 1880 and 2012, the average global surface temperature rose by 0.85 °C, while between 1912 and 2017, the average surface temperature in South Korea rose by about 1.8 °C [The total number of species currently living on Earth is estimated at 8.7 million , and somSince plants and animals have a clear seasonality depending on the appropriate environment, their activities reflect seasonal patterns . ChangesMany studies have focused on phenological changes due to global warming and climate change at the level of individuals and single species . The mosThe differential phenological response to climate among species is predicted to interfere with trophic interactions, however data sets to test this prediction are rare . During The timing of many phenological events results proximately from a complex interplay among an organism’s genes and several external environmental factors such as temperature, precipitation and photoperiod etc. . Among tWhile numerous studies have been studying long-term trends, recent studies have shown that very long-term linear trends mask phenological shifts . We had Therefore, the study aims to evaluate the phenological changes of trophic groups in representative species inhabiting Korea, which has experienced rapid global warming. We conduct an analysis of phenological shifts resulting from climate change, along with differences in phenological variations by trophic levels and phenological sensitivities to climate by group and period. We also identified temporal trends about the day difference of phenological events between species that interact with each other.Species from the phenological observations were selected by the Korea Meteorological Administration (KMA) to identify the biological seasonality of communities . The proPrunus mume), Korean forsythia (Forsythia koreana), Korean rosebay (Rhododendron mucronulatum), cherry tree (P. yedoensis), peach tree (P. persica), pear tree (Pyrus serotina) and Black locust (Robinia pseudoacacia). One species of insect which is very common throughout Korea was studied, namely the cabbage butterfly (Pieris rapae); one species of amphibian was studied, namely the black-spotted pond frog (Rana nigromaculata); and two species of bird were studied, namely the skylark (Alauda arvensis) and cuckoo (Cuculus canorus). Study species included interacting species, such as plants as producers and butterflies as pollinators, and prey and predators . The species also classified as: producers, primary consumers, and secondary consumers according to the status of organisms in the food chain in the ecosystem, i.e., the trophic levels  were used in the timing of activities. In addition, to compare with the previous 40 years when temperature increases were lower, 1973 phenological data were used at the six points where 11 species of data existed between 1936 and 1975. We analyzed the regression of phenological events and temperature, and examined the coefficient of slope and RFinally, we identified temporal trends about the day difference of phenological events between species that interact with each other. Therefore, we checked the phenological day differences between the seven species as producers and the cabbage butterfly as the pollinators, respectively, and checked the phenological day differences between the cabbage butterfly as prey and three species as the secondary consumers, respectively. We also conducted the temporal trend analysis for two different time periods, 1936~1975 and 1976~2015, in order to compare the changes in day differences between interacting species under different warming conditions. Hence we analyzed annual trends by calculating the day difference of interacting relationships at 61 sites during 1976~2015, and at six sites during 1936~1975 by site levels.p < 0.05) is given in parentheses in We performed a regression analysis of the phenological events at the 61 observation points for each of the 11 species by year to examine the variations in the phenological trends for each of the species . The speFor the seven plant species, which are producers, there were more stations where phenological events were advanced than stations where they were delayed, and the phenological events which were advanced had more statistically significant values. For the pollinator and primary consumer, cabbage butterflies, there were more stations where the phenological event was delayed, and the stations where the event was delayed often had statistically significant values. The phenological events of amphibians and birds, which are secondary consumers, were also delayed at more stations than they were advanced and often had statistically significant values in areas where they were delayed.Variation of statistically temporal trends of phenological dates of all species across 61 sites . In the In relation to phenological events and climatic factors, all of the species tended to be earlier in activity as temperatures increased . In the In comparison by periods, except for Korean forsythia and Korean rosebay, 5 species of plants and cabbage butterfly were more sensitive to temperature during the last 40 years. Especially, for all species except secondary consumers, the R-square value of regression analysis with temperatures for 1976~2015 was higher than that for 1935~1975.To examine the changes in biological season synchrony of interacting species, temporal trends were analyzed by calculating the day difference of the average phenological events between each trophic group . IncreasAccording to the Korea Climate Change Assessment Report 2020, which analyzed more than 1900 papers and reports, it is clear that since 1920 South Korea has experienced a higher rate of temperature increase compared to the global average, and since 1973 the trend of increasing temperature has been stronger , and KorFirst Flowering Dates of all plant species in this study showed advanced temporal shifts during 1976~2015. In particular, plum is the plant with the earliest FFD, with an average FFD of 83.13, and this species not only had a very large regional variation of phenological shift, but also had the most rapid advancement of its phenological event. This indicates that species with an early flowering date flower ever faster as the temperature increases. This is consistent with previous studies that showed that early-flowering plants are more sensitive to temperature increases ,32,33. IIn the consumer group, which includes insects, amphibians, and birds, the phenological shift was positive, unlike the producer group . This meIn other studies, phenological events of plants were found to have advanced rapidly during the past 40 years, whereas phenological events of flying birds have been found to show large variability .In the situation where the producer’s phenological time is being advanced, the delay of the consumer’s phenological time indicates presumably an asynchrony implying differences by trophic group. For example, the average flowering time of plum becomes faster than that of the butterfly while the appearance of the cabbage butterfly (a pollinator) is gradually delayed , and flo2 value of the regression equation was higher for the recent 40 years (R2 = 0.13~0.83) than previous periods (R2 = 0.11~0.66). This indicates more explanatory power can be given to temperature in last 40 years to explain the variation of phenology than in the previous period. This is consistent with previous findings that, among climate factors, temperature should be a key factor for the change of the community [Furthermore, by extracting and analyzing representative temperature factors that can cause phenological changes, it was found that all significant species have become more sensitive to temperature recently . The sloommunity .Moreover, it was shown that the lower the trophic level, the more sensitive to temperature changes, and the higher the trophic level, the less it was affected by the temperature change during the recent 40 years . This indicates that the mechanisms affecting the phenological events of species differ by trophic group, which is consistent with previous studies that producers with lower food chains are more sensitive than consumers to temperature . Plants Hirundo rustica), one of Korea’s spring birds, due to a decrease in the population [Additionally, according to a prior study that described a delay in the observation period of swallows (pulation , it is pThis study examined the differences in phenological responses between trophic groups using 40-year phenological data from 1976 to 2015 in Korea. It also compared this with the results of the previous 40 years from 1936 to 1975, when there was less warming. There is a possibility of mismatch between trophic groups in the future since there is a variation in sensitivity to climate and the phenological shift of trophic levels. Due to future global warming, large changes are expected to occur in the species and trophic levels, and consequently more diverse and integrated studies are needed. Our study suggests that it is necessary to develop climate change mitigation and adaptation strategies, food chain linkages, and biodiversity management plans.


