Human milk-based fortifiers have shown a protective effect on major complications for very low birth weight newborns. The current study aimed to estimate the cost-effectiveness of an exclusive human milk diet (EHMD) compared to the current approach using cow’s milk-based fortifiers in very low birth weight newborns.A decision tree model using the health states of necrotising enterocolitis (NEC), sepsis, NEC + sepsis and no complication was used to calculate the cost-effectiveness of an EHMD. For each health state, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (RoP) and neurodevelopmental problems were included as possible complications; additionally, short-bowel syndrome (SBS) was included as a complication for surgical treatment of NEC. The model was stratified into birth weight categories. Costs for inpatient treatment and long-term consequences were considered from a third party payer perspective for the reference year 2017. Deterministic and probabilistic sensitivity analyses were performed, including a societal perspective, discounting rate and all input parameter-values.In the base case, the EHMD was estimated to be cost-effective compared to the current nutrition for very low birth weight newborns with an incremental cost-effectiveness ratio (ICER) of €28,325 per Life-Year-Gained (LYG). From a societal perspective, the ICER is €27,494/LYG using a friction cost approach and €16,112/LYG using a human capital approach. Deterministic sensitivity analyses demonstrated that the estimate was robust against changes in the input parameters and probabilistic sensitivity analysis suggested that the probability EHMD was cost-effective at a threshold of €45,790/LYG was 94.8 percent.Adopting EHMD as the standard approach to nutrition is a cost-effective intervention for very low birth weight newborns in Germany. New-borns with very low birth weight show an increased risk of necrotising enterocolitis (NEC) , systemiThe feeding of very low birth weight babies seems to play a major role in the risk of developing complications and mother’s milk seems to have a protecting effect against these complications compared to infant formula –14. HoweIn addition to the significant complications of a very low birth weight birth, the health care utilization of those babies also comes with high economic costs. Taking newborns with a birth weight of 750-999g as an example, the immediate inpatient care in neonatal intensive care units or regular care units including no significant operating procedure has a mean cost of €72,702 in Germany and increases to €121,594 for a birth weight below 600g . The lonThe aim of the current paper is to estimate the cost-effectiveness of an EHMD compared to the current nutritional practice for very low birth weight infants in Germany, taking into account short-term and long-term outcomes, as measured by life-years gained, and costs.The model has been constructed as a decision tree as depicted in The model population consists of the average, yearly number of very low birth weight newborns in Germany from the years 2012 to 2016 –34. The An EHMD is administered dependent on the birth weight of the infant following the feeding protocol of the Texas Children’s Hospital (TCH) in the base case . In geneThe efficacy of EHMD has been taken from three different studies showing a relative risk (RR) of 40.0% [95% CI 30.4%–52.8%] against NEC , 38, 45.The cost of an EHMD was dependent on the weight-specific feeding scheme and is calculated with a price of €6 per ml for the fortifier. In the base case analysis it was assumed that the fortifier is added to the milk produced by the mother. The overall EHMD costs amount to €6,812 per person over all weight groups, i.e. the cost are €13,015 for infants <500g, €11,895 for 500-749g, €9,106 for 750-999g, €5,208 for 1,000–1,249g and €3,246 for the birth weight group of 1,250-1499g. Using milk from a donor milk bank at a price of €65 per litre  was explored as a scenario in the sensitivity analyses. For the standard care strategy, no additional costs were incorporated into the model, as they were already included in the diagnosis-related groups (DRGs). Two additional feeding scenarios  have been used as the lower and upper bound for the costs of an EHMD, but assuming the same degree of effectiveness.The costs for each health state were calculated via a price-resources framework for inpatient stays. The length of stay (LOS) was been extracted for each ICD code from the database of the Federal Statistical Office covering the period 2006 and 2016  and the For the societal perspective, indirect costs were calculated using the human capital approach, including the forgone productivity due to death or disability measured by the discounted life-time earnings of a newborn and the productivity loss of one parent during the inpatient stay. A scenario of the friction cost approach has also been applied. Using this approach, one parent staying with the newborn has a productivity loss for the friction period of 92 days . The refThe base case analysis was conducted from a third-party payer (TPP) perspective with 3% discount rates on costs and LYG using the TCH (+6) feeding scheme for EHMD and the friction cost approach as recommended by German guidelines . DiscounIn the base case analysis, assuming the Texas Children’s Hospital+6 feeding strategy, a third party payer (TPP) perspective and no use of donor milk, the cost-effectiveness of EHMD is €35,464 per LYG. Using the friction cost approach, the corresponding value for the societal perspective is €33,991/LYG. The cost-effectiveness from a societal perspective using the human capital approach improves to €9,681/LYG. The sub-group analysis for the different birth weight groups reveals an association between lower birth weight and a more favourable ICER. The ICER is €16,272/LYG in the base case for infants in the “<500g” group and increases to €70,910/LYG in the category “1250-1499g”. The cost-effectiveness for the clinical study population based on an EHMD (750g to 1249g) is €34,016/LYG from a TPP perspective and €32,061/LYG or €8,183/LYG from a societal perspective using the friction cost or the human capital approach. Detailed results for the base case can be found in The deterministic sensitivity analyses  reveal the probability for death due to sepsis and the efficacy with regards to mortality reduction to be the most influential parameters on the ICER value. Setting the sepsis mortality to the lower bound of 12.3% yields an ICER of €43,703/LYG, and €29,043/LYG for the upper bound of 23.6%. However, changing the RR for the health state-specific mortality yields ICERs of €44,902 and €30,584/LYG for the lower (0.90) and upper bounds (0.57), respectively. As can be seen in In the scenario analyses, further changes to the model assumptions have been explored. Firstly, assuming the use of donor milk instead of mothers own milk for an EHMD, slightly increases the ICER to €35,867/LYG from a TPP perspective and to €34,394/LYG from a societal perspective. Secondly, the costs of the formula in the current feeding have explicitly been included in the model to reflect the replacement of currently used formula by an EHMD. Including costs of the current formula at a price of €20 per 200g , the ICER would decrease to €35,091/LYG from a TPP perspective and to €33,618/LYG from a societal perspective with the friction approach. If no protective effect of an EHMD against neurological impairments and cerebral palsy was assumed, the cost-effectiveness increased to €43,459/LYG from a TPP perspective .Furthermore, several break-even analyses were conducted to evaluate the influence of key parameters beyond their statistical uncertainty had on the ICER. As the probability of NEC was from a non-German source, the NEC probability has been lowered below the lower 95% CI of 4.9 percent down to zero. The ICER for this scenario was €52,762/LYG, while increasing the probability of NEC leads to improvements of the base case ICER. The probability of sepsis would need to be set to 5.5 percent (lower 95% CI in the base case: 12.1 percent) for the ICER to reach the WTP threshold of €45,790. The costs of an EHMD could be increased by approximately 25%  above the base case costs before the cost-effectiveness would be above the WTP threshold.The result of the PSA for 1,000 model runs is shown in Based on these model iterations of the PSA, the population EVPI has been calculated and the results are shown in The results of this modelling study need to be interpreted in the light of several limitations. First of all, the study population of the clinical studies used for the EHMD efficacy is from the US and does not entirely match the German model population in terms of clinical complications and birth weight. The results for the birth weight subgroups from the clinical studies was very similar to the overall cost-effectiveness , but it remains unclear if the effectiveness estimates can be transferred to infants with birth weights below 750g or above 