The omphalomesenteric duct (OMD) usually involutes by the ninth gestational week. If this obliteration fails, OMD remnant will result in different pathologies mostly in the pediatrics and infrequently in adults. The most well-known OMD remnant disease is Meckel's diverticulum. Omphalomesenteric cyst is rather rare, and their combination is even more exceptional with few cases in literature.We present an adolescent patient with nausea and vomiting and occasional periumbilical abdominal pain who was diagnosed with concurrent omphalomesenteric cyst and ileal diverticulum, causing internal hernia and bowel obstruction that underwent surgery.OMD remnants mostly present in childhood with symptoms of intestinal obstruction, and rarely internal hernias for which conservative management is usually not curative, warranting surgery. Imaging presence of cystic lesion in mid abdomen in young patient with bowel obstruction should raise the suspicion for OMD remnants. Presence of OMD cyst together with Meckel's diverticulum necessitates more extensive resection, rare concurrence which is better to be prepared for in advance.Preoperative radiologic workup is helpful to diagnose the obstruction and its probable cause. Presence of periumbilical cyst should raise the suspicion of OMD remnant specially in young adults with previous episodes of crampy abdominal pain and obstruction without history of abdominal surgery. Being familiar with possible concurrence of OMD cyst and Meckel's diverticulum will increase preparedness at the time of surgery. •The most well-known OMD remnant disease is Meckel's diverticulum.•Concurrent omphalomesenteric cyst and ileal diverticulum is rare.•Preoperative radiologic workup is helpful to diagnose the obstruction and its cause.•Presence of periumbilical cyst should raise the suspicion of OMD remnant.•Concurrent OMD cyst with diverticulum might warrant surgical intervention.•Familiarity with OMD cyst & diverticulum concurrence grows preparedness at surgery. Failure of obliteration of OMD may result in various anomalies, with Meckel's diverticulum being the most common. Other less common abnormalities include OMD cysts, fistula and fibrous band between the ileum and umbilicus Abnormal obliteration of OMD is classified into three types. Type 1 is when the vitelline duct remains patent on both sides, resulting in umbilical discharge. Type 2 is when either end of the duct is patent, with the patency of the distal portion resulting in OMD fistula and the patency of the proximal portion resulting in Meckel's diverticulum. Type 3 is when the mid portion of OMD is patent with atresia of both ends, also known as OMD cysts Here, we present a rare case of concomitant omphalomesenteric cyst and Meckel's diverticulum in an adolescent, resulting in bowel obstruction.This work has been reported in line with the SCARE criteria. [6]2A 15-year-old male presented to our hospital in January 2021 with colicky abdominal pain mostly centered in peri-umbilical area. It had started the night before admission and was later accompanied by loss of appetite, nausea and vomiting.He mentioned previous episodes of nausea and vomiting with occasional periumbilical abdominal pain in childhood which was managed conservatively and was not referred for sub-special medical evaluation.He denied any history of diarrhea, constipation or fever. He had no previous gastrointestinal surgery, underlying medical condition or any allergies. His previous drug history was limited to oral anti-emetics for nausea. He had no family history of intestinal or any sort of genetic disorders.Physical examination revealed moderate abdominal distention and periumbilical tenderness without rebound tenderness. Routine laboratory tests were normal.In supine and upright abdominal x-ray, there were several distended small bowel loops with air-fluid levels indicating small bowel obstruction A, B.Fig.Abdominal ultrasound was performed and revealed a cystic lesion in mid-abdomen close to the undersurface of umbilicus C. No defAbdominopelvic computed tomography with contrast was performed. In mid-abdomen underneath the anterior wall, there was a cyst measuring 63 ∗ 39 mm. The upper portion of the cyst was in contact with the umbilicus suggestive for omphalomesenteric remnant. Proximal small bowels were distended with abrupt transition along the lower aspect of the cyst in favor of mechanical obstruction related to mentioned cyst. Mild interloop and pelvic free fluid identified, accompanied with several non-significant mesenteric lymph nodes .Fig. 2AbPatient underwent abdominal laparotomy in our general hospital by one of our associate professors of general surgery and their senior trainee with 3 years of surgical specialty training. A midline cyst was discovered, attached via a fibrotic band to the anterior abdominal wall in the umbilical region. The other end was connected with an ileal diverticulum A. Small The patient recovered without complication and was discharged after two days.Gross pathologic evaluation of the resection specimen showed omphalomesenteric duct cyst measuring 9 ∗ 5 ∗ 4 cm, attached to a fibrotic band measuring 3 cm in length and 0.5 cm in diameter and continued as Meckel's diverticulum, measuring 1 cm in length and 2 cm in diameter. Histopathologic evaluation of the sample showed small intestinal wall A with ga3The omphalomesenteric duct usually involutes by the ninth gestational week. If this obliteration fails, OMD remains which causes pathologies mostly in the pediatrics and infrequently in adults Nayak et al. reported an 8 year old child with concurrent presentation of OMD cyst, fibrous band and Meckel's diverticulum who had persistent abdominal pain for two years and was treated surgically without any complications We encountered small bowel obstruction associated with a periumbilical cyst in our case. These cysts are classified according to the type of embryonic remnants into three subgroups of uracal, omphalomesenteric duct and round ligament of the liver Urachal disorders are usually diagnosed by detecting their connection with the bladder in cross sectional imaging OMD remnants mostly present in childhood In conclusion, we presented a rare case of an adolescent patient with concurrent omphalomesenteric cyst and Meckel's diverticulum, causing internal hernia and bowel obstruction who underwent surgery. Presence of periumbilical cyst in young adult with previous episodes of crampy abdominal pain and obstruction should raise the suspicion of OMD remnants as the underlying etiology while being familiar with the rare concurrence of OMD cyst with diverticulum will increase the preparedness at the time of surgery.The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Not applicable.Ethics approval and consent have been obtained from ethics committee of Loghman Hakim Hospital.Written informed consent was obtained from the patient and his parents for publication of this case report.HBM contributed interpretation of radiological data and critical revision of the manuscript.MS contributed acquisition of data and drafting of the manuscript. MA contributed acquisition of data and revision of the manuscript. SS contributed interpretation of pathology data. SPR and HP contributed surgical procedures of this case report. SA contributed the interpretation of radiological data. All authors read and approved the final manuscript and have agreed to be accountable for the authors' own contributions and ensured that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, can be appropriately investigated, resolved, and the resolution be documented in the literature.Not applicable.Dr. Hooman Bahrami-Motlagh, Dr. Maryam Sadeghi.The authors declare that they have no conflicts of interests.