The Odon Device™ is a new device for assisted vaginal birth that employs an air cuff around the fetal head for traction. Assisted vaginal birth (AVB) is a vital health intervention that can result in better outcomes for mothers and their babies when complications arise in the second stage of labour. Unfortunately, instruments for AVB (forceps and ventouse) are often not used in settings where there is most clinical need often due to lack of training and resources, resulting in maternal and neonatal morbidity and mortality which could have been prevented.This is often due to a lack of trained operators as well as difficulties in the sterilisation and maintenance of AVB devices. This novel, single use device has the potential to mitigate these difficulties as it is single use and is potentially simpler to use than forceps and ventouse.All the studies of the Odon Device to date  suggest that the Odon Device does not present a higher risk to mothers or babies compared to current standard care, and recruitment to intrapartum research exploring the device is feasible and acceptable to women. The first study in which the Odon Device was used in clinically indicated conditions (the ASSIST Study) reported a lower efficacy than those reported with established devices. The reasons need to be explored, specifically focussing on learning curve, the technique of the doctors using this new device and potential modifications to device design. A follow-on clinical study to further investigate the efficacy and safety of the Odon Device in its indicated use, the ASSIST II Study, is therefore being undertaken.The primary feasibility outcome is study feasibility (recruitment and retention rates) whilst the primary clinical outcome successful vaginal birth completed with the Odon Device. Key secondary feasibility outcomes include participant withdrawal, compliance in data collection and acceptability of the device to women and operators. Secondary clinical outcomes include maternal, neonatal and device outcomes. Safety data will be reviewed following every birth exploring maternal, neonatal and device risks. Using A’Hern approach for sample size calculation, we aim to recruit 104 women requiring an assisted vaginal birth for a recognised clinical indication. Assuming an AVB success rate of 65% or more, a one-sided alpha risk of 5% and power of 90%.The data from the ASSIST II Study will provide the information required regarding acceptability, recruitment, outcome data collection, device design, technique of device use and operator learning curve in order to design a future randomised controlled trial of the Odon Device versus current modes of assisted vaginal birth.38829082 ISRCTN registration: The online version contains supplementary material available at 10.1186/s40814-021-00814-2. No new methods of assisting vaginal birth have been introduced into clinical practice since the development of the ventouse in the 1950s, despite the huge advances in medical care over the past 70 years. Complications of the second stage of labour remain a major cause of maternal and neonatal morbidity and mortality. Assisted vaginal birth (AVB) reduces adverse outcomes for women and their babies relative to a caesarean section performed in the second stage of labour . AVB is Currently, a vaginal birth may be expedited through the use of obstetric forceps or ventouse. Forceps are more likely to achieve an AVB when compared to a ventouse; however, they are associated with increased maternal perineal and vaginal trauma. The ventouse is more likely to fail than forceps and is associated with an increased risk of neonatal cephalohaematoma and retinal haemorrhage .The Odon Device is a new device for AVB, comprising two main components: a polyethylene sleeve and a plastic applicator Fig. . The appThe first in human pilot study of four earlier versions of the Odon Device in 49 healthy volunteers in Argentina and South Africa . FurtherThe ASSIST Study (conducted between October 2018 and April 2019) was the first study in which the Odon Device was used to assist vaginal birth for clinically indicted conditions  , 14.All the studies of the Odon Device to date  suggest that the Odon Device does not present a higher risk to mothers or babies compared to current standard care (forceps and ventouse). However, the number of births assisted to date with the device is small and more experience of using the device is required to generate an evidence based safety profile. Furthermore, the reasons for the lower than expected success rate of the device needs to be explored, specifically focussing on obstetrician learning curves and the potential need for modifications to device design. A follow-on feasibility study to further investigate the efficacy and safety of the Odon Device in its indicated use, the ASSIST II Study has therefore been designed.The main aim of the study is to assess the feasibility of conducting a definitive trial in terms of recruitment and acceptability of the intervention, follow-up and data collection methods. In addition, the study aims to explore successful vaginal birth completed with the Odon Device.(i)To estimate feasible eligibility, recruitment as well as refusal and follow-up rates(ii)To investigate the feasibility of collecting data as well as exploring the safety and efficacy of forceps and ventouse from women who did not receive the Odon Device(iii)To investigate the safety, efficacy and acceptability of a new device for the Odon Device(iv)To define the clinical circumstances in which the device is most effective.(v)To study the learning curve of the operator and to investigate the most effective user technique.(vi)To study the device design and functionality.The ASSIST II Study  is a non-randomised feasibility study of women who require an AVB for a recognised clinical indication. The study also includes a nested cohort study of women and babies who had a ‘missed’ Odon Device assisted birth. These cases comprise women who have consented to participate in the ASSIST II Study and require an AVB but are unable to have a Odon Device assisted birth due to operator availability. The inclusion of the nested cohort will explore the feasibility of collecting information from a ‘comparator group’. The information gained from this study will be used to plan a large randomised controlled trial that will directly compare the Odon Device with the ventouse.Refined participant inclusion criteria to exclude very complex births when the vertex is at the level of the ischial spines.Inclusion of a nested cohort of ‘missed’ births.Larger sample size to support investigation into efficacy (104 births compared to 40).Manufacturer will ensure the device is manufactured to the required specification to avoid malfunction of the bulb pump experienced in the ASSIST Study.A simplified clinical primary outcome.Streamline changes to the data collection forms.The key changes to the ASSIST II Study protocol as compared to the ASSIST Study protocol are as follows:A CONSORT diagram of the ASSIST II Study is shown in Fig. Participants will be pregnant women aiming for a vaginal birth who plan to give birth at North Bristol NHS Trust (NBT), Bristol, UK. Recruitment is projected to continue for 11 months (due to the AVB rate within the department) after which time it is estimated that 104 sets of clinical primary outcome data will have been recorded.Prospective participants will receive information on the study in early pregnancy (12 to 28 weeks) via the NBT Maternity ‘App’  and paper information leaflets, given to women at any hospital admission. Members of the study team will then approach women after 28 completed weeks of pregnancy during antenatal appointments or antenatal admissions, to discuss the study and offer women the opportunity to watch a video explaining the study. Women who are willing to take part (should they require an AVB) will then be invited to provide informed written consent. Figure When a woman who has previously consented to participate in the study arrives on the labour ward, her eligibility to participate in the study will be rechecked and verbal re-confirmation of her consent to take part in the study will be sought by a midwife and obstetrician.Women will be able to participate in the ASSIST II Study if all of the following apply at initial consent: ≥18 years of age; singleton pregnancy of at least 36 weeks’ gestation; negative antenatal screen for HIV and Hepatitis B; in active labour and requiring an assisted vaginal birth for a clinical indication  Greentop Guideline 26) : the verWomen will not be able to take part in the ASSIST II Study if there is the fetal vertex at or above the ischial spines, a diagnosis of a fetal skull abnormality  or osteogenesis imperfecta, suspicion of a fetal bleeding disorder , an intrauterine fetal death in the current pregnancy, the woman is sensitive to latex, the woman is currently serving a prison sentence, and there is a fetal bradycardia which is on-going and has not recovered.If the woman agrees to an AVB, an accoucheur who has had specific training in using the Odon Device will assist the birth with the Odon Device. Should the birth not be achieved with the Odon Device, the obstetrician will use their clinical judgement on an individual case basis to complete the birth using ventouse, forceps or caesarean section as appropriate. Primary, secondary and safety data will be gathered regarding the assisted birth and use of the device with additional qualitative investigation of recruitment processes to the study.If an obstetrician who has had specific training in using the Odon Device is not available to attend the birth of an eligible and consented woman, the woman and her baby will be included in the nested cohort group. The birth will be assisted by the on-call team as per routine care in the maternity unit. All birth and outcome data will be gathered regarding the assisted birth and use of forceps and/or ventouse.Study feasibility through descriptions of recruitment and retention rates of women who may require an AVB at the end of their labour.Follow-up rates and reasons for declining or withdrawal .Suitability of outcome measures and overall data collection processes, including complete list of data collection and recruitment rate to the study.Ability to collate data from a ‘nested’ cohort will help demonstrate whether collecting data on a control group in a RCT is feasible.As well as recruitment rates, the following feasibility outcomes will be explored in detail:Patient acceptability will be assessed through the patient perception score of birth experience days 1, 7 and 28 postnatal (score out of 15 where 3 is the lowest score possible) and through qualitative assessment.Instrument of choice if Odon Device was not used .Perceived overall ease of use of device .Ease of device set-up .Ease of device application to the baby’s head .Ease of withdrawal of the applicator after application (for Odon births only).Comfort with the level of force required to assist the birth of the baby .Ease of deflation of the cuff prior to crowning (for Odon births only).Ease of removal of the forceps or ventouse.Practitioner acceptability will be assessed through perceived outcomes following each attempted AVB. The following will be collected on a 5-point Likert scale.In order to further understand the technique for device use, any birth with the Odon Device, the practitioner (and research midwife if present) will document the angle of device application using a grid stating whether the handle of the device is pointing: up, down or horizontally.The birth of the baby is expedited with the Odon Device.There are no serious maternal adverse reactions related to the use of the device during birth.There are no serious neonatal adverse reactions related to the use of the device during birth Table .A birth will be defined as ‘successful’ if all of the following criteria are met:Secondary outcome measures are categorised