1,250g. The transferability of our results is also limited with regard to other countries due to the specific NEC rates, the German reimbursement scheme for inpatient costs and the cost of human milk and fortifiers in Germany. Secondly, the control group in the clinical studies received mother’s milk with a bovine milk-based fortifier. As feeding protocols may vary between hospitals, it is unclear if all very low birth weight infants in Germany currently receive the exact same feeding as the control group of the studies considered. However, the current guidelines only mention bovine-based fortifiers Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't KnowReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: Line 34 : Please provide the expansion of LYG and ICER hereLine 48 : need to be BPD instead of BDPLine 108-109 : what is meant by the statement"in cost scenario for EHMD a ratio of 30/70 is assumed using Prolact+8 (with a ratio of 40/60)". Why is it assumed as 30/70 when its 40/60Line 115-116 : If there are no available data for the effectiveness of EHMD on neurological sequelae, based on what criteria was the RR of 0.90 assumedLine 136-138 : What was the process used to calculate the LOS data based on birth weight? What is the adjustment factor and how was it arrived at?Line 160 : Put WTP in parenthesis here so that the reader can recognize what it stands for later in the manuscript.Line 177 - its showing both Table 2Table 1. which one is it? Table 2?Table 2 : Please add "for the base case" in the legend.Reviewer #2: The feeding of very low birth weight babies seems to play a major role in the risk of developing complications. Scholz and Greiner implemented a decision-tree approach to investigate the cost-effectiveness between human milk-based fortifiers and cos’s milk-based fortifiers in very low birth weight new-borns. They concluded that an exclusive human milk diet is a cost-effective intervention.1. Table or Figure should be self-explained. The abbreviation should be noted, e.g. what are DSA, PSA and so on.2. Authors mentioned that the health state specific probabilities of complication were either directly calculated or estimated from other studies. It would be good to indicate which is from direct calculation and which is estimated from other studies in the presentation of results/tables.3. Some estimates, e.g. health state specific probabilities, the efficacy of EHMD and so on, were not directly calculated based on the sample but estimated from other studies. For those from other studies, please comment on how compatible or generalizable to the German population.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  4 Nov 2019Reviewer #1: Thank you very much for taking the time to review our paper and thank you for your constructive feedback. We are grateful you even specified the lines where changes need to be made. Please see below our responses on your comments, which where all included in the new version of the manuscript.Line 34 : Please provide the expansion of LYG and ICER hereThank you very much, we added the expansion of LYG and ICER.Line 48 : need to be BPD instead of BDPThank you for noticing this. The typo has been corrected.Line 108-109 : what is meant by the statement"in cost scenario for EHMD a ratio of 30/70 is assumed using Prolact+8 (with a ratio of 40/60)". Why is it assumed as 30/70 when its 40/60Sorry for this relict of a previous version. The correct ratio is 40/60 and the sentence has been changed accordingly. It now reads as follows: “In the lower scenario, Prolact+4 is used with a ratio of 20/80ml and in the high cost scenario for EHMD a ratio of 40/60 is assumed using Prolact+8.”Line 115-116 : If there are no available data for the effectiveness of EHMD on neurological sequelae, based on what criteria was the RR of 0.90 assumedThere is no direct evidence for the effectiveness of EHMD on neurological sequelae as the manifestation of a neurological impairment will only become evident when the children are at around school age. But there are studies suggesting that NEC and sepsis are associated with a higher probability of neurological impairment and reducing NEC and sepsis thus also leads to a reduction in neurological impairments (please see references below). We therefore included – from our perspective – a conservative value of 0.90 for neurological sequelae. Please let us know if this acceptable in your opinion.Roze et al. 2011 Functional Impairments at School Age of Children With Necrotizing Enterocolitis or Spontaneous Intestinal Perforation, Pediatric Research 70(6):619-625.van der Ree et al. 2011, Functional impairments at school age of preterm born children with late-onset sepsis, Early Human Development 87:821-826.Ehrenkranz et al. 2006, Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants, Pediatrics 117(4):1253-1261.Line 136-138 : What was the process used to calculate the LOS data based on birth weight? What is the adjustment factor and how was it arrived at?Unfortunately, there is no data source available that would allow estimating the LOS for the different conditions  stratified by age. However, there are two different data sources available that give information about the marginal distributions of the LOS by birth weight and the LOS for each of the conditions, respectively. We used the data source giving the LOS by birth weight to calculate the ratio of the LOS for each birth weight category, compared to the LOS for all new-borns with a birth weight between 500g and 1499g.The LOS for the different conditions were then multiplied by this factor. We added some more information on the calculation and the sentence now reads as follows: “As the ICD-specific LOS data were not available stratified by birth weight, adjustment factors have been calculated from another German data source on LOS of very low birth weight infants by calculating the ratio of the LOS of the different birth weight categories and the overall LOS of all new-borns with a birth weight between 500g and 1499g.”Line 160 : Put WTP in parenthesis here so that the reader can recognize what it stands for later in the manuscript.The abbreviation WTP for willingness-to-pay has been added.Line 177 - its showing both Table 2Table 1. which one is it? Table 2?Sorry, this seems to be a problem with the automated numbering in Word. We removed all automated fields. It should read as Table 2.Table 2 : Please add "for the base case" in the legend.We amended the table caption as you suggested.Reviewer #2: 1. Table or Figure should be self-explained. The abbreviation should be noted, e.g. what are DSA, PSA and so on.Thank you for this suggestion. We added the explanations of the abbreviations used in the table and figures in the respective captions.2. Authors mentioned that the health state specific probabilities of complication were either directly calculated or estimated from other studies. It would be good to indicate which is from direct calculation and which is estimated from other studies in the presentation of results/tables.Thank you for this comment. We included a sentence in the methods section that states the probabilities which were estimated from other studies. The sentence now reads: “When this was not possible , relative risks have been calculated from studies  and were applied to German datasets to retrieve health state specific complication probabilities.” We also added asterisks to parameters in table 1 for which other studies were used.3. Some estimates, e.g. health state specific probabilities, the efficacy of EHMD and so on, were not directly calculated based on the sample but estimated from other studies. For those from other studies, please comment on how compatible or generalizable to the German population.You are correct, that the transferability of the results from the other studies is limited. We amended the limitations section in the discussion to put more emphasis on this point. The discussion starts as follows:“The results of this modelling study need to be interpreted in the light of several limitations. First of all, the study population of the clinical studies on EHMD efficacy is from the US and does not entirely match the German model population by the clinical complications and birth weight. The results for the sub-groups of the model population corresponding to the birth weights of the clinical studies were very similar to the overall cost-effectiveness , but it remains unclear if the effectiveness estimates can be transferred to new-borns with birth weights below 750g or above 1,250g. The transferability of our results is also limited with regard to other countries due to the specific NEC rates, the German reimbursement scheme for inpatient costs and the cost of human milk and fortifiers in Germany.