Is summer associated with a higher live birth rate after fresh IVF/ICSI?There was no support for a higher live birth rate after fresh IVF/ICSI when treatment was performed during the summer season.Seasonal variations in human natural conception and birth rates are well described. It has been hypothesized that serum vitamin D, levels of which are associated with sun exposure, may have a role in human natural conception rates. However, the association between seasons and IVF outcomes has not yet been clarified and conflicting reports have been published. Furthermore, it has been suggested that women with normal vitamin D levels have a better pregnancy outcome after ART compared to those with vitamin D insufficiency.A nationwide, register-based cohort study including all first-time fresh IVF/ICSI treatments (n = 52 788) leading to oocyte retrieval in Sweden between 2009 and 2018 was carried out.All first-time fresh IVF/ICSI cycles leading to oocyte retrieval were identified in the National Quality Registry of Assisted Reproduction. Data collected included patient characteristics as well as information about the treatment cycle and pregnancy outcome. The patients were divided into season subgroups,  based on the date of oocyte retrieval. The primary outcome was live birth rate, which was defined as the number of live births per oocyte retrieval and embryo transfer (ET). Other outcomes included clinical pregnancy per ET and miscarriage per clinical pregnancy. Logistic regression with multiple imputation was performed to evaluate whether there was an association between season and IVF/ICSI outcomes, with summer as reference. Adjustments were made for woman’s age, year of treatment, BMI, total FSH/hMG dose, type of treatment, fertilization type, embryonic stage at ET and number of embryos transferred.P = 0.02). No significant association was seen when winter and autumn were compared with summer. Live birth rate per ET ranged between 29% and 31% among seasons. A significantly higher live birth rate was seen for spring and autumn compared with summer, at 31% and 31%, respectively versus 29% , respectively. No significant association was seen when winter was compared with summer. Clinical pregnancy rate varied between 36% and 38% and miscarriage rate between 16% and 18%, with no significant seasonal associations.Live birth rate per oocyte retrieval ranged between 24% and 26% among seasons. A significantly higher live birth rate was seen for spring compared with summer, 26% versus 24%, respectively (adjusted odds ratio (OR) 1.08, 95% CI 1.02–1.16, Possible limitations are the retrospective design of the study and unmeasured confounders. Another limitation is that a generalized estimating equation (GEE) model was not used. The use of a GEE model would have made it possible to include all started fresh IVF/ICSI cycles since it allows for correction for any dependence between cycles within women.The results of this large registry study give no support for the hypothesis that IVF/ICSI treatments performed during summer season, with the highest degree of sunlight and vitamin D synthesis, is associated with higher pregnancy and live birth rates. In fact, our results showed significantly lower live birth rates during summer compared with spring and autumn. However, the magnitude of this difference was small and unlikely of clinical value. We suggest that season should not be taken into consideration when planning and performing fresh IVF/ICSI treatments.Financial support was received through the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70 940) and grants from the Hjalmar Svensson’s Research Foundation (HJSV2021019 and HJSV2021037). None of the authors declare any conflict of interest.N/A. WHAT DOES THIS MEAN FOR PATIENTS?This study looked at whether summer is associated with a higher live birth rate after IVF/ICSI. It is known that the number of births after natural conception shows seasonal variations associated with environmental temperature and light exposure, but the association between seasons and IVF/ICSI outcomes has not yet been clarified. Levels of vitamin D in blood vary with sun exposure, and this may play a role in human natural conception rates; however, it is unclear whether this is also the case in assisted reproduction. This large study included more than 52 000 women with infertility who underwent their first IVF/ICSI treatment with fresh embryo transfer (ET) in Sweden from 2009 to 2018. The women were identified from the national registry. The women were divided into seasonal subgroups: summer, spring, autumn and winter. We found that live birth rate per oocyte retrieval varied between 24% and 26% and was higher in spring than summer. Live birth rate per ET was 29–31%, and spring and autumn had higher rates than summer. There were no differences between seasons when looking at the rate of pregnancies confirmed by ultrasound 7–9 weeks after ET  or miscarriage rate. Our study showed that slightly higher live birth rates occur when IVF/ICSI takes place in spring and autumn compared to summer. However, the clinical impact of this difference is probably negligible and we suggest that season should not be taken into consideration when planning and performing IVF/ICSI.Seasonal variations in human natural conception and birth rates have been demonstrated by several studies . AlthougThe association between seasonal variation and IVF outcomes has not yet been clarified, and conflicting reports have been published. It has been hypothesized that the increased synthesis and higher blood levels of vitamin D, which are associated with sun exposure during summer months, may influence ART outcomes . All first-time fresh cycles resulting in oocyte retrieval and ET performed in Sweden from 2009 to 2018 were included. Cycles performed with donated and frozen oocytes, frozen/thawed embryos and cycles for fertility preservation were excluded. A flow chart of the study design and included patients is presented in Data collected from the Q-IVF included BMI of the woman, date of IVF treatment start, total gonadotrophin dose, type of GnRH protocol , type of IVF treatment , date of oocyte retrieval, number of retrieved oocytes, date of ET, number of culture days of the transferred embryo(s), number of embryos transferred, urine-hCG test result, number of gestational sacs seen in transvaginal ultrasound in early pregnancy, miscarriages, live birth and date of delivery. A live birth was defined as the delivery of at least one live born child regardless of whether the pregnancy was singleton or multiple.Women were treated with either a GnRH agonist or antagonist protocol and ovarian stimulation was performed with recombinant FSH or urinary-derived hMG. Standard techniques were used for oocyte retrieval and fertilization with conventional IVF or ICSI. In the vast majority of cycles, single embryo transfer (SET) was performed and no more than two embryos were ever transferred. ETs were performed with cleavage stage embryos (Days 2–3) or at the blastocyst stage.The primary outcome was live birth rate, which was defined as the number of live births per oocyte retrieval and ET.Biochemical pregnancy was defined as positive urine-hCG test. The biochemical pregnancy rate was defined as the number of women with positive urine-hCG test per ET. Clinical pregnancy was defined as the presence of at least one intrauterine gestational sac demonstrated by transvaginal ultrasound 7–9 weeks after ET. The clinical pregnancy rate was defined as the number of clinical pregnancies per ET. Miscarriage was defined as loss of pregnancy up to gestational week 22 and miscarriage rate was defined as the number of miscarriages per clinical pregnancy.In order to differentiate the association between seasons and biochemical and clinical pregnancy rate, miscarriage rate and live birth rate, the cohort of women was subdivided into seasons based on the date that oocyte retrieval was performed. Seasons were defined before analysis of data according to the calendar definition of seasons for Sweden, each season lasting 3 months; spring, 1 March to 31 May; summer, 1 June to 31 August; autumn, 1 September to 30 November; and winter, 1 December to 28 or 29 February.P-values below 0.05 were considered statistically significant. All analyses were performed using SAS 9.4 for Windows .Descriptive statistics are given as number and percentage for categorical variables and as mean with the SD and range for continuous variables. Logistic regression was used with summer as reference. Unadjusted and adjusted odds ratio (OR) with 95% CI are reported. Adjustment was performed for the following confounders: woman’s age, year of treatment, BMI, total FSH/hMG dose, type of treatment, fertilization type, embryonic stage at ET and number of embryos transferred. Owing to the amount of missing data on several of the confounders, multiple imputations were performed for the multivariable analysis. Missing data were assumed to be missing at random and 50 imputed datasets were generated with the Markov Chain Monte Carlo method using the expectation–maximization algorithm. Outcomes were not imputed and thus the procedure above was repeated separately for all first cycle oocyte retrievals and for each of the three outcome analyses  for first cycles where ET was performed. Rubin’s rules were used to pool the results from the imputed datasets. The study was approved by the Swedish Ethical Review Authority, Dnr 2019-06551.During the study period 2009–2018, a total of 102 730 fresh IVF/ICSI treatments leading to oocyte retrieval were started and, of these, 52 788 were first-time fresh IVF/ICSI cycles (51%). Among these IVF/ICSI cycles, there were 8429 cancelled treatments before fertilization  or before ET  . DemograP = 0.02; winter, OR 1.08, 95% CI 1.01–1.16, P = 0.02; and spring, OR 1.10, 95% CI 1.03–1.17, P = 0.005). After adjustment for confounders, spring had a significantly higher live birth rate per oocyte retrieval compared with summer . No significant association was seen when autumn and winter were compared with summer , respectively  ranged between 24% and 26% among the seasons. Autumn, winter and spring had significantly higher live birth rates per oocyte retrieval compared with summer in the unadjusted analyses . After adjustment for confounders, autumn and spring had significantly higher live birth rates per ET compared with summer , respectively. No significant association was seen when winter was compared with summer  (Live birth rates per ET (n = 13 501) ranged between 29% and 31% among the seasons. Autumn, winter and spring had significantly higher live birth rates per ET compared with summer in the unadjusted analyses  .Clinical pregnancy rates varied between 36% and 38% among seasons and no significant association was seen between summer and the other seasons in the adjusted analyses. Miscarriage rate varied between 16% and 18% among seasons and no association was seen between summer and the other seasons in the adjusted analyses .This large registry-based cohort study included 52 788 first-time fresh IVF/ICSI cycles where we examined the association between seasons and the rates of live birth, clinical pregnancy and miscarriage after IVF/ICSI. Our main findings were a slightly but significantly lower live birth rate per oocyte retrieval when IVF/ICSI treatment was performed in summer compared to spring and also per ET when treatment was performed in summer compared to autumn and spring. Live birth rates per oocyte retrieval ranged between 24% and 26% and live birth rates per ET between 29% and 31%. The miscarriage rate, ranging between 16% and 18%, is in line with large registry data from the USA and Europe (Several small studies have shown better pregnancy outcomes when IVF/ICSI treatment was performed during the period of the year with increased daylight length . HoweverThe results of this study do not support the hypothesis that longer sunlight exposure during summer, with expected higher serum vitamin D levels, is associated with better pregnancy outcomes after IVF/ICSI. This is in line with other smaller studies that showed no seasonal association with pregnancy outcomes after ART (The number of IVF/ICSI treatments performed during summer was lower compared to the other seasons owing to the summer vacation, with closed IVF clinics, in Sweden and thus limited resources during the summer months.Major strengths of the present study are the large sample size and inclusion of a complete national cohort during a given time period, without any selection. Furthermore, we included only the first cycle per patient, thus eliminating dependence between cycles from the same patient. The number of included fresh IVF cycles in previous studies ranged between 577 and 13 223 (Possible limitations are the retrospective design of the study and residual confounding. Another limitation is the inclusion of only first cycles, thus making the study population smaller. The use of a generalized estimating equation model would have made it possible to include all started fresh IVF/ICSI cycles since it allows for correction for any dependence between cycles within women.In conclusion, by analysing a large and complete cohort of fresh IVF/ICSI cycles, we showed that performing treatment in summer is not associated with a better pregnancy outcome. In contrast, other seasons showed a slightly higher live birth rate compared with summer; however, this difference is unlikely to have clinical value. We suggest that season should not be taken into consideration when planning and performing IVF/ICSI.