below and include measures needed to ascertain the feasibility of a future RCT:Time from ‘decision to perform assisted birth’ to ‘birth’ (minutes).Time from ‘device application” to ‘birth’ (minutes).Time between ‘decision to perform assisted birth’ to ‘time of Odon application’.Location of birth.Mode of birth following failed use of Odon device.Failure of a component of the Odon Device.Number of applications of device.Number of pulls of the device.Any trauma caused by first device application.Perceived reason for device failure from operator .Weighed blood loss.Perineal and anal sphincter injury (1st/2nd/3rd/4th degree tears and episiotomy).Ischio-rectal fossa defect.Cervical tear (present not requiring suturing).Cervical tear (present requiring suturing).Labial tear requiring suturing.Lower segment caesarean section performed (Yes/No).Use of analgesia days 1, 7 and 28 postnatal.Details of analgesia used at days 1, 7 and 28 postnatal.Maternal death.Length of hospital stay following birth.Umbilical artery pH and base excess.Umbilical vein pH and base excess.Shoulder dystocia.Apgar scores at 1, 5 and 10 min post birth.Neonatal Infant Pain Scores at 2 and 6 h post birth.Neonatal feed by 10 h post birth.Method of feeding days 1, 7, 28 and 90 post birth.Admission to Neonatal Intensive Care Unit (NICU).Time spent in NICU (hours).Neonatal soft tissue trauma .Neonatal vascular injury (subaponeurotic haemorrhage).Neonatal body maps (head and neck).Neonatal skeletal injury (bone fracture).Neonatal intra-cranial injury .Neonatal neurological injury still present at day 28 post birth.Neonatal seizure by day 28 post birth.Phototherapy for jaundice contributed to by bruising by day 28 post birth.Anaemia requiring transfusion by day 28 post birth.Neonatal encephalopathy requiring therapeutic hypothermia within 28 days post birth.Organ failure within 28 days post birth.Other neonatal injury.Neonatal death within 28 days post birth.Maternal health-related quality of life data (EQ-5D-5L) will be collected during the antenatal period and at day 1 and day 28 postnatal.Maternal perception of pain  at days 1, 7 and 28 postnatal.Maternal continence at day 90 postnatal.Data regarding visits to a health care professional in either the hospital or community setting within the first 28 days postnatal will be collected.A comprehensive assessment of the safety of the Odon Device will be undertaken following every attempted birth within the ASSIST II Study. Outcome measures and data collected will ensure capture of any potential adverse events associated with the Odon Device at time of birth by the operator and/or a member of the research team. All follow-ups will be performed by the research team. In the immediate postpartum period a member of the research team will follow-up the participant on a daily basis until discharge, collecting the day one data. To ensure that any serious adverse events that occur in the postnatal period are captured, an Adverse Event Reporting System will be initiated, for ward staff to highlight any adverse events that occur after birth. In addition, device failure (or failure of any component) will be reported as an individual outcome measure. Follow-ups at days 7, 28 and 90 will be conducted by a member of the research team telephoning the woman using their contact details provided to the study team. The Trial Management Group (TMG) and Sponsor will regularly review data from all births to ensure early identification of any trends of adverse events. All adverse events will be classified and reported according to the schedule of the Medicines and Healthcare Regulation Agency (MHRA) and the Research Ethics Committee.Women and their partners have been involved in the development of the feasibility ASSIST II Study prior to the submission for research approvals—patient and public involvement (PPI) has reviewed the proposed study design, as well as woman-facing documentation  and has supported both the general and specific aims of the study. A lay patient representative will be a member of the Trial Steering Committee (TSC) for the ASSIST II Study.Investigators had established a priori threshold for specific feasibility and acceptability criteria. These were the following: (i) the proportion of eligible women agreeing to participate in the study would be 54% or greater , (ii) rClinical outcomes will be reported as frequency and proportion, mean (standard deviation) or median (interquartile range) depending on their nature and distribution. The overall rate of successful AVB birth will be reported and the frequency of unsuccessful births will be reported by the three criteria defined for success. The overall number of safety events will be reported, as well as the number of events, by main reasons for adverse events. Events related to the device failure and/or mis-use of the device will also be described.In ASSIST II Study the integrated qualitative study (IQS) will focus exclusively on optimum processes for providing information about and obtaining informed consent for research studies that involve interventions that may be initiated in the intrapartum period.The aims of the IQS are to evaluate the model of information provision and receiving informed consent developed for the ASSIST II .Data will include audio-recordings of recruitment discussions between research midwives and women eligible to participate in the study and in-depth interviews with both women who have been invited to participate in the study and the research midwives involved in inviting them to participate. Written consent from all participants will be obtained prior to any qualitative research and verbal re-confirmation of consent will be obtained prior to each audio recording and interview. Findings will inform information provision during recruitment to any future study involving the Odon Device.Although a formal sample size is not required, the A’Hern approach for sample size calculation was performed in PASS (Power and Sample Size) software to help judgement regarding an appropriate figure. Assuming that the success rate (P) of a poor AVB is 50%, and the success rate of a good AVB would be 65% or more, and one-sided alpha risk of 5% and power of 90%, a study with 104 participants will be required to decide whether the success rate of the Odon Device is less than or equal to 50%, or greater than or equal to 65%. The success rate of 65% was identified from Attilakos et al., an AVB study conducted in the same unit as the ASSIST II Study which reported a success rate for a single-use, hand-held ventouse device of 66% .n=104) will be required to pursue the understanding of the device used in the clinical context of the study. This safety interim analysis will be performed around the 42nd attempted birth using the Odon Device.An interim safety analysis will be conducted to monitor and check the maternal and neontatal safety data only; no assessment of the Odon Device success will be conducted at this interim point. The whole sample size  and the Trial Steering Committee (TSC). The IDMC will sit after the 42nd birth has been attempted using the Odon Device. The IDMC will have no direct involvement in the running of the trial. The IDMC will generate a report on the performance of the device and safety of participants. The TSC will consist of an independent clinical expert, statistician and a lay representative, together with the investigators and Sponsor representative. The TSC will review all reports produced by the IDMC and make a recommendation to the Sponsor following every review to continue, modify or halt the study. The TSC will provide oversight of the progress of the study and ensure the study is conducted according to the principles of Good Clinical Practice (GCP). Auditing will take place when requested by the Sponsor.Study results will be published within one year of completion of data collection in an appropriate peer-reviewed open-access journal. The results will be presented at local, national and international meetings. Summaries will also be distributed using existing parent networks. A summary of results will also be sent to all women who participated in the study (including nested cohort participants), unless they express their wish not to receive such information. Results will be communicated to a lay audience by social media activities of North Bristol NHS Trust, University of Bristol and the research team.An appropriately conducted AVB, performed when clinically indicated, is associated with improved maternal and neonatal outcomes when compared to caesarean section in the second stage of labour or no action . The ASSThe success rate of the Odon Device was lower than the reported success rates of both forceps and vacuum and that of the initial pilot study , 11, 15.If found safe by the TSC, IDMC and Sponsor, findings from the ASSIST, ASSIST II Studies and parallel feasibility study in France  will infThe ASSIST II Study commenced on the 9th of August 2019, using version 0.2 of the protocol. The study will cease recruitment after 104 complete sets of primary outcome data are received. This is projected to be in June 2020.Additional file 1. SPIRIT 2013 checklist.Additional file 2. Ethics Committee Approval for the ASSIST II Study Format.Additional file 3. Confirmation of funding for the ASSIST II Study.


The number of infant deaths attributed to PM10 exposure is expressed in years of life lost. We used a three-step compartmental model to appraise neurodevelopmental impairment among survivors of preterm birth. We estimated that 12.8 infant deaths per 100,000 live births may be attributable to PM10 exposure, and about one third of these infants lived in deprived census blocks. In addition, we found that approximately 4.8% of preterm births could be attributable to PM10 exposure, and approximately 1.9% of these infants died . Quantification of environmental hazard-related health impacts for children at local level is essential to prioritizing interventions. Our study suggests that additional effort is needed to reduce the risk of complications and deaths related to air pollution exposure, especially among preterm births. Because of widespread exposure to air pollution, significant health benefits could be achieved through regulatory interventions aimed at reducing exposure of the population as a whole, and particularly of the most vulnerable, such as children and pregnant women.Several studies have found maternal exposure to particulate matter pollution was associated with adverse birth outcomes, including infant mortality and preterm birth. In this context, our study aims to quantify the air pollution burden of disease due to preterm birth complications and infant death in Paris, with particular attention to people living in the most deprived census blocks. Data on infant death and preterm birth was available from the birth and death certificates. The postal address of mother’s newborn was converted in census block number. A socioeconomic deprivation index was built at the census block level. Average annual ambient concentrations of PM The fact that preterm birth is associated with increased neonatal morbidity and mortality is now well established. The main complications of preterm birth include both several morbidity in adulthood and neurodevelopmental impairments that may, for instance, increase the risk of cerebral palsy which affects long-term physical health . Moreove10 increased significantly  [3 increase in PM10 [In addition, several studies found particulate matter pollution exposure to be associated with adverse birth outcomes, including infant mortality and preterm birth. Recent meta-analysis confirms that the risk of post-neonatal mortality all-causes for short-term exposure to PM2–1.025) . In addi in PM10 .10 exposure [The World Health Organization has identified air pollution as a leading cause of the environmental burden of disease in the European Region , estimatAssessment of environmental burden of