“AttachmentRebuttal_letter.docxSubmitted filename: Click here for additional data file. 2 Dec 2019An Exclusive Human Milk Diet for Very Low Birth Weight Newborns – a Cost-Effectiveness and EVPI Study for GermanyPONE-D-19-22800R1Dear Dr. Scholz,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact With kind regards,Prem Singh Shekhawat, MDAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: All comments have been addressedReviewer #2: All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response)Reviewer #2: (No Response)**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response)Reviewer #2: (No Response)**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: (No Response)Reviewer #2: (No Response)**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: (No Response)Reviewer #2: (No Response)**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: (No Response)Reviewer #2: (No Response)**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article (If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: NoReviewer #2: No 16 Dec 2019PONE-D-19-22800R1 An Exclusive Human Milk Diet for Very Low Birth Weight Newborns – a Cost-Effectiveness and EVPI Study for Germany Dear Dr. Scholz:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. 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Chronic subdural hematoma (CSDH) is one of the commonest diseases encountered by a neurosurgeon in daily practice. It is however rarely seen in young patients. Congenital arachnoid cysts have been implicated in both traumatic and spontaneous CSDH in young individuals. Optimum treatment strategies to address the CSDH and arachnoid cyst are not very well described. We report a young gentleman who was treated for a CSDH with arachnoid cysts, two months after a mild head injury. The patient was operated with a simple burr hole drainage of hematoma with a drain. He was discharged with no further need to address the arachnoid cyst. CSDH associated with arachnoid cysts can be treated with simple burr hole drainage. Craniotomy, fenestration and cerebrospinal fluid (CSF) diversion should be reserved only as secondary procedures. Chronic subdural hematoma (CSDH) is commonly seen in the elderly and is often attributed to minor inertial brain injury resulting in bridging vein injuries . The conA 21-year-old male had presented to the emergency with the history of one episode of generalized tonic-clonic seizures followed by altered sensorium and repeated episodes of vomiting for one day. His parents also noticed a paucity of limb movements on the right side. Past history revealed that he had sustained a minor head injury following a trivial road traffic accident two months ago, following which he was stable except for an occasional headache. A computed tomography (CT) scan brain was done two weeks after the initial trauma which revealed an incidental left Sylvian Type II arachnoid cyst  was seven (E1V1M5). His pulse rate was 56 bpm and he had features of left uncal herniation. An emergency CT of the brain was done which revealed an acute on CSDH on the left side with bleed into the cyst cavity and a significant midline shift Figure .Emergency surgery was performed and dark machine oil coloured fluid was evacuated through two burr holes. He showed good improvement neurologically post evacuation with complete hematoma evacuation and significant improvement of midline shift on follow up scan Figure . His posThe association of arachnoid cysts with CSDH seems to be more than coincidental. In a large retrospective study of 48,417 patients arachnoid cysts were identified in 661 patients (1.4%) . Parsch In addition, De Oliveira et al.  have sugThe optimal treatment strategy is unclear. Burr hole drainage of the clot without manipulation of the cyst, craniotomy/craniectomy with drainage of the clot and excision/fenestration of the cyst have all yielded similar results. Summary of all the published 169 cases by Wu et al. [Young patients with arachnoid cyst are at a high risk of developing a chronic subdural hematoma following trivial head trauma and should be kept under close observation. Burr hole drainage of the hemorrhage provides a good clinical outcome. The need for surgery for the arachnoid cyst is still unclear. The ideal management would be a burr hole drainage of hematoma. In the case of recurrence reoperation by burr hole drainage may still provide satisfactory results in the majority of cases. Craniotomy should be reserved only for cases which recur after resurgery. Cyst fenestration or excision is rarely required and has not been proved to be more efficacious than evacuation of hematoma in altering the ultimate outcome.


To determine the prevalence of Vitamin D (VitD) deficiency/insufficiency in mothers of preterm neonates less than or equal to 32 weeks of gestation and determine if the current level of VitD supplementation used for preterm neonates is appropriate.th May 2015 to 1st November 2016. Prospective study from 10 Neonatal Intensive Care Unit at the Canberra Hospital. Mothers and their preterm neonates born less than or equal to 32 weeks gestation. Maternal VitD levels were obtained within 3-4 days following delivery. Neonatal VitD levels were obtained in the first 3-4 days of life, at 3-4 weeks of age, and at 6-8 weeks of age. Demographic data and data on VitD intake from parenteral nutrition, enteral feeds, and vitamin supplementation agents were collected. 70 neonates were enrolled into the study. Median gestation was 29 (27-30) weeks and median birth weight 1197 (971.2-1512.5) grams. Median maternal VitD level was 54.5 (36-70.7) nmol/L, median neonatal Vit D level at birth was 57 (42-70) nmol/L. Median Vit D level at 3 weeks and 6 weeks were 63.5 nmol/L (53-80.2) nmol/L and 103 (71.5-144) nmol/L respectively. 22/55 (40%) mothers were VitD deficient/insufficient. 25/70 (36%) neonates were VitD deficient/insufficient at birth. Of those neonates who were VitD deficient/insufficient at birth 5/25(10%) were deficient/insufficient at 6 weeks. The median intake of VitD at 6 weeks was 826.5 (577.5-939.5) IU/day. VitD deficiency/insufficiency in mothers of preterm neonates and in preterm neonates at birth is common. Routine screening of maternal VitD and their preterm neonates along with individualized supplementation regimens in mothers and preterm infants may optimize VitD status and reduce risk of ongoing VitD deficiency/insufficiency. Vitamin D (VitD) deficiency has significant health impacts particularly related to calcium and bone metabolism. Significant calcium deposition in the fetal skeleton occurs in utero during the third trimester; thus preterm infants are at risk of osteopenia , which cMaternal Vit D deficiency has been shown to be detrimental to the fetus with increased risk of intrauterine growth restriction, preeclampsia, gestational diabetes mellitus, and preterm birth, all of which can have significant health impacts on the fetus and neonate , 8. StudStudies have shown 11-19% of neonates in Australia and New Zealand have levels <25nmol/L . A New ZThere is no worldwide consensus on the recommended daily requirements for VitD for preterm infants. In the United States a recommended daily intake for VLBW infants is 200 to 400IU  and the The aims of this study were to determine (1) the prevalence of VitD deficiency in mothers of preterm neonates and (2) if the current level of VitD supplementation is appropriate.th May 2015 to 1st November 2016.This is a prospective cohort study carried out in a single Neonatal Intensive Care Unit (NICU) at The Centenary Hospital for Women and Children, ACT from 10Inclusion criteria were mothers and their preterm neonates born less than or equal to 32 weeks gestation and admitted to the NICU. Neonates were excluded if they had significant chromosomal or congenital anomalies. Mothers and their babies were recruited and consented in the first 72 hours postdelivery. Maternal data collected included whether there was antenatal VitD supplementation, ethnicity and season of birth. Standard variables including sex, gestational age, and weight were recorded.3 was measured in the immediate postnatal period (day 1-4). Enrolled neonates had their 25(OH) D3 levels measured during the first 3 days of life, at 3-4 weeks, and 6-8 weeks of age. Neonatal serum calcium, phosphorus, and alkaline phosphatase were collected at the time of VitD collection. 