Anemia is still an unfinished global health problem, and adverse birth weight outcomes have everlasting influences on the health of later life. However, the non-linear connections and breakpoints of maternal hemoglobin with birth weight outcomes are still needed to be further elucidated. We aimed to reveal the non-linear connections between maternal hemoglobin during the third trimester of pregnancy and birth weight, low birth weight (LBW), macrosomia, small for gestational age (SGA), and large for gestational age (LGA) in full-term newborns and elucidate the breakpoints of the connections.A total of 11,411 singletons, full-term, and live newborns, whose mothers conducted the examination of hemoglobin concentration before delivery, were included in this study. A generalized additive model was used to identify and visualize the non-linear connections between maternal hemoglobin and birth weight outcomes. Piecewise linear regression model was adopted to estimate the breakpoints of the connections and report the non-linear connections in detail.There were inverted “U”-shaped exposure–response connections between maternal hemoglobin concentration and birth weight and the risk of macrosomia. There was an increasing trend of the risk of LBW and a decreased trend of LGA with the increase in maternal hemoglobin concentration. The breakpoints of maternal hemoglobin for birth weight were 100 and 138 g/L, and those for SGA were 97 and 138 g/L. The breakpoints of maternal hemoglobin were 119 g/L for LBW, 105 g/L for macrosomia, and 106 g/L for LGA. When maternal hemoglobin concentration ranged from 100 to 138 g/L, maternal hemoglobin concentration increased per 1 g/L, and birth weight significantly decreased by 2.58 g . When maternal hemoglobin concentration ranged from 97 to 138 g/L, maternal hemoglobin concentration increased per 1 g/L, and the risk of SGA significantly increased by 2% . When maternal hemoglobin concentration was equal to or lower than 119 g/L, maternal hemoglobin concentration increased per 1 g/L, and the risk of LBW significantly increased by 3% . When maternal hemoglobin concentration was higher than the breakpoints, the risks of macrosomia  and LGA  declined as the increase of maternal hemoglobin concentration.There were non-linear connections between maternal hemoglobin and birth weight outcomes, and there are breakpoints in the connections. Cost-effective interventions targeting pregnant women in the prevention of abnormal maternal hemoglobin concentration should be taken to reduce the incidence of adverse birth weight outcomes. Anemia in pregnancy is characterized by reduced maternal hemoglobin (Hb) concentration during pregnancy, which is one of the most common pregnancy complications. Although many countries have been devoted to attenuating the prevalence of anemia in pregnancy in the past decades by providing iron supplementation for pregnant women, it is still an unfinished global health concern. Approximately 32.4 million pregnant women are suffering from anemia in the world, and the prevalence of anemia in pregnancy is 22% in China . The maiNeonatal birth weight can mirror the fetal intrauterine growth situations, and adverse birth weight outcomes are assumed to be of lifelong health effects, increasing the risks of neurodevelopmental disorders in childhood, earlier pubertal onset, and chronic non-communicable diseases in adulthood –11. MateIn this study, we sought to verify the non-linear connections between maternal hemoglobin during the third trimester of pregnancy and birth weight, LBW, macrosomia, SGA, and large for gestational age (LGA) in full-term newborns and further estimate the breakpoints. These findings can enhance the attention to maternal Hb level during pregnancy and aid obstetricians to take timely actions to cope with the aberrant maternal Hb concentration, so as to facilitate fetal growth and development.Neonates who were born in the First Affiliated Hospital of Xi’an Jiaotong University from 2015 to 2019 were recruited. The clinical characteristics were extracted from the electronic medical records. Neonates were included for (1) singleton and live newborns; (2) full-term neonates with the gestational age of 37–42 weeks; (3) with the examination result of maternal Hb concentration within 7 days before delivery; and (4) maternal age was between 20 and 45 years old. We excluded those with missing information, whose mothers were with kidney diseases or hematological cancers influencing the hemoglobin concentration. This study was permitted by the Medical Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2020LSK-261).The collection of maternal venous blood samples was conducted before they were delivered. Then, the blood samples were detected in the department of clinical laboratory within 2 h after collection. Professional laboratorians detected the hemoglobin concentration of maternal venous blood samples with standard procedures. Newborns without clothes were placed on the electronic scale within 1 h after birth by professional midwives to evaluate their birth weight. The precision of the electronic scale was 10 g. Neonates were categorized into LBW, appropriate birth weight (ABW), and macrosomia according to the birth weight in grams of < 2,500 g, 2,500–3,999 g, and ≥ 4,000 g, and neonates were categorized into SGA, appropriate for gestational age (AGA), and LGA according to the birth weight in percentiles of < 10th, 10th–90th, and > 90th . The Chi1 as shown in Pregnant women with low social status tend to have less access to healthcare and take irregular prenatal visits, which are related to the increased risks of adverse pregnancy outcomes . The qua2 were used in this study, and the p-value < 0.05 was used to determine statistical significance.Descriptive analysis was used to outline the distributions of basic characteristics. Means and standard deviations were adopted to display the continuous variables, and frequencies and proportions were utilized to present the category variables. A generalized additive model was used to identify the non-linear connections between maternal hemoglobin and birth weight outcomes after adjusting for sociodemographic covariates. Piecewise linear regression model was applied to find the breakpoints of the non-linear connections and verify the non-linear connections in detail. Furthermore, the continuous maternal hemoglobin concentrations were divided into subgroups according to the breakpoints observed in the piecewise linear regression model. In each subgroup of maternal hemoglobin concentration, the generalized linear model was adopted to elaborate the linear connection between maternal hemoglobin and neonatal birth weight outcomes. In addition, the interaction term of maternal Hb concentration × neonatal gender was added to investigate the interactive effect of maternal Hb concentration and neonatal gender on birth weight outcomes. The “mgcv” and “segmented” packages of R 4.1.2A total of 11,411 singleton, full-term, and live newborns were included in this study. The distributions of descriptive characteristics of the study population are shown in The inverted “U”-shaped curve was discovered on the exposure–response connection between maternal hemoglobin and birth weight . The birThe breakpoints of the non-linear connections between maternal hemoglobin and birth weight outcomes are shown in P for interaction > 0.05), except for birth weight in the segment of maternal hemoglobin concentration ranging from 100 to 138 g/L (P for interaction = 0.02).The influences of maternal hemoglobin at different segments on birth weight outcomes are shown in We investigated the non-linear connections between maternal hemoglobin during the third trimester of pregnancy and birth weight, LBW, macrosomia, SGA, and LGA in full-term newborns, as well as estimated the breakpoints of the non-linear connections.The fetus grows fast during the third trimester for the rapid development of somatic cells and adipose tissues . TherefoThe relationships between anemia in pregnancy and birth weight outcomes divert in pace with the cutoff values of maternal hemoglobin concentration , 35. A mBoth extremely low and extremely high maternal hemoglobin concentrations jeopardize neonatal birth weight . Mild anThere were several strengths in this study. First, non-linear connections between maternal hemoglobin during the third trimester of pregnancy and birth weight outcomes in full-term newborns were manifested, which expanded the knowledge of exposure–response relationships between maternal hemoglobin and birth weight outcomes. Second, breakpoints of the non-linear connections were innovatively estimated with a piecewise linear regression model, which was beneficial to redefine the cutoff values of hemoglobin concentration for anemia in pregnancy and develop targeted intervention strategies. Meanwhile, there were still some limitations that need to be mentioned. First, anemia in pregnancy is mostly attributed to iron deficiency . WHO recTaken together, we revealed the non-linear connections between maternal hemoglobin during the third trimester of pregnancy and birth weight outcomes in full-term newborns and figured out the breakpoints of the dose–response connections. Our findings can drive cost-effective interventions targeting pregnant women in the prevention of abnormal maternal hemoglobin concentration, consequently, reducing the incidence of adverse birth weight outcomes.Data described in this manuscript will be made available upon reasonable request.The studies involving human participants used anonymized data, and were reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2020LSK-261). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.GX and RW: conceptualization, investigation, methodology, writing—original draft, and writing—review and editing. BZ, LS, WX, MX, and SZ: investigation and writing—review and editing. LG and XX: writing—review and editing. WY: conceptualization, funding acquisition, supervision, and writing—review and editing. All authors have read and approved the final manuscript.