disease estimates therefore offers an opportunity to identify policy priorities, particularly among newborns—a population recognized as more vulnerable to its living environment. An estimation of how many infant diseases and deaths are caused by air pollution constitutes a starting point with which to guide policymakers in drawing up infant and child health protection policies and measures. For policymakers, disease burden estimates can provide crucial information on the health benefits that could be achieved through the implementation of targeted actions against specific risk factors. With rising interest in the development of interventional research into public health issues, a crucial goal seems to be a design study quantifying what might be the “best” environmental intervention, in terms of cost and health benefits.To date, few studies  have est2. The city of Paris constitutes an appropriate place in which to investigate this issue, since average air pollution levels exceed the WHO guidelines. In addition, the population size  is high enough to calculate both Years of Life Lost (YLL) and disability adjusted life years (DALYs) from a substantial preterm birth and infant death sample.The study area is Paris, the capital of France. The number of inhabitants is about 2,250,000 distributed into 992 census blocks. It corresponds to 2199 inhabitants per census block on average and to a population density about 21,428 inhabitants per kmTwo different health databases were used in this study. First, infant death data was collected from death certificates recorded at Paris City Hall over the period between 2004 and 2009 . All casEthical approval was obtained from the French Data Protection Authority (CNIL). For reasons of confidentiality, in order to comply with the ethical authorization provided for this study (authorization numbers 914118 and 911149), it was not possible to store the individual localization of families.Census block socioeconomic level was assessed using a composite deprivation index. This composite index captures various socioeconomic dimensions: Family structure, household type, immigration status, employment, income, education and housing. The data for Paris is available from the National Institute of Statistics and Economic (INSEE—2012) . Princip10 for which newborn health effect are well documented and dose–response function available.A many epidemiological studies, toxicological evidence and WHO review supported that ambient Particulate Matter (PM) is considered responsible for the health effects ,17. Ther10 at census block level from January 2007 to December 2012. The model integrates integrate meteorological data: Air temperature, wind speed and direction, relative humidity, barometric pressure , emission sources according to their contribution to ambient air pollution and background pollution measurements as input parameters. Selected emission sources were linear sources (main roads), surface sources  and important point sources [AirParif is the local association, which monitor the air quality in Paris. Based on ESMERALDA Atmospheric Modeling system  they mod sources .Our statistical analysis was structured as follows:First, we described our study population in terms of infant death rate and preterm birth rate by specific gestational age group, and both health events by neighborhood socioeconomic classes.10 between 2004 and 2009 and the proportion of deaths for preterm births between 2009 and 2011. Next, the number of attributable deaths was converted to YLL.Second, we used the health impact assessment approach to calculate the number of infant deaths attributable to PM10 exposure.Third, we used the three-step compartmental model to estimate total Years lost Due to Disability (YLD) among preterm births, and the proportion of YLD attributed to PMLastly, we presented the results by quintile of the neighborhood socioeconomic index distribution. This step aims to reveal the potential existence of unequal YLL and YLD distribution by neighborhood socioeconomic class.10 concentrations in Paris, using the counterfactual method [We applied a Health Impact Assessments (HIAs) to estimate the number of health events  associated with a reduction in PMl method .(i)Population size  and level of exposure (population exposure),(ii)baseline of infant death rate and preterm birth rate,(iii)10 exposure [10 exposure were assessed for hypothetical air pollution reductions in line with WHO recommendations , using the following Equation (1).dose–response function derived from meta-analysis, which estimated the meta-relative risk, associated with the increase of PMexposure . In our This approach requires several data sources:0 corresponds to the total number of observed infant deaths or preterm births,Y10 and the guideline value of WHO, and,Δx measures the difference between the observed average of the PM3 of PM10β is the natural logarithm of meta relative risk expressed for an increase of 10 µg/m3 of PM10 concentrations is equal to 1.05 (95%CI = 1.02–1.07) [3 in PM10 concentrations [We used two different meta-risks arising out of the literature. Increased risk of preterm birth related to an increase of 20 µg/m02–1.07) . Risk oftrations .All input data used in our study were describe in the Table 2.10 can be converted to a number of Years of Life Lost (YLL) by using this equation:N is the number of deathsL is the standard life expectancy in yearsThe number of infant death associated with decreased PMIn Paris, average life expectancy for the period 2004–2009 was 82.8 years .YLD = P × DWP is the number of prevalent cases, andDW is the disability weightTo measure the burden of disease as a result of neurodevelopmental impairment due to preterm birth, we estimated the prevalence-based DALY, which incorporates YLL (Years of Life Lost) and YLD (Years lost Due to Disability), as defined by the following formula:We used the three-step compartmental model proposed by Blencowe et al., with estimated input parameters being used to assess neurodevelopmental impairment among post-neonatal survivors of preterm birth . In the 10 was assumed to follow the same distribution for all births.Firstly, we estimated live birth prevalence among preterm births. Since decreasing gestational age is associated with increasing mortality, disability, and a greater requirement for intensive neonatal care, gestational age of preterm birth was classified as the recommended subdivision: Extremely preterm birth (<28 weeks and >20 weeks), moderate preterm birth (28–32 weeks), and late preterm birth (32–36 weeks). The gestational distribution of preterm birth attributed to PMSecondly, we estimated number of Post-Neonatal Survivors. This step allowed us to estimate both post-neonatal survivors and number of preterm deaths, by gestational age group. As Blencowe et al. have already explained, a correlation exists between health system factors in place in each country and the neonatal mortality rate . They thFinally, we estimated number of Impaired Survivors. This step aims to estimate the number of impaired survivors, based on the risk of moderate/severe and mild long-term neurodevelopmental impairment after preterm birth. As shown in Equation (3), estimation of DALYs relies on assessing prevalence using disability weights. In our study, in order to take into account the severity level of neurodevelopmental impairments, we distinguished two distinct disability weights. The disability weight used for moderate-to-severe neurodevelopmental impairment was 0.38 (uncertainty range: 0.29–0.49). Assuming that about 50% of those with mild impairment had isolated mild problems, and 50% had mild motor and mild cognitive impairment, the disability weight used for these people was 10 fold lower, at 0.03 (uncertainty range: 0.02–0.05) . Table 210 between 2007 and 2012 was 30.1 µg/m3 (Standard Deviation = 1.72 μg/m3). The rate of infant death was 3.36 per 1000 live births over the period 2004–2009 , while the rate of preterm birth reached 6.1% between 2009 and 2011 . The number of preterm births among all births is equal to 0.22%, 0.62% and 5.34% at less than 28 weeks (and >20 weeks), at 28–31 weeks and at 32–36 weeks, respectively. We also estimate that 3.6% of all preterm births were at less than 28 weeks (and >20 weeks); 10.0% at 28–31 weeks and 86.4% at 32–36 weeks.The mean concentration of PMp < 0.016). The death rate is 1.9 fold higher among newborns living in the most deprived census blocks of Paris than among those living in the least deprived census blocks (The trend test reviled that the death rate per 1000 live births increased significantly with the level of neighborhood socioeconomic deprivation (s blocks .p < 0.029), moderate preterm (p < 0.001), and late preterm (p < 0.002). More precisely, we found that the percentage of extreme preterm is 1.9 fold higher among newborns living in the most deprived census blocks than among those living in the least deprived census blocks  function by gestational-specific preterm birth category , we found that 118 died among 5363 preterm infants born in Paris between 2009 and 2011. This corresponding to about 1.36 per 1000 live births, which contributed to 9770 YLL. Knowing that the infant death rate was estimated at 3.36 per 1000 live births, about one third of these infants would be born preterm. We estimated that about 46% of deaths were of infants born in the extreme preterm period. YLD value was 71.3 including both severe/moderate and mild long-term neurodevelopmental impairments. The DALY value from preterm birth complications was 9841.3.10 exposure, equivalent to 1987.2 years of life lost: It corresponds to about 12.8 deaths per 100,000 live births, and 1049.9 YLL per 100,000 live births.Of the 629 infant deaths occurring during the period 2004–2009, we quantified that 24 (95% CI = 12–43) deaths were attributable to PM10 exposure . This also corresponds to 5.75 deaths per 100, 000 live births. The number of preterm births attributed to PM10 exposure and living with long-term neurodevelopmental impairment was equal to 71.1 (95% CI = 66.0–77.6).Of the 5363 preterm births counted among all births in Paris (2009–2011), we estimated that 258 (95% CI = 106–354) maybe attributable to PM exposure. Of the preterm birth infants who died, 5 (95% CI = 2–8) were attributed to PM10 exposure, we observed that about 1/3 of the deaths occurred in families living in the most deprived census blocks; however, to due to the very low number, it is impossible to formulate a general conclusion from this observation.In terms of preterm birth complications, we found that about 13% of infant deaths occurred in families living in the least deprived census blocks, whereas this percentage increased to 20% for those living in the most deprived census blocks. Concerning deaths attributed to PM10 exposure estimated at a fine spatial scale among a newborn population; thus, it is difficult to make literature comparison.The WHO states that DALY is traditionally used in the quantification of the burden of disease, to estimate the magnitude of health loss due to diseases and risk factors for specific populations at a given age. To our knowledge, our study is one of the first to quantify the health consequences of PM10 exposure. Our finding is coherent with a US study published in 2004 [3 PM10 would contribute in a substantial way to post-neonatal infant mortality: About 14.7 infant deaths (95% CI = 7.3–25.6) per 100,000 live births.We estimated that 12.8 infant deaths per 100,000 live births may be attributable to PM in 2004 , whose r10 exposure, which is equivalent to 53.77 (95% CI = 28.87–84.95) per 100,000 live births [In a study recently conducted in Kuwait, 17 excess death cases may be attributable to PMe births .10 was equal to 167.5 mg/m3 and the threshold used was 70 mg/m3.However, it is difficult to make comparisons with our findings, as their current average of PMThe difference between the result of our study and the previous studies