25(OH) D3 was measured using the Liaison ® 25 OH vitamin D immunoassay. The definitions of VitD deficiency used for this study were deficiency <30nmol/L, insufficiency 30-49nmol/L, and sufficiency ≥ 50nmol/L.Maternal 25(OH) DNeonates were supplemented with VitD as per departmental guidelines - 160IU/day when on TPN with lipids; 800 IU/day from 7 days or when on full feeds from Pentavite; 120IU/100ml preterm formula; 120IU/100ml human milk fortification and 25IU/L in maternal breast milk. The daily amount of VitD supplementation was estimated for the first 8 weeks of life from neonatal fluid and medication charts. This was estimated from the combined intake of pentavite (400IU/0.45ml), TPN with lipids, formula, human milk fortifier, and breast milk. The amount received by each preterm neonate varied throughout their NICU stay and depended on feeding regimen and fluid intake.During the early part of the study period (after 14 patients had had their 6-8 weeks VitD level measured) it was noted that 50% of neonates had VitD levels >150nmol/L, with an average level of 152nmol/L for all subjects at that time point. While there had been no evidence of adverse effects of high VitD levels, the routine supplementation dose of pentavite was reduced from 800 IU to 400 IU daily.Data were stored and analysed using IBM SPSS statistics version 22 . Data will be presented as number and percentage with odds ratio and 95% confidence interval (CI) or median and interquartile ranges.This study was approved by the ACT Health Human Research Ethics Committee.Seventy premature neonates were enrolled in the study. The median (IQR) gestational age was 29 (27-30) weeks and birth weight was 1197.5 (971.2-1512.5) grams. Majority of neonates (70%) were enrolled during the autumn-winter period and Caucasians formed the major ethnic group comprising 71.4% of the cohort with 8.5% of neonates being of Aboriginal descent. Demographic characteristics are shown in Of the 70 neonates enrolled in the study, maternal serum VitD level in the immediate postnatal period was available for 55 mothers, therefore only these were included for analysis of VitD status in mothers. The median (IQR) VitD level at delivery was 54.5 (36-70.7) nmol/L. VitD deficiency was noted in 18.2% of mothers, 21.8% had VitD insufficiency, and 60% had sufficient VitD levels . Thirty 3 and bone markers were available for all 70 neonates within the first 3 days of life. This data was available for 60 neonates at 3-4 weeks and for 49 neonates at 6-8 weeks. The decrease in available results was predominantly due to transfer to other hospitals for convalescent care. The median (IQR) VitD level within the first 3 days of life was 57 (42-70) nmol/L, which increased to 63.5 (53-80.2) nmol/L between 3 and 4 weeks and to 103 (71.5-144) nmol/L between 6 and 8 weeks (25 (OH) D 8 weeks . Serum lThe prevalence of VitD insufficiency at birth was 30%; which decreased to 15% at 3-4 weeks and to 10.2% at 6-8 weeks (p=0.001). Also, a reduction in the prevalence of VitD deficiency was seen from 5.7% at birth to 1.7% at 3-4 weeks to none at 6-8 weeks . OverallLow serum maternal VitD was associated with a higher likelihood of VitD insufficiency/deficiency in neonates at birth (p<0.001) and at 3-4 weeks (p=0.006) but not at 6-8 weeks (p=0.14). The prevalence of VitD insufficiency/deficiency in preterm infants whose mothers did not receive VitD supplementation was 44% as opposed to 37% in infants whose mothers received Vit D supplementation (p=0.60). Thus, there was no difference in neonatal birth VitD levels in relation to maternal supplementation during pregnancy alone. However, there was a strong positive correlation between maternal VitD levels and preterm VitD levels at birth, r=0.622 .Neonates of non-Caucasian descent were more likely to be VitD insufficiency/deficiency compared to Caucasian neonates (65% versus 24% (p=0.002)). However, no association was observed between VitD status and sex, season of birth, gestational age, and birth weight. Comparison of incidence of sepsis and necrotizing enterocolitis with VitD status at birth also showed no significance .Subgroup analysis comparing the prevalence of VitD deficiency amongst premature neonates receiving high dose pentavite (800 IU/day of VitD) against those receiving low dose pentavite (400 IU/day of VitD) showed that, at 6-8 weeks, the prevalence of VitD insufficiency was 7.1% in the high dose group as compared to 11.4% in the low dose group (p=0.65). The median serum VitD level in the high dose group at 3-4 weeks was 61(49.5-100.5) nmol/L, similar to that in the low dose group 64 (53.7-76.7) nmol/L. However, at 6-8 weeks, the high dose group had a higher VitD level [126 (69.2-182.2) nmol/L] compared to the low dose group [96 (73-131) nmol/L], p=0.25. The differences between serum bone markers-calcium, phosphate, and alkaline phosphatase were not statistically different in the high and low dose group .The majority of preterm neonates between 3-4 weeks and 6-8 weeks of age were breast fed, 60% (n=42) and 57.1% (n=44) respectively. The median VitD intake at 3-4 weeks increased from 749.5 (554.2-861) IU/day to 826.5 (577.5-939.5) IU/day at 6-8 weeks (p=0.06). At 3-4weeks the median VitD intake in sufficient group was 761.5 (604.5-866.7) IU/day which was significantly higher as compared to insufficient/deficient group, 618 (197.2-755.7) IU/day (p=0.04). However, at 6-8weeks the median VitD intake in sufficient group as compared to insufficient/deficient group was not statistically significant, p=0.22.This study shows that maternal VitD status has implications on VitD status of preterm neonates at birth and at 3-4 weeks post birth. Our study indicates that current dosing regimens of VitD may not be adequate for some neonates and that VitD levels should be performed on all preterm neonates at 3-4 weeks of life. In addition, VitD levels at birth correlated with those at 3-4 weeks. Hence, we suggest that VitD levels should be performed in all high risk VLBW neonates - those born to non-Caucasians or to mothers with VitD deficiency. Our recommendation of targeting a higher dose of VitD in deficient babies is similar to that suggested by Fort et al .3 less than 50nmol/L [3) [In our cohort maternal VitD level was insufficient/deficient in 40% of mothers, despite the fact that 55% of the mothers were supplemented with VitD. This was slightly higher than in the population study done by Perampalam et al. where 35% of pregnant women had 25(OH) D50nmol/L . This ma50nmol/L , 13, 23.50nmol/L . In non-ol/L [3) . MetanalEpidemiological surveys from Australia and New Zealand have shown that 40-57% of neonates have VitD levels <50nmol/L , 11. TheAt the beginning of our study, high levels of VitD (>150nmol/L) as well as hypercalcemia  was observed in 50% of neonates (7 out of 14 babies) at 6-8 weeks. In view of these results, pentavite supplementation was ceased in all 7 neonates. All these neonates were receiving VitD supplementation at 800IU/day. The amount of breast milk fortification, calcium and phosphate supplementation remained the same both during 800IU/day and 400 IU/day of Vit D supplementation as per our unit protocol. Furthermore, median phosphate and ALKP levels were similar in both the groups suggesting hypercalcemia was due to high Vit D levels rather than hypophosphatemia. High VitD levels can cause increased calcium absorption from the intestines resulting in hypercalcemia and hypercalciuria leading to polyuria, dehydration, poor growth, and extra-skeletal calcification especially nephrocalcinosis. Therefore, reviewing VitD levels in preterm neonates with hypercalcemia on VitD supplementation can become important to guide supplementation dosage. The calcium levels normalized in all 7 babies following cessation of pentavite. As such, we did not perform renal ultrasound prior to discharge for nephrocalcinosis. Levels of serum VitD being high at 6-8 weeks have been reported in studies by Fort et al.  and TergVitD status of preterm infants is entirely dependent on extrinsic supplementation as VitD synthesis from sunlight is lacking. The recommendations for VitD supplementation vary widely between different NICUs' from 400IU to 1000IU , 9 and tThe limitation of our study was that it was not powered to assess clinical outcomes such as sepsis, necrotizing enterocolitis, chronic lung disease, and growth and developmental outcomes. The amount of maternal supplementation of VitD was not documented as this was not part of our study protocol. Also, there was a 30 percent attrition rate in our sample size from enrollment at birth to that at 6-8 weeks secondary to inter hospital transfer.To our knowledge, this study is the first showing a trajectory of vitamin D status at three different time frames in extremely preterm neonates. These results are generalizable to other NICUs, as the cohort of patients is similar to other neonatal intensive care units across Australia and New Zealand, with similar VitD supplementation regimens in parenteral nutrition, vitamin supplementation, and fortification of feeds. Given the significant proportion of preterm neonates that are deficient/insufficient at birth with a proportion still being deficient/insufficient at 3-4 weeks of life, there is a potential role for VitD screening of all preterm neonates at 3-4 weeks of life to ensure adequate VitD supplementation.This study shows that VitD deficiency/insufficiency is common in mothers of preterm neonates and consequently in preterm neonates at birth. Our current supplementation practices ensure that the majority of neonates have sufficient VitD levels at 6-8 weeks of life; however VitD supplementation in mothers and postnatally in preterm infants needs to be individualized so as to normalize the serum VitD level in the mothers during the third trimester as well as in the preterm infants from the first few days of life.