Pediatric traumatic brain injury (TBI) is a significant problem of public health importance worldwide. Large population-based studies on the effect of birth order on health phenomena are exceedingly rare. This study examines the relationship between birth order and risk for pediatric TBI among sibling groups. We performed a retrospective cohort study following 59,469 Finnish newborns from 1987 until age 18 years. Data on first diagnosis of TBI was recorded within the 1987 Finnish Birth Cohort (FBC). Compared with first born siblings, later born siblings had an increased risk of TBI during the follow-up period . When adjusted for sex and maternal age at child’s birth, HRs (95% CIs) for TBI during the follow-up period were 1.12 (0.99–1.26) for second born, 1.31 (1.12–1.53) for third born and 1.61 (1.33–1.95) for fourth born or higher children, respectively. Within this large register-based population-wide study, order of birth modified risk for pediatric TBI among sibling groups. Taken together, these study findings may serve to stimulate further inquiry into genetic, psychological, or psychosocial factors which underlie differences in risk and depth of effect within and between sibling groups. These alterations may have immediate, proximate, and long-term consequences on the health and functional well-being of those affected2. In 2014, there were 56,800 TBI-related deaths in the US, including 2,529 deaths among children3. Severe TBI has a high mortality rate, estimated at 30–40% in observational studies on unselected populations4. Moreover, TBI caused 8.1 million years of life lived with disability (YLDs) globally in 20165.A traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force6 than all forms of cancers combined7 and are among the costliest health conditions to treat and rehabilitate across the entire care continuum9. The total direct and indirect costs associated with TBIs in Europe have been estimated to be about EUR 33 billion per year10. Falls and road injuries are considered the leading causes of new cases of TBI in most countries5. In high-income countries, the TBI diagnoses are on the rise among children11. Among the pediatric population, special considerations are warranted in the diagnosis and treatment of TBI. These considerations involve taking into account the child's physiology and increased susceptibility for post-traumatic seizures, each within the context of increasing evidence for long-term consequences for even mild TBIs12. These long-term consequences include physiological, cognitive, and behavioral changes14 such as antisocial behaviors, weaker educational performance as well as distress within family and spousal relationships due to the increased care needs of a family member affected by TBI17, hence, long-term follow-up is often required to confirm physical and cognitive consequences.TBIs occur with greater frequency 18. Early research about birth order and its influence on sibling behavior and health was theorized by Austrian physician Alfred Adler19. Adler postulated that one's birth position among siblings influences their psycho-social make-up. While little empirical evidence existed initially to support this claim, later research has contributed to the understanding of some of the underlying aspects of the initial hypotheses as they relate to health outcomes18.Classically, birth order refers to the order in which children are born from one set of male and female parents into a family setting20. Various physical injuries22, psychological conditions—such as depression, emotional disorders, attention-deficit disorders, suicide attempts, and even intelligence level and handedness25, were found to have been associated with sibling birth order28. Mortality risk for some conditions appears to increase within specific birth order categories, and that pattern is relatively stronger among females29.Personality, genetic, environmental as well as parental factors seem to play a role in forming the relationship between birth order and health conditionsPediatric TBIs have a complex socio-environmental etiology. More research is needed to understand the particular risks of pediatric TBI, along with efforts to educate parents and caregivers to prevent TBI in this vulnerable group. Sibling birth order remains a relatively unexplored aspect of childhood which might help to explain some of the statistical variation in risk profiles for TBI. The present study examines the hypothesis that later born children are more prone to TBI in comparison to their earlier born siblings. Furthermore, the incidence of TBI among the different birth categories are examined in the study.31. The 1987 FBC has an ethics approval from the Finnish Institute for Health and Welfare (THL) (decision §28/2009) and all relevant permissions from all register-keeping authorities. The legal basis for the processing of personal data is public interest and scientific research , Article 6(1)(e) and Article 9(2)(j); Data Protection Act, sections 4 and 6). Since neither cohort members nor their guardians were contacted, no informed consent was required for this study. Informed consent is waived by the ethics committee . All methods were carried out in accordance with relevant guidelines and regulations.We performed a retrospective cohort study based on data derived from the 1987 Finnish Birth Cohort (FBC). The FBC is a longitudinal nationwide register that includes a complete census of all children born in 1987 in Finland . The FBC contains information on health and social circumstances from the perinatal period up to and including early adulthood. The cohort contains information about all live and stillborn infants weighing more than 500 g or those with a gestational age of at least 22 weeks. Detailed information about the cohort may be obtained elsewhere35. Nine cohort members had a diagnosis of a comorbidity at the time of TBI diagnosis. Cohort members who had been diagnosed with a TBI in a hospital setting or visited outpatient clinics (since 1998) in the region were included in this series. Repeated TBIs were defined as having two or more TBIs per child during the follow-up period. Repeated TBI (reported in 13% of the cohort) among individual children were excluded. Thus, we report a single index TBI diagnosis per cohort member. The study sample included all severities of TBI. Hospital diagnoses of TBIs were all obtained from the 1987 FBC which is based on linked and validated administrative register data30.TBI diagnoses have been coded according to the International Statistical Classification of Diseases and Related Health Problems  as follows: We operationally defined TBI to include cases of concussion, diffuse injury, focal intraparenchymal lesions  and convexity hematomas, cranial nerve injuries and crush injuries as a result of trauma. Moreover, also fractures of the calvarium and skull base were included  . Co-morbidities at the time of the TBI diagnosis were identified using ICD-9 and ICD-10 as shown in Annex 137.For this study, we identified the children belonging to each set of parents by utilizing the combined parent birth dates that were registered on the birth certificates of each child in the cohort. We included all children with complete information who were followed up from birth until age 18 years (1987–2005) unless they died or emigrated before the year at entry. The final number of included children in the study was 59,469. To reduce possible bias due to e.g. household disruption due to divorce, we restricted the analysis to intact family units consisting of both biological parents who had never been separated/divorced during the cohort period. This was also done to reduce the probability of introducing factors such as having multiple unpaired mothers with the same birth date, or different children residing concurrently with multiple or non-biological parents. Data are presented in three periods each encompassing 5–6 years  in order to allow for comparison of the different time periods and evolution of the phenomena over time. Furthermore, data are also presented for the whole period (1987–2005) to have a broad overview of the study cohort. The main outcome of the study is TBI. Validation studies were conducted to ensure the accuracy of measurement of birth order and the outcome in the studyp < 0.05. We did model performance assessment before our analyses, and all the requirements were fulfilled. The analyses were performed using RStudio Desktop 1.2.5042 for Microsoft Windows. There were no missing data of the participants for the study.Because all children entered the observation window at the same time point, in 1987, age at entry reflects each person's birth year and is, together with sex and mother's age at delivery, used as a control variable. The incidence rate of TBI was calculated as the number of TBI cases divided by the person time for the children in each birth order during the different periods until TBI, death, emigration, or end of the follow-up. Statistical significance of birth order differences was analyzed using Pearson's chi-square test. To examine the ratio of the risk over time for TBI risk, we calculated hazard ratios (HR) along with their 95% confidence intervals (CI). All statistical tests were two-tailed and the limit for statistical significance was set at Table Within the different periods Table , later bp value = 0.004). Otherwise, in the following years as well as in the whole study period, there were no statistically significant differences between the eldest versus non-eldest child , ,  in the years 1993–1998, 1999–2005 and 1987–2005, respectively.Nevertheless, there was a trend of decrease in this association between birth order and TBIs among siblings within the families as we compare the different time intervals Table ; the cruBeing a male was associated with a higher risk of being diagnosed with TBI among the siblings within the family in comparison with a female counterpart within the same birth order Table . The HRsThe incidence of TBI per 100,000 child-year 95% CIs) in the cohort for the whole study period (1987–2005) was as follows; 143.8 (132.4–155.2) for the earliest born, 146.4 (134.4–158.5) for the second born, 157.2 (138.8–175.8) for the third born, 183.8 (155.0–212.6) for the latest born, respectively . Male over-representation among injury diagnoses is generally consistent with existing literature, in which the reported average ratio for injury is around 1 8:1 (M: F)50.The majority of pediatric TBIs occurred among children with younger mothers aged 20–29 years, taking into account that the highest incidence of pediatric TBI was among earliest born children due to the high number of them compared to their siblings from other birth categories. The reason for the high