may be related to several reasons.10 exposure among all live births (<1 year).First, there was a difference in the definition of outcome between the studies. The US and Kuwait studies analyzed post-neonatal mortality (between 28 days and 1 year) ,27, MoreThe second difference in the method of assessment of environmental burden of disease is related to the choice of Dose response function. In US study, the environmental assessment were of the two studies based on the only currently available cohort US study . In the 10 levels from the monitoring station data, whereas in our study, we used modeled average annual ambient concentrations of PM10.The third difference between studies is related to environmental data used in the assessment approach. The US study  and Kuwa10 exposure measured at the census block level, in the US study [10 estimated at counties level.Another reason for this study to be different is the spatial level of input data included in the assessment of environmental burden of disease. While in our study we estimated the infant death attributed to PMUS study  and KuwaUS study  attributOur study also revealed that the YLL value from preterm birth complications (independent of air pollution exposure) was about 11,245.8 YLL per 100,000 live births. A recent study conducted in Korea found that about 18,961.2 YLL were related to preterm birth. The Korean estimate is in the same order of magnitude as ours; however, it is not directly comparable because of the high preterm birth rate in Korea, which ranged from 13.5% and 15.7% between 2008 and 2013, compared to Paris where the rate is about two times lower [10 exposure, we estimated that about 4.8% of preterm birth could be attributable to PM10 exposure, while about 1.9% of these infants died . In a US study, Trasande et al. found that 3.32% of preterm births reported in 2010 could be due to PM2.5 (PM2.5 > 8.8μg/m3). They also explained that preterm births also have emotional and psychological consequences for parents and families, which need to be considered in the total benefits assessment [2.5 exposure, with a low concentration cut-off set at 10 μg/m3 and at 4.3 μg/m3, respectively [2·5 concentration to 10 μg/m3 during pregnancy would reduce low birthweight at term by 22% (95% CI = 8–33) [In addition, due to PMsessment . A globaectively . Another = 8–33) .10 exposure. However, the study period was not long enough to count an adequate number of health outcomes per neighborhood socioeconomic class. The statistical power is too low to show a significant increase; for this reason, we cannot rule out the possibility that our observation could be put down to chance.We have shown that both infant deaths and preterm births increased significantly with the level of neighborhood socioeconomic deprivation. We also suggest a possible increase in health burden related to PM10 attributed to each newborn and health data.The main strength of our study is linked to the quality of the input data. The advantage of the health data used in our study is the rate of completeness of the birth certificate, which reached 93% on average, coupled with the large population size, resulting in a small variability of our estimates . The air(i)10 and NO2 exposure during pregnancy and the risk of low birthweight at term PM10 , NO2  [10 and NO2 [10 and NO2 is inversely associated with fetal growth and with weight at birth. The authors revealed that only PM10 exposure levels were positively associated with preterm birth and Small Gestational Age (SGA) [The generalization of this evidence. Many recent studies, including meta-analysis  have con00–1·19) . In Euro and NO2 . In addige (SGA) ). Even s(ii)Evidences for causality. It is also important to recall the existence of uncertainty in any epidemiological studies (detailed above) suggesting (or not) significant association between air pollution exposure and birth outcomes. This uncertainty may affect the causal relationships or the shape of the exposure–response relation. Thus, due to these uncertainties may bias the input data of the Environmental Burden of Disease (EBD) and turn in uncertain assessment of DALYs, which have to be interpreted with caution.One main limitation of our work is the uncertainties related to the assumptions that air pollutant exposure during pregnancy would increase significantly the adverse birth outcome including preterm birth and infant mortality. This hypothesis rise two main weakness:Finally, an additional limitation, also source of uncertainty, is related to the geographic extrapolation of the dose–response function derived from international meta-analysis.We have not attempted to use only one cohort study for a meta-analytic estimate because we considered that differences in study regions do not allow transferring results.3 of PM10 concentrations is equal to 1.05 (95% CI = 1.02–1.07) and [10 concentrations [Then, we hypothesis increased risk of preterm birth related to an increase of 20 µg/m.07) and  risk of trations .However, to our knowledge no European meta-analysis was available to document more appropriate dose–response function to our geographic area.There is clearly a need for further research to define the dose–response function more appropriate to the European shape of the risk function.In addition, estimates of the burden of disease attributable to air pollution due to preterm birth complications and infant death are subject to a broad range of uncertainties . Hereaft-The combinations of multiple sources of input data that have each their own level of uncertainty.-The assumptions choice in the applicability of the exposure or exposure–risk relationship to the country of concern.-The multiple steps structuring the method, probably tend to accumulate the uncertainty.-The few number of available studies assessing the risk of neurodevelopmental impairment among the preterm population, crucial information to estimate the DALYS.-Potential biases in information include, for instance, the exposure–risk relationship derived from epidemiological studies or meta-analysis studies.-Heterogeneity or validity of data sources for instance, the measure of exposure and health data.Therefore, estimates of burden of disease have to be interpreted with caution due to complex assessment and wide of uncertainty that could affect the strength of the precision of estimate and then the formulation of accurate conclusions.Secondly, we used all cause of infant death among all live birth without taking into account of sub-group  or specific causes of death. However, in the present study more appropriate data were not available at the census block level.10 value, ignoring both date and place of birth. The exposure level included in this risk assessment study is equal to the PM10 average in Paris over the study period. This could lead to misclassification of the exposure. It is known that both the number of births and the PM10 concentrations vary widely by season. The number of births is high during the spring and low during the last three months of the year. The three main PM10 emission sources in Paris are road traffic (28%), residential sector (26%) and “construction sites and quarries” (18%) [10 concentrations are lower, due to the slowdown of activities in Paris and the decrease in traffic that is associated with the holiday period. Taking into account the combination of the two sources of seasonality may affect the health consequences attributed to PM10 exposure.Thirdly, we hypothesized that all the newborns were exposed to the same PMs” (18%) . During Finally, despite the fact that the evidence supports increased neonatal morbidity and mortality for males across all gestation periods in comparison to females, we were unable to include sex-specific risk in the model because insufficient data was available. In addition, our study included too low a number of health events, which is why we did not stratify our analysis by time and space. This is also one reason why it was not possible to conduct in-depth analysis by neighborhood socioeconomic level.Moreover, consideration of the dose–response function by socioeconomic class would be necessary to an examination of the well-documented interaction between air pollution and socioeconomic characteristics. However, no such data is available from the literature to perform a meta-analysis assessing a robust dose–response function per socioeconomic deprivation level: It is a call for additional environmental epidemiological studies investigating health consequences of air pollution exposure by socioeconomic class. The number of births is higher in the north-eastern part of Paris, where both air pollution and neighborhood socioeconomic deprivation are higher. Consequently, we expect to find a higher environmental burden of disease in this part of Paris, as has already been found for all-causes mortality .From a public health perspective, with regard to maternal and child practice, individual-level interventions predominate. However, adverse birth outcomes result from a complex combination of individual determinants  and the characteristics of the neighborhood in which the pregnant woman lives . A healthy pregnant woman is more likely to have a healthy newborn; but a neonate born in a healthier place of residence  will tend to have better health trajectories throughout their life. Thus, it is essential to quantify health impacts related to environmental hazards for children at fine spatial scale, if we are to prioritize interventions. The French government is making efforts to provide medical care for pregnant women and to ensure good health for both newborn infants and mothers. However, our study suggests that additional effort is needed if we are to reduce the risk of complications and deaths associated with air pollution exposure among the preterm infants.10 may contribute substantially to the burden of preterm birth and infant death in Paris. Because of widespread exposure to PM10, significant health benefits could be achieved through regulatory interventions aimed at reducing exposure during pregnancy. Furthermore, the differential impact of air pollution by neighborhood socioeconomic level, though not statistically significant in our study, suggests that policymakers should consider the socioeconomic deprivation situation in their regulatory actions, in order to tackle the well-documented and longstanding disparities in terms of preterm births and risk of infant death.Indeed, our estimates suggest that PM