Maternity care has to be available 24 hours a day, seven days a week. It is known that obstetric intervention can influence the time of birth, but no previous analysis at a national level in England has yet investigated in detail the ways in which the day and time of birth varies by onset of labour and mode of giving birth.We linked data from birth registration, birth notification, and Maternity Hospital Episode Statistics and analysed 5,093,615 singleton births in NHS maternity units in England from 2005 to 2014. We used descriptive statistics and negative binomial regression models with harmonic terms to establish how patterns of timing of birth vary by onset of labour, mode of giving birth and gestational age.The timing of birth by time of day and day of the week varies considerably by onset of labour and mode of birth. Spontaneous births after spontaneous onset are more likely to occur between midnight and 6am than at other times of day, and are also slightly more likely on weekdays than at weekends and on public holidays. Elective caesarean births are concentrated onto weekday mornings. Births after induced labours are more likely to occur at hours around midnight on Tuesdays to Saturdays and on days before a public holiday period, than on Sundays, Mondays and during or just after a public holiday.The timing of births varies by onset of labour and mode of birth and these patterns have implications for midwifery and medical staffing. Further research is needed to understand the processes behind these findings. The times at which services are available have taken a prominent place in policies about the National Health Service (NHS) in England. The aims set out in the Five Year Forward plan for the NHS in England included ‘Ensuring that hospital patients have access to seven day services where this makes a clinical difference to outcomes’ . Care inA study of daily variations in numbers of births in England and Wales in the 1970s found a pronounced weekly cycle, with the daily maximum numbers of births occurring between Tuesday and Friday, while fewer births occurred on Mondays and Saturdays, and fewest on Sundays. Numbers of births were also low on public holidays, with Christmas Day and Boxing Day having the lowest numbers of births in each year ,7. BroadMost of these analyses did not include data about the time of day of birth. The time of birth was not recorded in national routine data systems in England and Wales until 2005, for example. On the other hand, it has long been established that numbers of spontaneous births vary by time of day and are higher at night than during the day –25, withEarly evidence was provided by Adolphe Quetelet in his ‘Essai de physique sociale’  publisheHigh rates of obstetric intervention have been shown to alter the circadian rhythms of births. In a recent study in Spain, births without intervention were found to follow a roughly sinusoidal curve, with the familiar night-time peak, but a high rate of caesarean births in day time meant that overall the majority of births occurred during the day . In the A study of data from the 1990 National Perinatal Database in the Netherlands found that patterns of birth times of vertex singleton term births without oxytocic drugs depended on who provided care–midwives or obstetricians . In womeThe aim of this paper is to describe in detail how day and time of birth vary by onset of labour, mode of birth, and gestational age in NHS maternity units in England. This is the first study to use a national data set to analyse numbers of births by hour of birth in England.st January 2005 to 31st December 2014. The data were derived from a larger dataset linking all births in England and Wales during this period. After piloting in an earlier collaborative project [This study used linked data from birth registration, birth notification, and Maternity Hospital Episode Statistics (HES) for singleton births in England from 1 project , linkage project ,35. Sing project . The worThe steps we took to derive a data set for analysis are illustrated in To derive our study dataset, we included only the 6,054,536 births recorded as having taken place in NHS maternity units, excluding 83,409 births that took place at home, in private hospitals, in NHS hospitals without maternity facilities, or elsewhere outside a hospital. Births outside NHS hospitals, including those occurring at home have low rates of inclusion in Maternity HES and as a consequence, low rates of linkage, so overall data quality would have suffered had we included them in the analysis.Finally, we excluded 960,921 births records most of which had missing or inconsistent data about the onset of labour, a key variable, and a few of which had mode of birth or gestational age missing. The excluded births made up 15.9% of the records, leaving data for 5,093,615 births. We investigated whether the exclusion of records with missing information changed the distribution of births with respect to region of residence, year, month, type of day and hour of birth, age of mother, sex and gestational age of baby. We found statistically significant differences between included and excluded births for all variables, except the baby’s sex. Nonetheless, differences between all linked NHS hospital births and our analysis data set were small, the biggest difference being 1.02 percentage points for a category. These analyses are reported in detail in The onset of labour is recorded in the HES delivery record maternity tail in the variable ‘DELONSET’. We grouped codes for onset of labour into three categories, spontaneous, induced, or no labour (caesarean), as shown in Mode of birth was derived from the procedure codes in the core admitted patient care record using the Office of Population Censuses and Surveys (OPCS-4) Classification of Interventions and Procedures, versions 4.2 to 4.7. These procedure codes are submitted to the HES database by local NHS providers, who in turn derive the codes from locally held clinical notes. We coded mode of birth as spontaneous, instrumental, elective caesarean, or emergency caesarean. Details of the derivation are described in Birth notification records gestation length in completed weeks since the first day of the last menstrual period. We coded gestational age into three categories: pre-term (22–36 weeks), term (37–41 weeks), and post-term (42 weeks or more).At birth notification, the time of birth is recorded as hour and minute of the day. We grouped this into hourly intervals, with hours running from 0 to 23, where 0 means 0:00 hrs to 0:59 hrs. The time of birth was missing for 45,364 births in the analysis data set. Of these missing values, 43,414 related to births in October 2008; times were available for only eight births during this month. Births whose times are missing were excluded from analyses involving the time of birth, but were included in analyses involving the day of birth only.Day of birth was derived using the date of birth recorded at birth registration, which is the most complete and accurate record of dates of birth in England and Wales. Dates of birth were missing from 16.9% of Maternity HES records. Although the dates of all births are recorded at birth notification, it is not known whether any quality checks are carried out. Pilot linkage of birth notification data to birth registration data for 2005 had shown that the date of birth was discordant in only 0.3 per cent of the linked records .For descriptive analyses, we grouped the day of the week into eight categories: non-holiday days of the week from Monday to Sunday, and public holidays which included bank holidays given in lieu of public holidays that occurred at weekends. For the purpose of statistical modelling, we constructed a variable ‘type of day’ that distinguishes eleven types of day, including the seven days of the week, and in addition:Holiday: bank holidays, including those given in lieu of public holidays falling on a weekend, but excluding 25 and 26 December)Christmas: 25 and 26 DecemberDay before holiday: the last weekday before a holiday period e.g. Maundy ThursdayDay after holiday: the first weekday after a holiday period, e.g. the Tuesday after Easter.Categories were mutually exclusive; for example, Good Friday was categorised as a holiday rather than as a Friday.We performed descriptive analyses of time of birth and day of the week separately for eight combinations of onset of labour and mode of birth, as shown in There were 3652 days from 1 Jan 2005 to 31 Dec 2014. Our model aimed to predict the number of births on each of these days, separately for each of eight combinations of onset of labour and mode of birth. To account for overdispersion, we fitted negative binomial regression models with a logarithmic link, and included the following predictor variables:Type of day as described aboveHarmonic terms to account for the yearly cycle of birth frequencies . This isA natural cubic spline term to control for trends over time, estimated using the 120 months from Jan 2005 to Dec 2014, where the months were coded sequentially 0 to 119. We allowed 3 degrees of freedom per year. Without this adjustment, trends in numbers of births and trends in intervention rates over our study period could have confounded our estimates of holiday effects.Two dummy variables identifying days of clock changes. Days on which the clock changes to British Summer Time have 23 hours and thus a lower expected number of births; days on which the clock changes back to Greenwich Mean Time have 25 hours and a higher expected number of births.Estimates are presented as rate ratios (RR): the ratio of the expected number of births on one type of day over the mean number of births per day. For example, a RR of 1.10 for a Friday means that the expected number of births on Fridays is 10% higher than the mean, and a RR of 0.88 for a Sunday means that the expected number of births on Sundays is 12% lower than the mean. All rate ratios are adjusted for yearly cycles, trend, and clock changes, as described above. Model comparisons were performed using likelihood ratio tests.We