number of earliest born children is that the birth rate has declined considerably in Finland over time as the total fertility rate has diminished markedly in the 2010s21. Additionally, long bone fractures among children up to 5 years of age, are associated with being later born, in which among the 4th or older sibling there is a threefold increased risk of fractures in comparison to the first child in the family22. In Egypt, Halwa et al. also confirmed this relationship by showing that higher birth order in Egypt is correlated with fracture injuries, with more than half of injured children being either second or third in their birth order in their families51. Polly et al. claimed according to their study that the increased risk of injury appears to be restricted to later-born siblings in large families52.This trend of increasing risk of injuries among later-born children is mentioned in different studies in low-, middle- as well as high-income countries in the literature “Annex 29. Several explanations about birth order-related injuries have been postulated in recent years. Personality differences seem to play a role, last-born children are described as being athletic, curious, and more aggressive compared to earliest-born children in the same sibling group and hence potentially more outgoing and rebellious53. In contrast, later-born siblings are cautious and more fearful20. This difference in personality is supported by genetic and environmental evidence. From a genetic standpoint, Scarr et al. suggested that each child in a family receives a random half of each parents' genes, which by chance average to a common sibling share of about half of their genes, and that explains a part of not just the physical differences, but as well the behavioral differences among siblings54. This explains partially the difference in personality among siblings and hence the difference in the risk of TBIs. Environmentally, although children share the same household, their experience is different. This due to different factors including sibling interaction with each other, accidental factors of each child's experiences, family composition, extra-family network sources such as peers, teachers, and TV exposure16. Parental factors are as well as important, some researchers have suggested that divided attention from the parents in large families may play a role in the increased risk of injuries among later-born children17. Mothers may be more cautious in the home environment in dealing with the earliest born children55.There are several mechanisms and suggested theories that could generate a relationship between birth order and health, including differences in biological endowments, early parental investment, and later parental or environmental factorsOne of the strengths of this study is the large, population-based cohort and the long follow-up period of a geographically representative sample. Data were collected through a national health system, which assures uniform access to health care and hence a homogeneous, standardized data collection process. One of the limitations of the study is that we did not consider multiple births, in which the age ranges are thus similar, exposing the entire sibling group to similar risk profiles as they develop. Furthermore, some data of the cohort members could be missing or not well documented, which may as well influence the results of the study. TBI cases could be as well missed, if the diagnosis was made in an outpatient setting before 1996, as this data is not included in the cohort. Furthermore, socio-economic status and rural place of residence, which could increase the risk of exposure to an injury, could not be examined in the study.There is also an aspect in the inclusion criteria that requires attention. We have included patients with calvarial and skull base fractures. The rationale for this is that possible forces, strong enough to cause a skull fracture may injure the underlying brain or result in intracranial bleeding such as epidural hematoma.51, is needed. Public health measures to be taken may include expanding public and professional awareness about TBI risks in general as well as maintaining and expanding access to health care providers. Additionally greater emphasis is needed on primary and secondary prevention-related initiatives to reduce the occurrence TBIs and related sequalae and expand research to promote best practices concerning TBI treatment and care for the affected.We conclude that there is an association between traumatic brain injuries and being later born in birth order. Due to the potential for serious short and long term consequences, more nuanced research should be carried out with the aim of clarifying which social- biological- and environmental factors influence risk for TBIs within the birth order context. Additionally, further examination of the implications of the phenomena on health systems and public health policies, especially in the setting of low- and middle-income countries, where family sizes are relatively largerMO, MLW, MM and MG had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Supplementary Information.


Visiting a close relative who resides in a nursing home is an opportunity for family members to extend their caring roles and find reassurance that the older person’s life is continuing as well as possible. At the same time, visits allow family members to observe the quality of formal care in the facility. In Finland, the COVID-19 pandemic led to the imposition of visiting bans in nursing homes in March 2020, thereby preventing customary interaction between residents and their family members. The aim of this study is to investigate family members’ experiences of the visiting ban and its effects on their concern over the wellbeing of close relatives living in nursing homes.n = 366) conducted among family members in May–June 2020. Binary logistic regression analyses were performed to explore the association between the independent variables and reported concern.A cross-sectional study was conducted to explore family members’ self-reported concerns and the factors associated with those concerns. In the context of this unpredictable pandemic, this was considered an appropriate approach, as information at the very beginning of the visiting ban was sought, and causal relations were not investigated. The data consist of a quantitative survey (The results showed that increased concern was extremely common (79%). The factors associated with this notable increase were adequacy of contact and information, observations of changes in the wellbeing of the relative in question, and doubts over the appropriateness of the visiting restriction.In light of the findings, care providers should improve their information provision to residents’ family members and find new ways of allowing visits to nursing homes in the future in all circumstances. The COVID-19 pandemic spread quickly across Europe in March 2020 , which sAlthough the Finnish Emergency Powers Act was repealed on 16 June 2020, and many social restrictions were lifted during the summer, visiting in nursing homes was not normalized. Visits were allowed outdoors, and sometimes in specific meeting spaces constructed inside the facilities, but FMs were only permitted to enter residents’ private dwellings under exceptional circumstances, such as in cases of terminal care. In early autumn, visits to residents’ rooms were allowed, albeit with the imposition of strict safety measures, but in late 2020 the situation worsened again with the spread of the second wave of the virus –12. VisiThere are some 50,000 residents in Finnish nursing homes , thus, iThe individuals who are most likely to visit nursing homes are female FMs, including wives, daughters, and daughters‐in‐law , 26. PreIn this context, mistrust arises from poor communication between FMs and nursing staff . AccordiUltimately, nursing home care is a socially constructed process , 37, andThis exploratory study investigates family members’ concern over relatives residing in nursing homes and the factors associated with the concern. We seek answers to two distinct research questions: (i) to what extent did the visiting restrictions of spring 2020 cause changes in levels of concern and wellbeing among the FMs of nursing home residents? (ii) Which factors were associated with increased concern among FMs?We conducted a cross-sectional study, which, in this unpredictable pandemic situation, was considered an appropriate approach, as we sought information at the very beginning of the visiting ban and were not interested in causal relations. An online questionnaire was created to capture FMs’ experiences of the visiting ban: it comprised seven questions on the backgrounds of the respondents and 17 multiple-choice questions on the research topic. Since the COVID-19 situation was sudden and the duration of the pandemic unpredictable, it was necessary to create the questionnaire quickly. Therefore, we chose not to pre-test it with our target population; to compensate, we nonetheless involved several researchers in its drafting process.The questionnaire was created with a SurveyHero tool and distributed primarily via Facebook and Twitter. On Facebook, it was shared specifically with groups linked to elderly care. On Twitter, the call to participate was re-tweeted 41 times. In addition, two major Finnish non-profit organizations advancing the wellbeing of older people promoted the survey on their webpages and bulletins. The survey was launched on 11 May and closed on 30 June 2020.The dependent variables were the wellbeing of the FM and concern among FMs over the wellbeing of a close relative residing in a nursing home during the visiting ban. All the questions used in this study are described in Table The survey contained two items on the wellbeing of relatives: “Have you been so concerned about the wellbeing of your close relative living in a nursing home that your own wellbeing has decreased 1) before the visiting ban and 2) during the visiting ban?” The answer was “yes, I have,” or “no, I have not.”The survey item inquiring about the concern was “compared to the time before the visiting ban, has your concern about the wellbeing of your close relative living in a nursing home 1) stayed at the same level, 2) increased notably, 3) increased to some extent, 4) decreased? or 5) I have not been concerned during the time my relative has been residing in a nursing home.” We used this five-point scale in the preliminary analyses. In turn, we coded the variable for the binary logistic regression analyses as follows: 1 = increased notably and 0 = remained similar, decreased, no concern, and increased to some extent. We chose a notable increase in concern as the dependent