Preterm birth continues to be a major public health problem contributing to 75% of the neonatal mortality worldwide. Low birth weight (LBW) is an important but imperfect surrogate for prematurity when accurate assessment of gestational age is not possible. While there is overlap between preterm birth and LBW newborns, those that are both premature and LBW are at the highest risk of adverse neonatal outcomes. Understanding the epidemiology of preterm birth and LBW is important for prevention and improved care for at risk newborns, but in many countries, data are sparse and incomplete.We conducted data analyses using the Global Network’s (GN) population-based registry of pregnant women and their babies in rural communities in six low- and middle-income countries . We analyzed data from January 2014 to December 2018. Trained study staff enrolled all pregnant women in the study catchment area as early as possible during pregnancy and conducted follow-up visits shortly after delivery and at 42 days after delivery. We analyzed the rates of preterm birth, LBW and the combination of preterm birth and LBW and studied risk factors associated with these outcomes across the GN sites.A total of 272,192 live births were included in the analysis. The overall preterm birth rate was 12.6% . The overall LBW rate was 13.6% (ranging from 2.7% in the Kenyan site to 21.4% in the Pakistani site). The overall rate of both preterm birth and LBW was 5.5% (ranging from 1.2% in the Kenyan site to 11.0% in the Pakistani site). Risk factors associated with preterm birth, LBW and the combination were similar across sites and included nulliparity [RR − 1.27 (95% CI 1.21–1.33)], maternal age under 20 [RR 1.41 (95% CI 1.32–1.49)] years, severe antenatal hemorrhage [RR 5.18 95% CI 4.44–6.04)], hypertensive disorders [RR 2.74 ].Preterm birth, LBW and their combination continue to be common public health problems at some of the GN sites, particularly among young, nulliparous women who have received limited antenatal care services.Trial registration The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475.Trial registration: The identifier of the Maternal and Newborn Health Registry at ClinicalTrials.gov is NCT01073475. Addressing the global burden of preterm birth (before 37 weeks of pregnancy) is critical to reducing neonatal and childhood mortality and to achieving Sustainable Development Goal #3—to ensure healthy lives and to promote well-being for all at all ages . The WorThere have been calls for improved estimates of the burden of preterm birth and LBW, particularly in countries where the data are sparse, incomplete or not population-based . There iEunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Global Network (GN), is a multi-site research network representing partnerships of U.S. and international investigators at rural and semi-urban study sites in Guatemala, India (2 sites:Nagpur and Belgaum), Pakistan, Kenya, Zambia and the Democratic Republic of the Congo. The GN Maternal and Newborn Health Registry (MNHR) has been collecting data on a population-based sample of pregnant women and their babies starting in 2008. The GN has consistently focused on improving the quality of its data [The its data , by focuits data –14 that This study is a secondary data analysis using the GN’s population-based MNHR. The details of the MNHR have been published . The MNHWomen were excluded from the analysis if they did not consent; were lost to follow-up prior to delivery; or if the information on gestational age at birth, vital status or birth weight was missing. Women who died prior to delivery, who had a miscarriage or medical termination of pregnancy, a multiple birth or a stillbirth were also excluded from analysis.Data on the enrolled women were collected by trained health workers at three time points: at enrolment ; at delivery visits; antenatal ultrasound information; date of delivery; gender of the baby; birth weight; mode of delivery; maternal conditions such as obstructed labor, severe antepartum or postpartum hemorrhage, hypertensive disorders, and fetal malpresentation; neonatal status; and place of delivery); at 42 days postpartum  –20.Senior Foreign Investigators (on-site primary investigators) at all sites were trained centrally. They then trained their site’s data collectors prior to collecting study data. Data sources included medical records as well as interviews with the participating women. Data collected on paper were entered into a database at a site-based data management center and transmitted to a central data coordinating center at Research Triangle Institute (RTI), Durham, NC, USA. RTI monitored the data with monthly reports of data quality (completeness and timeliness) and edit reports to identify out of range or inconsistent data that were then addressed by the site staff as well site visits.The primary outcomes for the study were rates of preterm birth, rates of LBW and their combination. Preterm birth rate was defined as the number of neonates delivered before 37 completed weeks of gestation per 100 live births. Gestational age was estimated from the most reliable variable using the following hierarchy of reliability (1) ultrasound, (2) date of LMP, if menses are regular, (3) neonatal examination and (4) gestational age recorded at birth. The LMP was considered reliable if the LMP date given was consistent with other information about the pregnancy , the pregnant woman states that she has a regular menstrual cycle, seems relatively sure of the date and was not using contraception. Ultrasound examinations were conducted either as a part of a GN study wherein standardized training was provided to sonologists or as a part of routine antenatal care. However, availability of ultrasound information any time during pregnancy with information on gestational age varied across sites. Additionally, babies with birthweight between the 99th percentile at 36 week  and 5500 g were classified as term births , 22.Low birth weight (LBW) rate was defined as the number of neonates with a birthweight less than 2,500 g per 100 live births. Birth weight was measured (not estimated) within 6 days of birth in more than 96.8% of neonates in the MNHR .Preterm and LBW rate was defined as the number of neonates both preterm birth and LBW per 100 live births.The Institutional Review Boards and Ethics Research Committees of all participating institutions approved the MNHR. Prior to initiation of the study, agreement to participate was obtained from the communities through sensitization meetings. Individual informed consent for study participation was required from each study participant. No monetary reimbursements were provided to study participants nor to the communities participating in the study. A Data Monitoring Committee appointed by NICHD oversaw and reviewed the study at annual meetings.We computed summary statistics  overall and by GN site for rates of preterm birth, LBW and the combination of preterm and LBW, as well as maternal and neonatal characteristics. Generalized linear models (GLM) with generalized estimating equation (GEE) working correlation structure were used to evaluate the relationship of potential factors and preterm birth, LBW and the combination of preterm birth and LBW to develop point and interval estimates of relative risk associated with these factors. GEE were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals. The risk ratios for the factors associated with preterm birth, LBW, and their combination in the overall study population and by site are represented graphically and also described using multivariable regression analyses separately for preterm birth, LBW and their combination. All analyses were conducted in SAS 9.4 . A two-sided p-value < 0.05 was considered to be statistically significant.From January 2014 to December 2018, a total of 303,883 women were screened. Among these, 272,192 (89.6%) met the inclusion criteria of maternal survival through delivery and a pregnancy resulting in a singleton, live birth with gestational age and birth weight assessed.These mother-baby pairs were analyzed for rates of preterm birth, LBW and the combination of both preterm birth and LBW Fig. . For thiAs shown in Table Overall, 31% of the women were nulliparous, ranging from 17% in the Pakistani site to 50% in the Nagpur site. During antenatal period, more than 94% of the women received at least any one of iron, vitamins or calcium in all sites, except in the Pakistani site where only 82% had received one or more of these supplements. A similar pattern was seen with administration of tetanus toxoid .Overall, 60% of the women had four or more antenatal care (ANC) visits, with the Pakistani site having only 40% of women who had at least four ANC visits. Maternal hypertensive disorders were reported to be more common in the Asian and Guatemalan sites and lower in the African sites.Severe antepartum hemorrhage was less than 0.6% in all sites except the Pakistani site (1.5%) and fetal malpresentation was 0.7% or less in the African sites, but between 1.6% and 2.9% in the Asian and Guatemalan sites.Figure Figure As shown in Fig. Figure Figure However, the effect size of the antenatal care, antepartum hemorrhage and hypertensive disorder risk factors were higher than for preterm birth or LBW alone  was associated only with LBW in the Nagpur site and not associated with preterm at either of the sites. Moderate to severe anemia (< 10 g/dL) was associated with preterm birth, LBW, and the combination of preterm birth and LBW when data from the two Indian sites were combined.Maternal BMI was available in all sites except the Kenya site. BMI < 18.5 kg/mThe Global Network’s population-based estimate of the preterm birth rate was 12.6% with the highest rates in the Pakistani and the DRC sites and the lowest rates (< 10%) in the Indian and Kenyan sites. LBW rates were 13.6% but showed a different pattern with the highest rates in the Asian and Guatemalan sites and the lowest rates in the African sites. The combination of preterm birth and LBW was highest in the Pakistani site (11%) and lowest in the Kenyan site (1.2%).Our rural and semi-urban population rates for preterm birth are similar to country-wide estimates in previously reported studies –28. HoweOur estimates of LBW are slightly lower, but within range of recent global estimates for LBW in 2015 (14.6%—uncertainty range 12.4–17.1%) . To our 2 and its association with LBW [Risk factors for prematurity, LBW and their combination varied by GN site. Therefore, the antenatal factors that are associated with these neonatal conditions may be monitored according to their region. The African sites had higher rates of preterm birth in the nulliparous women, whereas parity was not associated with preterm birth in the other GN sites. This was perhaps due to the higher proportion of women in Africa being < 20 years of age and likely to have their first pregnancy at younger ages , 37. Thewith LBW . Moderatwith LBW –20.Another interesting observation from this study was the association of gender of the newborn with preterm birth and LBW. In African sites, female newborns were more likely to be preterm. Although reported previously the reasons for this finding are unclear , 43. At The strengths of our study are that it is a population-based assessment of the burden of preterm birth and LBW across different LMIC community sites and their risk factors that differ by site indicating that further exploration of association of these risk factors may help to tailor public health strategies. The GN uses uniform and rigorous criteria across sites for assessment of gestational age, increasingly based on ultrasound dating (particularly first trimester) to improve precision of estimates of preterm birth rates. The GN has also focused on accurate estimation of measured birth weight within 6 days of birth in approximately 99% of neonates, to avoid rounding errors and delayed reporting of birth weight . MissingLimitations of the study include the population under study – it is not countrywide, because it is based on access to a rural and semi-urban population. Another limitation is that while estimation of gestational age and therefore preterm birth rates are improving, they are not yet optimal.LMP may not be a reliable indicator in this population due to recall bias and inability to remember the exact LMP by less educated individuals. Even when the LMP is known, there is a risk for potential bias as the estimation of LMP is based on the assumption of a uniform 28-day cycle with ovulation on day 14 of that cycle, both of which may not necessarily be true, especially if contraceptives have been used before conception –46. TherAdditionally, the association of plausible risk factors like socio-economic status, income, history or previous preterm as well as modifiable risk factors should be accounted for in the future research.Rates of preterm births, LBWs and their combination remain high at the GN sites. Prominent risk factors that were similar across sites included nulliparity, maternal age under 20 years, less than 4 antenatal care visits, severe antenatal hemorrhage, and hypertensive disease.While all pregnancies need care and consideration to prevent preterm births, the younger nulliparous women who may have received limited access to ANC services and so are at higher risk for preterm births need more attention to prevent prematurity and LBW.