calculated 99% confidence intervals around parameter estimates, and for hypothesis tests used a significance level of α = 0.01. All statistical analyses were carried out in R, version 3.1.2 .Ethics approval 05/Q0603/108 and subsequent substantial amendments were granted by East London and City Local Research Ethics Committee 1 and its successors.Permission to use confidential patient information without consent under Section 60 of the Health and Social Care Act 2001 was initially granted by the Patient Information Advisory Group PIAG 2-10(g)/2005. Renewals and amendments under Regulation 5 of the Health Service (Control of Patient Information) Regulations 2002 were granted by its successor bodies, the National Information Governance Board and the Health Research Authority.A second permission CAG 9-08(b)2014 to use confidential patient information without consent under Regulation 5 of the Health Service (Control of Patient Information) Regulations 2002 to create a research database held at the Office for National Statistics for analyses relating to inequalities in the outcome of pregnancy and to inform maternity service users about the outcome of midwifery, obstetric and neonatal care was granted by the Health Research Authority.Permission to access data from the Office for National Statistics in the VML, now known as the Secure Research Service, was granted by ONS’s Microdata Release Panel. All members of the research team successfully applied for ONS Approved Researcher Status.Permission to link and analyse data held by the Health and Social Care Information Centre, now NHS Digital, was granted under Data Sharing Agreement NIC-273840-N0N0N.In It is relevant to consider the proportion of births that occur outside of what are considered to be usual working hours. In our study data set, 71.5 per cent of births occurred out of hours, that is at weekends, on holidays, or on weekdays between 17:00 and 8:59. Conversely, 28.5 per cent of births occurred within usual working hours, that is on weekdays between 9:00 and 16:59. Among all singleton births in NHS maternity units, 71.4 per cent occurred out of hours, and 28.6 per cent within usual working hours.While In contrast, average numbers of instrumental births after spontaneous onset of labour are higher between 9:00 and 17:00 than in the night and early morning. The lowest hourly numbers of births in this group was from 8:00–8.59. Numbers of births where spontaneous onset was followed by an emergency caesarean were higher between 21:00 and midnight than in the early hours of the morning. There are three distinct dips in the numbers, most pronounced at 8:00, and somewhat less deep at 13:00 hrs and 20:00.In general, the variations in numbers of births after spontaneous onset over the course of day did not vary much between weekdays, weekends, and holidays. Nonetheless, numbers of spontaneous births after spontaneous onset were slightly lower on Sundays and holidays compared to weekdays, as we will explore in detail below.The same midnight peak appears when inductions are followed by instrumental births or emergency caesareans, although in these groups the patterns are less regular than for induced spontaneous births. The three groups of induced births share a weekly cycle that has its highest peak on Friday night and its trough on Monday morning.Emergency caesareans without prior onset of labour are distributed somewhat similarly to elective caesareans, with a pronounced peak between 9:00 and 12:00. However, mean numbers of emergency caesareans without prior onset of labour are higher than mean numbers of elective caesareans in the evening, at night and in the early morning, and the same applies to weekends and holidays.R2 values ranged from 0.42 (spontaneous onset and emergency caesarean) to 0.97 (elective caesarean). Differences by type of day were statistically significant (p < .001) for all groups, but their strength varied considerably. Type of day accounted for 94.6% of the variation in daily frequencies among elective caesarean births, but only for 0.4% of the variation among instrumental births after spontaneous onset of labour.We fitted statistical models to estimate differences in the daily numbers of term births by type of day, separately for each of the eight groups, adjusted for yearly cycles in numbers of births and trends over time. Results are presented in As we have already seen in Differences between days are most pronounced among elective caesarean births, which rarely occur at weekends or on public holidays. Numbers of elective caesareans tend to be highest on Mondays and on weekdays after a holiday period followed by Thursdays and weekdays before a holiday, and then Tuesday, Friday, and Wednesday.Emergency caesareans without prior onset of labour are also more frequent on weekdays compared to weekends and holidays, although the differences are small compared to those in elective caesareans. Numbers of emergency caesareans without prior labour are highest on Mondays, Tuesdays and weekdays after holidays.Next we analysed the differences by type of day within each group for pre-term and post-term births as well as for term births. Estimated rate ratios and their confidence intervals, and p-values relating to the interaction effect for all eight groups, are shown in Figs For spontaneous births after spontaneous onset, shown in Among induced births Figs –13, the For elective caesareans , the patFinally, in emergency caesareans without prior onset of labour, again there is little to suggest differences between post-term and term births . Pre-terThis is the first study to analyse, at a national level for England, data showing how the numbers of births vary by time of day and how these patterns vary by onset of labour and mode birth and from day to day. Having a large dataset with over five million births over a ten year period made it possible analyse the effects of time of day and day of the week, and produce estimates with good precision, even for the less common combinations of onset and birth.This study showed that spontaneous births after spontaneous onset showed broadly the same sinusoidal patterns, peaking at night, seen in local analyses in England in 1950 and 1951 ,42 BirthIn contrast, while data about spontaneous births in New York State in 1929 and 1936 showed these same patterns, numbers of spontaneous births in hospitals in the United States in 2013 were higher between noon and 5pm than at other times, but the reasons for this were not analysed. The older patterns were still present in out-of-hospital births in the United States, which showed a pattern similar to that in earlier, with numbers of births being highest between 3am and 5am .While patterns of spontaneous births have remained unchanged in England, overall patterns of birth have changed with the rise in rates of obstetric intervention. The rising rates of elective caesarean section have concentrated increasing numbers of births onto weekday mornings. In contrast, although the rationale for increasing rates of induction in the 1970s was to concentrate births into day time hours, our data show that numbers of induced births peak at night, irrespective of the mode of birth. Overall, 48.1 per cent of births in our study data took place in the 12 hours from 6pm to 6am, compared with 39.5 per cent in the US in 2013 .The shapes of the distributions also differed between the UK and the US. In the US, elective caesareans were concentrated into mornings with two peaks at 8am and 12 noon, while numbers of emergency caesareans were highest during late afternoons and early evenings. Numbers of induced vaginal births showed a very different pattern from those in England, being highest between 12 noon and 6pm. Vaginal births after spontaneous onset varied considerably less but numbers were higher between noon and 5pm than at other times. These patterns illustrate the obstetric practice and use of interventions in the US.A study in the Netherlands using data from 1990 suggested the type of care provider may also affect the time of birth. Women without obstetric intervention who had care from midwives had shorter labours than those who had care from obstetricians . Among wThe overall weekly patterns of births in our study are similar to those seen in analyses of registered births in England and Wales by day from 1970–76  and fromThese patterns have also been seen in many other countries and the consensus is that they reflect staff working patterns, especially the concentration of elective caesareans onto weekday mornings. In contrast, emergency caesareans would be expected in response to an urgent clinical need and thus be independent of the day of the week. Yet we found that numbers of emergency caesareans without any record of prior onset of labour were considerably lower on Sundays and holidays than on weekdays, and that their numbers were highest on days immediately preceding weekends and public holidays. Coding discrepancies may have contributed to our findings relating to emergency and elective caesareans. We found that a small number of births coded as elective caesarean sections occurred at weekends or on holidays. Some of these may have been wrongly coded. Coding discrepancies in mode of births have been found to be more common for elective and emergency caesarean sections than for other modes of birth .It is also difficult to find a ready explanation for the finding that numbers of spontaneous births after spontaneous onset varied by days of the week, although to a much lesser extent. Over the years in our study, average numbers of these births were about one per cent lower on Saturdays, two per cent lower on Sundays and public holidays apart from Christmas, and seven per cent lower on Christmas and Boxing Day, compared to the overall daily average. It was not surprising, however, as similar patterns were seen in past analyses of births without obstetric intervention. Among births occurring at home or in NHS hospitals without a consultant obstetric unit from 1970–76, numbers of births were lower at weekends  and all A Lancet editorial