variable given that people tend to choose the middle option , and weThe independent variables represent the background information and the situation prior to and experiences during the visiting ban Table . Age wasThe question on receiving information during the visiting ban included five aspects: “did you receive enough information about your close relative concerning 1) wellbeing, 2) safety, 3) daily life, 4) being able to keep in contact, and 5) changes in daily life?” The response options were “yes” or “no.” We coded a sum variable to describe receiving sufficient information in general . Both the original responses and the sum variable are described and used in the preliminary analyses, but we only included the sum variable in the binary logistic regression analyses.Given that all the variables were categorical, we present the frequencies and the percentages. We tested the associations of between the independent variables and the dependent variables using cross tabulation and Chi square tests, having excluded respondents with missing observations in each variable from these preliminary analyses.We then performed binary logistic regression analyses to explore the association between the independent variables and a notable increase in concern. We ran three models:Model 1: variables describing background information,Model 2: model 1 + variables describing the situation before the visiting ban, andModel 3: model 2 + variables describing experiences during the visiting ban.The analyses were performed using IBM SPSS Statistics (v. 28.0).https://tenk.fi/en). Participants were informed about data management on the first page of the survey. Currently, the dataset is being used in several academic projects, but it will be deleted once these projects have been finalized.The Ethical Review Board in the Humanities and Social and Behavioural Science, located at the University of Helsinki, was consulted about the need for ethical approval for the research, and the committee confirmed that it was unnecessary to apply for ethical approval. While no external ethical evaluation was required for this survey study, data were collected in accordance with the General Data Protection Regulation of European Union  and Finnish research ethical principles (n = 329). The university of (Anonymized) owns the data.A total of 410 persons responded to the online questionnaire, of whom 42 returned it incomplete. Moreover, one response concerned a person who had died many years ago, and another contained missing information concerning one of the dependent variables. After excluding these responses, the dataset comprised answers from 366 participants. In addition, for the regression analyses, we excluded all respondents with missing observations in any of the independent variables  of the respondents reported no adverse effects on their wellbeing due to concern before or during the ban. In turn, almost one fifth (19%) reported a decrease in wellbeing both before and during the ban, whereas 27 percent reported adverse effects during the ban but not prior to its imposition (figures not shown).As many as 79 percent of respondents reported increased concern about the wellbeing of their relatives during the visiting ban: 37 percent to some extent, and 42 percent markedly Table .Fig. 1ChFifty-one percent of those whose own wellbeing had deteriorated before the ban due to concern reported a notable increase in concern during the ban, compared with 69 percent of those whose wellbeing had deteriorated during the ban Table .Table 3VWe found a statistically significant association between the time relatives had lived in the nursing home and concern about their wellbeing, but the pattern was nonetheless opaque Table . Visit fAll the variables describing experiences during the visiting ban were statistically significantly associated with the change in concern Table . A largeAccording to the results of the multivariate analyses, grandchildren were much less likely to report a notable increase in concern than were spouses Table , a findiThose who visited close relatives living in a nursing home less frequently than “almost every day” were less likely to report a notable increase in concern Table , Model 2Respondents who felt that they lacked sufficient contact with their close relatives during the visiting ban were several times more likely to report a notable increase in concern Table , Model 3R2 was highest in Model 3 (0.46) (Table The Nagelkerke odel 3 0.6 (Table Our aim was to explore the factors associated with experienced concern among the FMs of nursing home residents during the visiting restrictions in spring 2020. Increased concern about the wellbeing of a close relative living in a nursing home was extremely common (79%), and almost half of the respondents reported a deterioration in their own wellbeing on account of this concern. However, it is worth noting that 49 percent of respondents failed to report any decrease in their wellbeing. Relatives’ wellbeing obviously depends on a variety of factors. However, within the framework of this study, our multivariate analyses revealed that the factors associated with a notable increase in concern were primarily connected with the visiting ban: the adequacy of contact and information, observations of changes in the wellbeing of relatives, and doubts over the appropriateness of the visiting restriction. We are unable to draw conclusions about causality based on the findings from these cross-sectional analyses. Thus, we can only state that those who considered the visiting restrictions to be the wrong solution were more likely to report markedly increased concern: whether this concern occurred before or after the arising of such an opinion cannot be assessed. By contrast, the associations between respondent background variables and concern were generally weaker.In line with previous research , perceivAlthough increased concern was largely attributable to the respondents’ experiences during the early COVID-19 pandemic, rather than to background variables, some pre-COVID-19 behaviors were strongly connected to their level of concern. For example, concern was clearly linked to the frequency of visits to the nursing home: those who had visited almost every day before the pandemic reported extremely high levels of concern compared to those who had visited less frequently. The vast majority of both our entire sample (88%) and frequent visitors (92%) were female FMs of residents, which is consistent with previous research , 26. DisOne potential reason for concern rooted in pre-COVID-19 times is decreased public confidence in elderly care in Finland, which has been widely reported as a “care crisis” in news media. Several cases of inadequate eldercare came to light in 2018, and many nursing homes managed by private enterprises were either closed or taken over by municipal actors. As Szebehely and Meagher  indicateThe respondents were individuals with a close relative living in a nursing home during the data-collection period. We found no information available on this target population with which to compare our sample. However, we were able to reach people from different age groups. In line with previous research findings , 27, theThe invitation to participate in the online survey was not targeted at any special sample and was distributed on Facebook, Twitter, and via the webpages and bulletins of two major Finnish non-profit organizations advancing wellbeing among older people. Thus, the oldest FMs may be underrepresented due to the online form of the survey.Although our data contained many neutral responses, it is also possible those individuals experiencing concern were more likely to participate in the survey. Thus, our results on the frequency of concern may contain some selection bias; however, this is unlikely to impact our findings on the associated factors. Our primary goal in this study was to explore factors that could explain an increase in concern among FMs with a close relative living in a nursing home rather than to describe levels of concern in the total population with relatives residing in such institutions.We found increased concern about the wellbeing of a close relative living in a nursing home to be extremely common—a result which mirrors previous research –44. Howe


Both short and long interpregnancy intervals (IPIs) have been associated with risk of preterm birth, but the evidence is limited in Asians. It is also uncertain whether the association is modified by dietary folate intake or folic acid supplementation during pregnancy. Thus, we examined associations between IPI and risk of preterm birth and effect modification of those associations by dietary intake of folate and supplementation with folic acid on the basis of a nationwide birth cohort study.Among 103,062 pregnancies registered in the Japan Environment and Children’s Study, 55,203 singleton live-birth pregnancies were included in the analysis. We calculated IPI using birth date, gestational age at birth of offspring, and birth data of the latest offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) of the risk of preterm birth were estimated according to IPI categories.Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth, compared with an 18–23-month IPI. The multivariable ORs were 1.63  for <6-month and 1.41  for ≥120-month IPIs. These associations were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. Multivariable ORs were 1.76  for <6-month IPI and 1.65  for ≥120-month IPI.Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth. These higher risks were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. The World Health Organization (WHO) reported that approximately 15 million infants were born preterm in 2014.3 Both short and long IPIs have been associated with increased risks for preterm birth in the previous studies reported from the United States, Latin America, and Europe,4–8 but the evidence is limited in Asians. Because IPI has become shorter rapidly in Japan since the early 2000s,9 there is a need to consider this association. Nevertheless, there is only one report of the association between IPI and preterm birth in Japanese women.10 In that retrospective cohort study of 547 women with a previous history of preterm birth, an IPI of <12 months was associated with 2.1-fold higher risk of recurrent preterm birth than that with an IPI ≥12 months.10Interpregnancy interval (IPI) is defined as the interval between the birth date of the latest delivery and conception of the next pregnancy.11 A short IPI without folic acid supplementation was associated with a lower birthweight and higher risk of small size for gestational age12; however, it remains uncertain as to whether the association between IPI and risk of preterm birth is modified by dietary intake of folate or supplementation with folic acid during pregnancy. Therefore, we evaluated the associations of IPI with risk of preterm birth and the modification of this association by dietary intake of folate and supplementation with folic acid in a large birth cohort study from Japan.There is limited evidence regarding modification of risk of preterm birth related to IPI; however, dietary intake of folate and supplementation with folic acid during pregnancy may be potential protective factors for perinatal outcomes related to IPI.13,14 The protocol of this study was approved by the Ministry of the Environment’s Institutional Review Board on Epidemiological Studies  and by the Ethics Committees of all participating institutions. The JECS obtained written informed consent from all participants.The Japan Environment and Children’s Study (JECS) is a nationwide birth cohort study funded by the Ministry of the Environment, Japan. Pregnant women were recruited between January 2011 and March 2014 from medical facilities or local municipal offices. A total of 103,062 pregnancies were confirmed. The details of the study are described elsewhere.Among 98,255 singleton livebirth pregnancies, we excluded 7 individuals with missing maternal age, 38,586 individuals because of primiparity, 4,045 individuals with missing birth history, and 414 individuals who had uncertain information regarding IPI. Finally, 55,203 singleton livebirth pregnancies were included in the present analysis .We distributed self-administered questionnaires at registration and during the second/third trimester. Questions included maternal demographic characteristics, socioeconomic status, lifestyle, mental health, and birth date of siblings. Data on the history of use of anemia medication before and during pregnancy were obtained during interviews at registration and during the second/third trimester. Maternal anthropometric data before and during pregnancy and data on complications before and during pregnancy, maternal age at delivery, number of births, birth dates of offspring, gestational age, and perinatal outcomes were obtained from medical records provided by the participants’ obstetricians. Body mass index (BMI) before pregnancy was calculated as weight before pregnancy (kg)/height3 We defined IPI as the interval between birth date of the latest sibling and the conception of pregnancy registered in the JECS. We converted gestational age from weeks into months and calculated IPI by subtracting the gestational age (in months) at birth of the offspring registered in the JECS from the interval between the date of the two deliveries (in months).3 IPI was categorized as <6, 6–11, 12–17, 18–23, 24–29, 30–35, 36–41, 42–47, 48–53, 54–59, 60–89, 90–119, or ≥120 months.IPI is the interval between the birth date of the latest delivery and conception of the next pregnancy.Preterm birth was defined as delivery at <37 weeks of gestation, based on medical record transcripts. Gestational age was estimated clinically from the date of last menstrual period, by measuring the crown–rump length, or from the date of in vitro fertilization.15 administered during the second/third trimester. In the FFQ, we estimated daily dietary intake by multiplying frequency by the standard portion size of food items, on the basis of the Japanese Food Composition Tables, 5th Revision.16 Spearman’s correlation coefficient comparing FFQ and 12-day food records over four seasons at intervals of each 3 months was 0.62 for dietary intake of folate.15Dietary intake of folate during pregnancy was calculated from the food frequency questionnaire (FFQ)Information about supplementation with folic acid during pregnancy was included in the questionnaire and in FFQ administered during the second/third trimester. In that questionnaire, we asked about the frequency of supplementation with folic acid: ≥2 times/day, once/day, 4–6 times/week, 1–3 times/week, 2–3 times/month, once/month, or never. In the FFQ administered during the second/third trimester, if participants used supplements during pregnancy, they wrote down the trade names or types of supplements used and selected the category for the frequency of use of each supplement: ≥4 times/day, 2–3 times/day, once/day, 5–6 times/week, 3–4 times/week, or 1–2 times/week. When participants answered the frequency of folic acid supplementation as once or more times/day in the questionnaire or FFQ during the second/third trimester, we defined these cases as daily supplementation of folic acid.17 and most folic acid supplements in Japan contain ≥400 µg/day folic acid.18 Bioavailability of folate is 50 percent lower than that of folic acid.19Furthermore, we defined dietary intake of ≥400 µg/day of folate and/or daily supplementation with folic acid as adequate intake during pregnancy. We defined folate dietary intake <400 µg/day and no daily supplementation of folic acid as inadequate intake during pregnancy. This is because Japanese pregnant women are recommended to take at least 400 µg/day folate as part of their diet during the second/third trimester,20 In the multivariable model, we adjusted for maternal age at delivery (continuous) and potential confounders including residential area , maternal BMI before pregnancy (quintile), maternal education levels , maternal smoking during pregnancy , frequency of maternal passive smoking during pregnancy , maternal drinking during pregnancy , maternal physical activity during pregnancy , household income during pregnancy , maternal occupation during pregnancy , marital status during pregnancy , number of children , maternal stress during pregnancy , maternal dietary intake of iron during pregnancy (quintiles), maternal use of anemia medication during pregnancy (yes or no), maternal dietary intake of folate and supplementation with folic acid during pregnancy (inadequate intake of dietary folate and folic acid supplementation during pregnancy or adequate intake of dietary folate and/or folic acid supplementation during pregnancy), the latest pregnancy outcome (livebirth or stillbirth/miscarriage/abortion), spontaneous pregnancy (yes or no), previous history of preterm birth (yes or no), maternal medical history of hypertensive disorder of pregnancy (yes or no), and gestational diabetes (yes or no). Missing data for confounding factors were included as categorical variables in the model. The proportions of missing values were 7.4% for household income during pregnancy, 6.4% for previous history of preterm birth, 5.8% for maternal physical activity during pregnancy, and 0 to 1.8% for other confounding factors.The present analysis is based on the dataset jecs-an-20180131, which was released in March 2018. We calculated means and prevalence of characteristics according to IPI. Test for trends were performed modeling with the median value in each category of IPI. Multivariable logistic regression models were used to calculate the maternal age-adjusted and multivariable odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for the association between IPI and the risk of preterm birth. The reference category of IPI was defined as 18–23 months, because WHO recommends that the next pregnancy be avoided for at least 18 months from birth.N = 54,685).We measured the interaction between IPI and folate/folic acid intake on the risk of preterm birth, and a stratified analysis was conducted according to folate and/or folic acid intake. We divided dietary intake of folate and supplementation with folic acid during pregnancy into two categories (adequate or inadequate) .All statistical tests were two-tailed, and Table Table P for interaction between IPI and folate/folic acid intake during pregnancy on the risk of preterm birth was 0.38. Higher risks for preterm birth related to <6-month and ≥120-month IPIs compared with 18–23-month IPI were found among women with an inadequate intake of dietary folate and folic acid supplementation, while there was no association among women with an adequate intake of dietary folate and/or folic acid supplementation during pregnancy. The multivariable ORs were 1.76  for <6-month IPI and 1.65  for ≥120 month-IPI among women with an inadequate intake of dietary folate and folic acid supplementation during pregnancy, and 1.26  for <6-month IPI and 0.88  for ≥120-month IPI among women with an adequate intake of dietary folate and/or folic acid supplementation during pregnancy.Table In a large birth cohort study, we found that both <6-month and ≥120-month IPIs were associated with increased risk of preterm birth. For <6-month and ≥120-month IPIs, the risks of preterm birth were 1.4- to 1.6-fold higher than those with 18–23-month IPI. The interaction between IPI and folate/folic acid intake on the risk of preterm birth was not statistically significant; however, higher risks of preterm birth were confined to women with inadequate intake of dietary folate or those with folic acid supplementation during pregnancy.4,5 A United States study using vital statistics data among approximately 170,000 singleton livebirths found that, compared with 18–23-month IPI, both 0–5-month and ≥120-month IPIs were associated with 1.4- to 1.5-fold increased risk of preterm birth (livebirths at <37 weeks of gestation).4 Another United States study using birth certificate data of approximately 430,000 singleton livebirths reported that both 0–5-month and ≥120-month IPIs were associated with higher risk of preterm birth (live births at <37 weeks of gestation), regardless of race; multivariable-adjusted ORs compared with 18–23-month IPIs according to race were 1.3  for white women with 0–5-month IPI, 1.4  for white women with ≥120-month IPI, 1.2  for black women with 0–5-month IPI, and 1.3  for black women with ≥120-month IPI.5 Regarding the Asian population, a Taiwanese retrospective cohort study reported that <12-month IPI led to a 1.3-fold increased risk of preterm birth (live birth at 20–36 weeks of gestation) compared with ≥12-month IPI24; however, a detailed analysis of the association between the fine categories of IPI and risk of preterm birth was not conducted.Our findings are consistent with those of previous studies.25,26 Maternal folate concentrations remained lower after delivery, and 20% of women had folate deficiency 6 months after delivery.11 Pregnant women with short IPI have an increased risk of folate deficiency—a risk factor for preterm birth.27–29The observed higher risk of preterm birth associated with short IPI may be explained by the maternal nutritional depletion hypothesis, in which lactation and insufficient time to recover from the physiological stress of the previous pregnancy adversely affect maternal nutritional status.4 The first is the “physiological regression