Birth defects prevalence may vary seasonally, but previous studies have focused on a few commonly occurring phenotypes. We performed a phenome-wide association study (PheWAS) in order to evaluate the associations between season of conception and a broad range of birth defects. Date of conception was estimated for all livebirths and birth defect cases in Texas from 1999–2015 using data from vital records, provided by the Texas Department of State Health Services Center for Health Statistics. Birth defects diagnoses were obtained from the Texas Birth Defects Registry, a statewide, active surveillance system. We estimated prevalence ratios (PRs) for phenotypes with ≥50 cases according to conception in spring (March-May), summer (June–August) or fall (September–November) relative to winter (December–February), using Poisson regression. Season of conception was associated with 5% of birth defects studied in models adjusted for maternal age, education, race/ethnicity, and number of previous livebirths. Specifically, summer conception was associated with any monitored birth defect  and five specific phenotypes, most notably Hirschsprung disease . These findings suggest that seasonally variable exposures influence the development of several birth defects and may assist in identifying novel environmental risk factors. Birth defects are health problems or abnormal physical changes that can affect any part of the body . Relatively common birth defects include structural defects such as neural tube defects and congenital heart disease, as well as chromosomal anomalies such as trisomy 21  . In the As maternal diet, exposure to infectious agents, and ambient temperature vary throughout the year, season of conception can serve as a proxy for these factors and could provide new insights into the etiologies of birth defects overall, as well as specific phenotypes. A handful of studies have demonstrated that birth defects, including congenital heart disease, cleft lip and palate, and lower limb reductions ,11,12, sPopulation-based birth defect registries ascertain the occurrence of birth defects in a defined geographic area for all pregnancies that last longer than a specific duration . Importantly, these data can be linked with demographic and exposure data to evaluate associations between these factors and the prevalence of birth defects . Using tOur analysis was focused on all infants and fetuses with a definite diagnosis of any structural or chromosomal birth defect, regardless of pregnancy outcome that was recorded by the TBDR from deliveries in 1 January 1999 through 31 December 2015. The TBDR is a population-based, active surveillance system that ascertains cases from multiple sources, including birth and fetal death certificates, and records from hospitals and other facilities where affected children are born or treated. This information is abstracted into case records, which are subject to review by registry staff. TBDR records are linked to birth certificates and fetal death certificates, resulting in >95% of cases being linked to their vital record. Diagnoses flagged as “possible” or “probable” based on qualifiers found in the medical record (approximately 4%) were excluded from our analyses. The TBDR classifies birth defects using Centers for Disease Control (CDC)-modified British Paediatric Association (BPA) 6-digit codes. The original 6-digit codes were collapsed to the first four digits for comparability to the International Classification of Disease, Ninth Revision (ICD-9). These are referred to as BPA4 codes. Exceptions to this include: spina bifida ; cleft lip alone (749.1) and cleft lip with cleft palate (749.2), which were both assigned 749.1, and cleft lip with or without cleft palate; omphalocele (756.700) which was assigned 756.70; and gastroschisis (756.710), which was assigned 756.71. In addition, a BPA4 code of 888.8 was created to reflect the presence of any monitored birth defect in a case. Cases with two or more of the same BPA4 code were de-duplicated to ensure that they had a maximum of one of each code. All livebirths in Texas for the same time period between 1 January 1999 and 31 December 2015 are included in this study for birth prevalence denominators.From birth and fetal death certificates, data was obtained on infant’s sex, maternal age, maternal race/ethnicity, maternal education, number of previous livebirths, and estimated date of conception (EDC). Maternal age was grouped into six categories . Maternal race/ethnicity was classified as Hispanic, non-Hispanic White, non-Hispanic Black, and other. Maternal education was classified as less than high school, high school, or greater than high school and number of previous livebirths were grouped into four categories . EDC was calculated based on last menstrual period (LMP) and the clinical estimate of gestational age. If both LMP and estimate of gestational age were present, LMP took precedence, and if neither variable was available, EDC was set to missing.This study was approved by the Baylor College of Medicine and Texas Department of State Health Services Institutional Review Boards (IRB), IRB numbers H-31777 and 18-046, respectively, and performed in accordance with the principles of the Declaration of Helsinki. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [The distributions of maternal characteristics among cases and livebirths were summarized using counts and percentages. A season of conception  variable based on the EDC and on the temperature cycle was created. We adhered to meteorological and climatological recommendations and classified December, January, and February as winter months; March, April, and May as spring months; June, July, and August as summer months; and September, October, and November as fall months . Birth pOnly those BPA4-coded structural birth defects  with ≥50 total cases were included in the PheWAS. We computed crude and multivariable Poisson models to estimate the prevalence ratio (PR) and 95% confidence interval (CI) for the index birth defect among offspring by season of conception as a categorical variable, with winter as the referent. We additionally computed models for any monitored birth defect in offspring based on month of conception, with January as the referent. All multivariable models were adjusted for maternal age, race/ethnicity, education, and number of previous livebirths.p < 3.55 × 10−4. This was derived by dividing the desired family-wise error rate of α = 0.05 by the number of association tests (n = 141) to be performed. While season of conception was associated with the prevalence of any monitored birth defect at this threshold, no individual birth defect was significant. Consequently, we evaluated their statistical significance at a nominal p-value of 0.05. The two stage modeling approach reduces the possibility of Type I errors, as an association observed in the discovery partition must then be independently validated in the replication partition. Birth defects that were associated with ≥1 season of conception in the discovery partition were validated in the replication partition. A season-anomaly association was declared statistically significant if they were associated at p < 0.05 in multivariable models and showed the same direction of effect in both partitions. For these birth defects, we present PRs and 95% CIs estimated in the pooled dataset. Analyses were performed in R v3.6.2 .During the period of 1999–2015, there were 6,543,397 livebirths and 964,054 birth defects diagnosed. p < 3.55 × 10−4 and with 34 specific birth defects at p < 0.05 , scant data are available for many anomalies ,19,20,21A number of epidemiological studies have investigated the role of seasonal variation in the prevalence of birth defects. However, these studies have largely focused on a few common birth defects. One of the largest studies to date investigated 42 birth defects across body systems by season of conception using four different statistical tests . SpecifiSiffel et al. examined the prevalence of nine birth defect groups, including anencephaly, spina bifida, total NTDs, cleft palate, and anomalies of the pulmonary and aortic valve, among children born to residents of Atlanta from 1978–2001 . The autThis study found significantly increased prevalence of birth defects for children conceived in the spring and summer. In Texas, temperatures typically reach 90° F in May and can exceed 100° F by August . High teThere are additional seasonal exposures that may contribute to birth defects. For example, there is some evidence that maternal diet and exposure to infectious agents vary seasonally ,29,30,31This study has several key strengths. The large sample size allowed us to investigate the associations between season of conception and a broad range of individual birth defects, which has not been possible in previous studies. Because analyses were performed in an unselected, racially, and ethnically diverse population of Texas women, we anticipate that our findings will be generalizable to the general US population. Another strength is that season of conception was evaluated rather than season of birth. The early weeks of pregnancy are a critical developmental period and the use of birth month may lead to misclassification as it does not account for gestational length .A limitation of this study was the use of vital record data for estimating date of conception using LMP and clinical estimate of gestational age. We did not directly measure certain exposures that we hypothesize may underlie seasonal variation in the prevalence of birth defects . This may lead to non-differential misclassification and could bias our results towards the null. More comprehensive assessment of these exposures may result in the detection of stronger associations. Additionally, information not ascertained as part of birth records  could not be adequately accounted for in our assessment. Finally, another limitation of the study is that we aggregated some related birth defects based on BPA4 prefixes, for example, cleft lip alone and cleft lip with cleft palate. This could obscure patterns that are specific to one or the other. However, it is justifiable given that, in many cases, these phenotypes likely have shared etiologies.Our findings suggest that a number of birth defects are associated with the season of conception. These findings offer clues to critical developmental periods and exposures . This argues for additional research into putative teratogens that vary by season. As this study is one of the first to investigate a comprehensive range of specific birth defects, it is an important advance in our understanding of how timing of conception is associated with birth defects. Our findings may help inform the search for novel risk factors as well as prevention and surveillance efforts.