commenting on the earlier data and pointing to the higher proportions of low birthweight babies among those born at weekends, suggested that this might reflect selective induction of term babies during the week ,46 and pUnlike the earlier analyses, we had data available to analyse preterm, term and post term births separately. We found that, unlike those at term, numbers of spontaneous preterm births after spontaneous onset did not vary by time of day and were not lower at weekends and on holidays. A similar result was found in a study of 2,005,096 births from 1 January 1960 to 30 September 1994 in Denmark. Lower than usual numbers of term births occurred on Christmas Eve, when the most important family gathering takes place, and the following three days, but there was no reduction in numbers of preterm births .These analyses were based on a large dataset, derived from over five million births, giving sufficient numbers of births for detailed analyses. By linking three datasets together, we have greatly increased the numbers of variables available for analysis and there is scope for further analysis to look at social, demographic and clinical factors which we have not touched on here. Linkage has also made it possible to use the much more complete data about gestational age recorded at birth notification to compensate for the poor quality data about gestational age recorded in HES.On the other hand, we had to exclude 15.9 per cent of the births in our study dataset from analysis, mainly because data about onset of labour was missing. This could mean that the ‘maternity tail’ was missing from HES records for a number of maternity units as well as for some individual births. This has been a long standing problem , but theEven after using data linkage, some key variables used in previous analyses were not available to us. Previous analyses showed differences by parity in the timing of birth, but parity is missing from many HES records and until 2012 was not recorded at birth registration for births outside marriage. As part of our project, methods have been developed for imputing parity , so it cThese analyses pose questions for further research. Further analyses of this linked dataset could explore how differences in timing of birth vary between social and demographic groups and between maternity units, with their widely varying rates of obstetric intervention. Intervention rates for migrant women often differ from those of the host population, and these may influence the pattern of the timing of birth –55 OtherElective caesareans can be scheduled to fit day-time hours and the shift patterns of many hospital staff. On the other hand, over 70 per cent of all births in NHS maternity units in England occur either at weekends or on weekdays between 17:00 and 8:59, and thus outside of usual working hours. The peak time for births after induced labour is the hour before midnight, regardless of mode of birth, while for spontaneous births after spontaneous onset, it is around 4:00am. Maternity services in England continue to do a substantial proportion of their work out of hours. These patterns must be taken into account in decisions about midwifery and medical staffing, as well as in analyses of weekend or ‘out of hours’ effects in maternity care.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.


To examine the correlation between birth season and early childhood development.Almost all previous studies that examine the effect of birth season on early childhood development were conducted in developed countries with a limited sample size. The present study was conducted in poor, rural areas of western China, a developing region with a continental monsoon climate.We administered a hemoglobin test to 650 infants (52% boys), aged 8–10 months, using a Hemocue Hb 201+ finger prick system, and assessed the cognitive and psychomotor development of sample infants using Bayley Scales of Infant Development.t = 3.63, p < 0.001) compared to infants born in summer. Similarly, cognitive development scores  and psychomotor development scores  were significantly higher among winter-born infants.Infants born in winter have higher Hb concentrations (The findings point to the involvement of birth season in early childhood development and suggest that aspects of the environment shape the experiences that contribute to early childhood development. Policy suggestions such as providing infants with ample opportunities for movement and stimulation during the cold season are discussed. The first years of life comprise a critical development period that affects lifelong outcomes. This period has been identified as an important window for skill formation, especially for cognitive development . ResearcAn increasing number of studies have shown that young children in developing countries experience more cognitive and psychomotor delays than young children in developed countries; they also have higher rates of anemia, indicating poor nutrition during the important 1000-day window ,12.Young children in rural China are no exception ,14. A reWhile many different factors may affect early childhood development, one significant factor is season of birth . This faWhy do we observe this relationship between season of birth and development outcomes of infants? According to Bayley , infantsWhile previous studies have made important contributions in demonstrating the importance of the birth season, there are some weaknesses in the existing research. Many researchers have often only studied a limited number of outcomes linked to birth season. For example, Atun-Einy  examinedIn this paper, we examine the relationship between season of birth and early child development by using a unique dataset of infants drawn a developing county setting in northwest rural China. Unlike previous research, this is a large scale study conducted in a developing country setting. We hypothesize that, compared to summer-born infants, winter-born infants will have lower rates of anemia and higher scores on cognitive and psychomotor development scales. We further hypothesize that caregivers of summer-born infants will take their charges outside less frequently, feed them more limited diets, and bundle them in more restrictive clothing than caregivers of winter-born infants.The rest of our paper is organized as follows. In the next section, we describe our research design, sampling methods, and statistical analyses. In the third section, we describe our results. The final section discusses and concludes.Our sample comes from 11 nationally-designated poverty counties located in poor rural Qinba mountainous area in the northwest of China. The overall climatic pattern of this part of China is characterized by two main seasons: a hot, humid summer and a cold, dry winter. In 2013, winter daily mean temperatures ranged from -2 to 16°C. Summer daily mean temperatures ranged from 18 to 38°C. This coIn 2013, the research team undertook the research initiative in eleven counties that the national government designated as being “officially poor.” The counties were in the Qinba mountainous area. The research team selected all townships in the eleven study counties. A township is the administrative district that is between a county and a village. After selecting the townships, the researchers randomly selected a village from every one of the sample townships.We conducted our study in two waves. The first wave took place in April 2013, the second wave 6 months later, in October 2013. In each wave, we surveyed rural families with infants aged from 8 to 10 months old. The infants of first wave were born from June to August 2012. The infants of second wave were born from December 2012 to February 2013. In this way, we created two identically random samples according to our definition of the birth season. The sample size of infants born from June to August 2012 is 308; the sample size of infants born from December 2012 to February 2013 is 342.We collected Hb concentrations from all participating infants and their mothers. Hb concentrations were measured onsite using a Hemocue Hb 201+ finger prick system. Anemia status was assessed based on finger blood analysis for Hb, following the internationally accepted standard. The WHO considers children in our sample age range to be anaemic if their Hb concentration is less than 110 g/L ; moderatIn the study the enumeration team assessed the sample infants/toddlers using the Bayley Scales of Infant Development (BSID). In this manuscript, we use version-I of the Bayley Scales of Infant and Toddler Development. We use this version because in 2013, when this study was conducted, there were no Chinese versions of either Bayley-II or Bayley-III available. The BSID is a test that is scaled according to international norms. The scale was developed to analyze the cognitive and motor development of infants and toddlers . To prepThe Bayles scale is one of the most frequently used assessment tool for assessing infant and toddler cognition and motor development. It is well recognized by researchers in the field of psychology. The American Psychiatric Association recognized it as a assessment tool that is able to diagnose certain developmental disorders ,38. OrigWhen assessing the level of development of an infant/toddler with the BSID, the protocol considers the age (in days/months) of each sample child. Additional consideration is given to children if they were born premature. When the study team considers these 3 factors, and assesses them in conjunction with the performance of the sample child on a series of tasks (using a standardized toy kit), the team is able to produce 2 standardized scores: the MDI, which evaluates memory, habituation, problem solving, early number concepts, generalization, classification, vocalizations, and language to produce a measure of cognitive development; and PDI, which evaluates gross muscle groups . The testing team also is able to assess fine motor manipulation (and create the PDI measure—).A careful protocol was followed in giving both the MDI and PDI parts of the Bayles protocol. After scoring by the testing team, both the MDI and PDI have been re-scaled. The expected mean of the score is 100 and the standard deviation is 16. When examining the entire spectrum of scores, they can span a range from 50 to 150, according to Yi . After tTrained enumerators collected socioeconomic information and parenting behaviors from all households participating in the study. Each child’s primary caregivers were identified  and administered a detailed survey on individual and household background, including child characteristics , the primary caregiver’s characteristics , and household information (whether the family was receiving Minimum Living Standard Guarantee Payments). The birth date of the infant was confirmed by checking the birth certificate issued by the birth hospital.This study received ethical approval from the Stanford University Institutional Review Board (IRB) (Protocol ID 25734), and from the Sichuan University Ethical Review Board (Protocol ID 2013005–01). All participating caregivers gave their oral consent for both their own and their infant’s involvement in the study. Children who were found to have severe anemia were referred to the local hospital for treatment.Statistical analyses were performed using STATA 14.2. P-values below 0.05 were considered statistically significant. The following Ordinary Least Squares (OLS) regression model was used for multivariate analysis:ECDic, indicates the Hb concentration, MDI score or PDI score of infant i in village c. Seasonic is the birth season of the infant, and β is the parameter of interest. The term Xis is a vector of covariates that are included to capture and control for the characteristics of infants and their households. In particular, we included the following variables as potential confounders in the multivariate analysis: gender, age, whether the infant was premature, whether the infant’s mother was the primary caregiver, maternal educational level, maternal age, and whether the infant’s family received minimum living standard guarantee payments. Other non-time varying county effects are captured by λ. We adjusted standard errors by clustering at village level.Where the dependent variable, We sampled 650 infants (52% boys) aged 8–10 months. According to our data, around 4.6% of the sample infants were premature. The mother was the primary caregiver for 85.9% of the sampled infants. The majority of the mothers (74.9%) had completed at least junior high school; half (49.7%) were over 25 years old. Nearly 21.9% of sample families reported receiving ‘minimum-living-standard guarantee payments,’ a form of government welfare available for China’s lowest income families. Summary statistics for our sample are presented in t = 0.89, p = 0.38), whether the infants are premature , the mother being the primary caregiver , maternal age , maternal educational level , or whether the family was receiving minimum living standard guarantee payments .Applying the classification used by McGrath  and Atunp < 0.001). The BSID test results show that 4.6% of infants had an MDI score below 70, classifying them as moderately or severely impaired in their cognitive development. Around 7.7% of infants had an MDI score between 70 and 80, which indicates mild cognitive impairment. In total, 12.3% had MDI scores lower than 80. The mean PDI score for the sample was 90.4, significantly lower than both the observed MDI score and the expected mean PDI score of 100 . The data show that 10.0% of sample infants were moderately or severely impaired in their psychomotor development (PDI < 70) and 10.46% were mildly impaired (PDI score between 70 and 80). In total, 20.5% had PDI scores lower than 80.Our sample infants experienced high rates of anemia and experienced more cognitive or psychomotor delays in comparison to the urban population used to scale MDI and PDI scores . Hb conct = 4.85, p < 0.001). In terms of MDI scores, we found that the winter-born group scored significantly higher on the MDI scale  compared to infants in the summer-born group . When comparing the PDI scores, we also found that the winter-born infants  scored significantly higher than summer-born infants . Similar results can be seen in The comparison of early childhood development outcomes between the winter-born and summer-born groups is presented in t = 4.36, p = 0.00) and were taken outdoors more frequently by caregivers compared to summer-born infants .In terms of parenting behavior, our analysis also found significant differences between the winter- and summer-born groups. Infants born in winter were fed more iron-rich foods  when they were 6 months old  rise in Hb concentration, a 7.1-point rise in MDI score  and a 12.2-point rise in PDI score . No differences were found between the groups in other aspects, including infant gender, whether the infant was premature, whether the mother was the primary caregiver, maternal age, maternal educational level, or whether the family received Minimum Living Standard Guarantee Payments.The multivariate analyses show a significant association between season of birth and cognitive and psychomotor development after controlling for potential confounding variables . More prThe current study examined the seasonality effect on early childhood development by comparing infants born in different seasons in poor rural Qinba mountainous area in China, which is characterized by a continental monsoon climate. This study represents the largest administrations of the Bayley Scales of Infant Development (BSID) ever conducted in rural communities. The data collected include a rich set of indicators on early childhood development and its relevant factors, including cognitive and psychomotor development, nutrition and health, and feeding behavior. This study is also the first, to the best of our knowledge, to investigate the relationship between season of birth and early childhood development in rural China.Our findings of high anemia and developmental delay rates in rural Chinese infants are supported by previous literature. For instance, our finding that 50.6% of infants had a hemoglobin concentration below the 110 g/L cut-off is in line with the findings of Grantham-McGregor , that haAs predicted, we found that infants born during the winter months tended to have higher average Hb concentrations, MDI scores, and PDI scores compared to summer-born infants. Our analysis found no other significant differences in terms of gender, whether the infant was premature, who the primary caregiver was, maternal age, or maternal education level, indicating that birth season in fact had a causal effect on these results.The role of climatic factors and seasonal changes in shaping experiences should be underlined as a potential explanation for the observed seasonal effect on early childhood development. For example, in cold weather, it is typically necessary to use many layers of clothing to bundle up infants, which can constrain their movement. Groenen, Kruijsen, Mulvey and Ulrich  maintainThe consequences of bundling infants are particularly relevant in poor rural Qinba mountainous area, where daily average temperatures in winter range from -2 to 16°C. Mothers and caregivers in this area often perceive this weather as ‘very cold,’ and dress their infants in multiple layers . It is aHowever, during the hot summer, infants in poor rural Qinba mountainous area often wear very light clothing, and there are more opportunities for them to crawl on the (warm) floor. Caregivers are more willing to take their infants outdoors in summer, which means their infants are exposed to more stimulation. And indeed, our analysis found that infants born in winter were taken outdoors more frequently by caregivers than infants born in summer.Another seasonal environmental factor that should be noted is the availability of iron-rich food (including meat and green vegetables) in summer. Winter-born infants are typically ready to begin complementary feeding in summer, when parents might be more able to provide them with iron-rich foods. This was also borne out by our results, which showed that winter-born infants typically ate more green vegetables, meats, and fruits at around 6 months of age than summer-born infants.Finally, a third important environmental factor associated with season is sunlight, which has been identified by several international studies as a contributor to early childhood development. A study conducted in Finland found that activity level is linked to day length: longer days are associated with increased mean total day activity levels . InteresIn this paper, our findings should be interpreted in the context of the following limitations. First, the analysis in this paper is limited by the relatively short-term follow-up period for the measurement of the MDI and PDI scores. It is possible that if we followed the children over time, the gap between summer-born group and winter-born group would gradually narrow. A paper by Tsuchiya et al.  did findThe results of this study, especially when viewed in the context of the international literature on birth season and early childhood development, suggest that there may be several ways for parents to guard against developmental delay in summer-born children. Parents should focus on providing infants with ample opportunities for movement and stimulation during the cold season . Additionally, parents should invest in heating methods that keep indoor temperatures suitably warm during winter, allowing their infants to move around more freely indoors and wear bulky clothes for a shorter amount of time. If heating their own houses is not feasible, parents should seek out other warm indoor areas where their children can move around unencumbered. For example, investments should be made in rural areas to build public parenting centers that provide warm, infant friendly spaces so that infants can experience more mobility and interaction with their environment even in cold weather.S1 FigPanel A: Mean MDI scores in different seasons.Panel B: Mean PDI scores in different seasons.(TIFF)Click here for additional data file.