The electric eel is a unique species that has evolved three electric organs. Since the 1950s, electric eels have generally been assumed to use these three organs to generate two forms of electric organ discharge (EOD): high-voltage EOD for predation and defense and low-voltage EOD for electrolocation and communication. However, why electric eels evolved three electric organs to generate two forms of EOD and how these three organs work together to generate these two forms of EOD have not been clear until now. Here, we present the third form of independent EOD of electric eels: middle-voltage EOD. We suggest that every form of EOD is generated by one electric organ independently and reveal the typical discharge order of the three electric organs. We also discuss hybrid EODs, which are combinations of these three independent EODs. This new finding indicates that the electric eel discharge behavior and physiology and the evolutionary purpose of the three electric organs are more complex than previously assumed. The purpose of the middle-voltage EOD still requires clarification. This special force of “electricity” has attracted the attention of scientists since the early stage of the development of science3: Williamson and Walsh3, Von Humboldt3, and Faraday4 used electric eels as electricity sources in experiments. The electricity utilized by these scientists is currently known as high-voltage electric organ discharge (EOD), which can reach at most 860 V according to recent research5. Biologists Hunter6 and Darwin7 dissected and studied the electric eel. Hunter6 reported on the electric eel electric organs in 1775 and found that these eels have two separate electric organs. Sachs8 found the third electric organ in 1877. Therefore, to date three pairs of electric organs of electric eels have been described in Electrophorus, and these are known as the Hunter’s organ, the main organ and the Sachs’ organ13. Coates et al.14 reported that electric eels can generate a second form of EOD, i.e., low-voltage EOD, in 1937. In 1958, Lissmann15 found that weak electric fish use low-voltage EOD for electrolocation and communication, thus revealing the function of the gymnotiform low-voltage EOD. Catania16 reported that electric eels emit three distinct types of EOD: (i) low-voltage pulses for sensing their environment, (ii) pairs and triplets of high-voltage EODs given off periodically while hunting in complex environments, and (iii) high-frequency volleys of high-voltage pulses during prey capture or defense. Although Catania classified EODs into three types, both type 2 and type 3 EODs are high-voltage EODs. From the voltage amplitude point of view, two types of EOD have been found: high-voltage EOD for predation and defense and low-voltage EOD for navigation and communication. Since the 1930s, electric eels have been assumed to control these three pairs of organs to generate the above two forms of EOD, with many studies related to electric eel discharge behavior and physiology being based on this assumption16.Humans have known of the special ability of electric eels to stun prey and people since ancient times11 and Crampton17 described that high-voltage EOD was generated by the main organ and the anterior portion of Hunter’s organ, while low-voltage EOD was generated by Sachs’ organ and the posterior portion of Hunter’s organ. Gotter et al.18, Sillar et al.19 and Souza et al.20 described that high-voltage EOD was generated by the main organ, while low-voltage EOD was generated by Sachs’ organ and Hunter’s organ. The key point is that the discharge mode and function of Hunter’s organ are not clear, even though this organ was found in 17756.However, this assumption has two problems: (1) Why did electric eels evolve three separate electric organs to generate two forms of EOD? (2) How do these three electric organs work together to generate these two forms of EOD? Problem 1 has yet to be solved, but some conflicting descriptions regarding Problem 2 exist in different papers: Traeger et al.By precisely measuring the voltage waveform and space distribution along an electric eel’s body, we found that electric eels generate three independent forms of EOD instead of just two, and each EOD voltage space distribution matched one electric organ’s shape and position: The low-voltage EOD space distribution matched the shape and position of Sachs’ organ. The high-voltage EOD space distribution matched the shape and position of the main organ. The third EOD form, which we define as middle-voltage EOD, has an amplitude that is approximately 2.4 times that of low-voltage EOD and 1/5 that of high-voltage EOD and a voltage space distribution along the body of an electric eel that matches the shape and position of Hunter’s organ. This observation indicates that electric eels use three pairs of electric organs to generate three forms of EOD independently. We also found some irregular EOD waveform, and they can be explained as simply combinations of low-voltage EOD, middle-voltage EOD and high-voltage EOD. This conclusion reveals that the electric eel discharge behavior and physiology are more complex than previously assumed. However, the purpose of the middle-voltage EOD and why electric eels evolved Hunter’s organ still require clarification.Electrophoruselectricus and placed it into a 50 × 32 × 35 cm (L × W × H) glass tank. We then designed a 48 × 36 cm (L × H) acrylic board, which was used to mount the voltage-measuring electrodes. We employed 33 electrodes made of nickel-titanium alloy, as shown in Fig. We experimented on a 48 cm long We used a glass rod to touch the electric eel’s head to evoke discharge and a computer to record all 32 electrode voltage waveforms. Figure We first analyzed the low-voltage EOD waveform at 3.518 s, as shown in Fig. The blue line is the waveform 0.32 ms after the pulse peak instant, and the red line is the waveform 0.48 ms after the pulse peak instant. From these three lines, we can find that all 33 electrode voltages reached their maximum value at the same time and dropped synchronously, which means that no voltage phase delay occurs along the electric eel’s body within our measurement accuracy. Supplementary Movie We dissected this eel. Figure We analyzed the high-voltage EOD at 12.64 s, as shown in Fig. The high-voltage EOD negative pole and positive pole positions matched the main organ’s position, as shown by the green region of Fig. 21, is an underrepresentation of the maximum voltage of the high-voltage EODs and low-voltage EODs, measured between the positions of the negative and positive poles. Measuring the voltage between the two ends of the electric organ will yield a more precise result.Compared the low-voltage EOD with the high-voltage EOD, we found that their waveforms in the time domain are very similar, except for the amplitude difference, as Fig. We found that some EOD voltages are different from the low-voltage EOD and high-voltage EOD, as shown in Fig. The maximum voltage of the magenta line reaches 56 V, which is 2.4 times that of the low-voltage EOD and 1/5 that of the high-voltage EOD. This EOD negative pole is the same as the low-voltage EOD, but the positive pole is the same as the high-voltage EOD. This EOD voltage space distribution waveform is similar to a straight line, different from the low-voltage EOD convex waveform in Fig. The middle-voltage EOD negative pole and positive pole matched the position of Hunter’s organ, as shown by the purple region of Fig. According to circuit theory, these three EODs have different voltages; if two or three of them discharge at the same time, a loop current will flow inside the electric eel body. This current will increase the voltage of the lower EOD but decrease the voltage of the higher EOD, harming the EOD normal function. However, we found some irregular EOD waveform, they can be explained only as the discharging of two or three electric organs, as shown in Fig. The pulse waveform in Fig. Although the middle-voltage EODs were easily recorded, and frequently generated, they have never previously been treated as an independent EOD type. According to the description above, we use the joint spatiotemporal analysis method: we use the EOD waveform voltage amplitude (time domain) as shown in Fig. The amplitude difference between the middle-voltage EOD and the low-voltage EOD is not as apparent as the difference between the high-voltage EOD and the low-voltage EOD, as shown in Fig. The middle-voltage EOD always occurs once between a low-voltage EOD and a high-voltage EOD. Figure For these three basic EOD voltage amplitudes, based on the 45 s data of the 48 cm eel, the minimum value of the low-voltage EOD is 22.8 V, the maximum value of the low-voltage EOD is 25.8 V, and the difference is approximately 12%. The minimum value of the middle-voltage EOD is 38.5 V, the maximum value of the middle-voltage EOD is 56.5 V, and the difference is approximately 32%. The minimum value of the high-voltage EOD is 210 V, the maximum value of the high-voltage EOD is 279 V, and the difference is approximately 33%. The hybrid EODs voltage change from 52.9 to 212.2 V. The minimum value of the middle-voltage EOD is approximately 1.5 times the maximum value of the low-voltage EOD, and the minimum value of the high-voltage EOD is approximately 2.4 times the maximum value of the middle-voltage EOD.When checking all the data in Fig. We have also recoded the discharge of a 22 cm eel, a 42 cm eel and a 53 cm eel, all the data are summarized in Table Electrophoruselectricus. These results also show if an eel wants to launch a high-voltage EOD series after low-voltage EOD electrolocation, a 90% possibility that it will launch a middle voltage before the high-voltage EOD exists, and there is some possibility that the high-voltage EOD will conflict with the middle-voltage EOD. However, all of our data were recorded in an unnatural environment. The electric eel was placed in a narrow tank where it could not swim and move. We used a glass rod to touch its head, which threatened it.These results show that the middle-voltage EODs are common among all these 16 reported electric eel use pairs and triplet high-voltage EODs in complicated environments to stimulate hidden prey uncontrolled movement, which can enable eels find hidden living prey. Is middle-voltage EOD used to stimulate hidden prey? We do not believe so: (1) The amplitude of the middle voltage is 38.5–56.5 V in our experiment, and this voltage will attenuate greatly in deep water and at some distance. (2) The middle-voltage EOD occurs only one time after low-voltage EOD and before high-voltage EOD, and its duration is less than 2 ms. Thus, the amplitude and quantity are not sufficient to stimulate the prey to respond. Middle-voltage EOD occurs only once after a low-voltage EOD and before a high-voltage EOD, where it works as a “bridge” to “connect” the low-voltage EOD and high-voltage EOD. Even though sometimes no middle-voltage EOD exists between the low-voltage EOD and high-voltage EOD, we suppose that the middle-voltage EOD is used for coordinating the low-voltage EOD and high-voltage EOD, adjusting the electric eel body internal environment, such as balancing the charge inside. If used for any external function such as hunting or electrolocation, no reason exists for it to occur only one time and for less than 2 ms. More research is needed to reveal the function of middle-voltage EOD and the reason why electric eels evolved Hunter’s organ.CataniaElectrophoruselectricus of 48 cm in length was purchased from a commercial fish supplier and housed in an 80 × 40 × 40 cm (L × W × H) glass tank with fresh water, and the water temperature was maintained between 20 and 30 °C. The eel was fed fish.The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the National Research Council. The experimental protocol was approved by the animal care and use committee of North China Electric Power University. To record the EOD, the electric eel was transferred to a 50 × 32 × 35 cm (L × W × H) customized Plexiglas aquarium. The EOD was recorded by 33 nickel-titanium alloy electrodes  in the water, connected at their exposed tips to wire leads connected to the voltage divide circuit. We used a 100 K ohm/3.3 K ohm resistor serially connected to divide the electric eel EOD signal into ± 10 V spans. The output of the voltage divide circuit was connected to the input of the AD converter. We used two USB3103 AD converters, which have 16 channels each, and made them work synchronously to record 32 channel signals. Every channel has a 16-bit accuracy with a sample rate of 31.25 ksps. The 33 electrodes, voltage divider circuit, and AD converter module were all mounted on a 48 × 36 cm acrylic board. This board was used to push the electric eel to one side of the glass tank to ensure that all the electrodes were connected to its body well. Fresh water was added to the glass tank to a depth of 4 cm to ensure that every electrode recorded some voltage. The water temperature was 25–26 °C. The conductivity was 250 μS/cm. A glass rod was used to touch the electric eel’s head to evoke discharge, and all the sampling data were transferred to a Lenovo P50s laptop by a USB cable.Supplementary Movie 1.Supplementary Movie 2.Supplementary Movie 3.Supplementary Movie 4.Supplementary Movie 5.