hypothesis,” by which pregnancy causes anatomical, physiological, and biochemical adaptations in the reproductive system that gradually return to baseline conditions after delivery. When women are not pregnant or have not delivered a baby for a long time, the characteristics of reproductive system may become similar to those of women who become pregnant for the first time. The second hypothesis is that a long IPI may be caused by infertility-related factors, thereby increasing the risk of preterm birth.30Nevertheless, it is unclear why a long IPI increased the risk of preterm birth. Zhu et al offered two hypotheses about the mechanisms for this.31–34 which is a risk factor for atherosclerosis35 and thrombosis.36,37 For pregnant women, lower folate levels might affect placentation during pregnancy. A previous study reported that pregnant rats without folate supplementation tended to have lower plasma folate levels, higher plasma homocysteine levels, and decreased placental DNA methylation and placental weight.38 For pregnant women, lower blood folate levels (≤9.2 nmol/L) during pregnancy (median: 13.2 weeks of gestation) were associated with lower placental weights and higher risks of preterm birth (<37 weeks of gestation).27We found a higher risk of preterm birth related to <6-month and ≥120-month IPIs among women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. Folate is a cofactor for single-carbon transfers in the metabolism of nucleotides and amino acids; folate deficiency caused higher homocysteine levels,The strengths of our study include its prospective design and the large sample size in a national birth cohort. We examined associations between fine categories of IPI and risk of preterm birth after extensive adjustment for potentially confounding factors.39 Second, information regarding supplementation with folic acid during pregnancy was collected from self-reported questionnaires. Nevertheless, a previous study reported that Pearson’s correlation coefficient for comparing questionnaire data with interview responses was 0.76 for supplementation with folic acid.40 Third, due to the lack of information on presence or absence of labor, which is necessary to define spontaneous preterm birth,41 we could not discriminate preterm birth as spontaneous or indicated preterm birth. However, a previous study showed that <6-month IPI was associated with an increased risk of both spontaneous and indicated preterm birth (<37 weeks of gestation) than was 18-month IPI.42Our study has a few limitations that need mentioning. First, we could not consider pregnancy following miscarriage to calculate IPI. A recent meta-analysis of ten studies indicated that a <6-month IPI following miscarriage was not associated with a higher risk of preterm birth.In conclusion, both <6-month and ≥120-month IPIs were associated with increased risk of preterm birth in pregnant Japanese women. The interaction between IPI and folate/folic acid intake on risk of preterm birth was not statistically significant; however, higher risks of preterm birth related to <6-month and ≥120-month IPIs were found in women with inadequate intake of dietary folate and folic acid supplementation during pregnancy, suggesting that adequate intake of dietary folate or folic acid supplementation during pregnancy may contribute to decreased risk of preterm birth related to IPI.


The subjective childbirth experience is crucial from a public health standpoint. There is a correlation between a negative childbirth experience and a poor mental state after birth, with effects that go far beyond the postpartum (PP) period. This paper offers a new approach as to how birthing experiences, and birth in general, can be navigated. The theory of set and setting proves that psychedelic experiences are shaped, first and foremost, by the mindset of an individual entering a psychedelic experience (set) and by the surroundings in which the experience happens (setting). In research on altered states of consciousness during psychedelic experiences, this theory explains how the same substance can lead to a positive and life-changing experience or to a traumatic and frightening experience. Because recent studies suggest that birthing women enter an altered state of consciousness during physiological birth (“birthing consciousness”), I suggest analyzing the typical modern birthing experience in terms of set and setting theory. I argue that the set and setting key parameters can help design, navigate, and explain many psychological and physiological elements of the human birth process. Thus, an operative conclusion that emerges from the theoretical analysis presented in this paper is that framing and characterizing the birth environment and birth preparations in terms of set and setting is a central tool that could be used to promote physiological births as well as subjective positive birthing experiences, which is currently a primary, yet unreached goal, in modern obstetrics and public health. This theoretical paper aims to introduce the critical parameters of “set and setting” from the field of psychedelic research to the field of childbirth research and argue that, if taken seriously, these parameters would significantly advance scientific understanding concerning the birth process and the factors that contribute to or hinder the physiological birth process as well as concerning polar birth experiences.1In spite of the many advances in the field of modern obstetrics, childbirth has become more dangerous to women in the Western world—because of the increase in highly medicalized birth , 2. PracThus it is crucial to understand the factors that shape birth experiences. I propose that a fruitful way to do so would be through comparing physiological birth experiences to psychedelic experiences. There are at least four clear resemblances between the two phenomena.First, both experiences are, in many cases, associated with altered states of consciousness: the phenomenology of both states is similar, and there is a probability that both have the similar brain mechanism of hypofrontality see –14]. Alt. Alt14)]Second, both birth experiences and psychedelic experiences, have an intensive inner dynamic , 17 deriThird, seemingly connected to this intensity, both can be analyzed in terms of surprising causal feedback loops. Causal feedback loops encompass response dynamic: the results of a certain variation, even a minor one, may strengthen, or contradict the initial variation. They introduce complex dynamics by which a shift in one feature may impact a different feature, which then is capable of impact the initial feature. Feedback loops can amplify an event in either a positive or negative direction . The birFourth, there are two opposing, extreme subjective experiences possible for both phenomena. Psychedelic substances can generate a tremendously good experience–a “good trip”–but the same substance can sometimes generate the opposite sensation–a “bad trip” . A good On the face of it, this looks like an enigma: how can the same substance in the case of psychedelics, or the same physiological process in the case of childbirth, produce such extreme and opposing experiences, with such extreme and opposing consequences? For psychedelic experiences, the enigma has been solved through the theory of set and setting parameters that predict and explain how the set and setting surrounding the experience have the power to influence and design the opposing psychedelic experiences , 25–29. Because of the similarities between birth and psychedelic experiences  The experience of spontaneous altered states of consciousness may well be a hallmark of physiological childbirth in humans and therefore its research may offer a unique opportunity to understand consciousness and transcendental growth [emphasis added] … This knowledge is important to include in birth preparation courses and consultations.This description of women’s experiences during labor and birth and its potential for transformation resembles descriptions of mystical states of consciousness. Classically these states have been achieved through meditation and religious practices  or through intake of substances with hallucinogenic properties such as psilocybin or LSD, which interact with serotonin receptors. Childbirth has not been mentioned in those classical descriptions. 2Thus, I maintain that the existence of polar extremes of the birth experience, with opposite sensations and consequences, calls for investigation using consciousness studies tools.3 The set includes the personality, preparations, expectations, and intentions of the person having the experience, and the setting includes not only the physical location but also the people around and the broader sociocultural context  and the important elements of the freedom to exercise autonomy and access to psychological and physical support ],It should be remembered, though, that designing better birthing rooms cannot be counted as a magical solution for supporting natural births; they are merely one factor in the setting and not necessarily the determinative one. The set of the preparations and intentions, e.g., the will, of the women play a crucial role in the outcomes. Another crucial role plays the hospital’s birth philosophy, a function of setting. A recent study  emphasizOne-on-one support decreases the rate and need of various medical interventions  and incrObstetrician comes from the Latin phrase obstetrics, which plainly means “she who stands before,” which refers to “midwife.” Moreover, midwife is an old German term that simply means “with woman”  perpetuate the medical approach to childbirth, while coverage of more physiological births is generally absent from the media . In a seThis picture of childbirth is inaccurate, however, it does not show what usually happens in the advanced stages of medical birth, such as the association between epidural anesthesia and instrumental and emergency cesarean births ; the corAnother example of the effect of cultural factors is the rising use of epidural anesthesia in Western countries. While epidural is highly effective form of pain relief, it does not automatically improve the birthing woman’s experience . Social Electronic fetal monitoring is usually used in admission to the hospital with no consideration of the risks in using it continuously during the birth process . A contiAnother example of the effect of cultural factors are studies that show that ethnocultural differences, such as language, values, or religious beliefs–can affect women’s perceptions and beliefs about childbirth, and also influence birth experiences, even when there is no difference in the levels of medical interventions .The analysis I have offered shows how the same set and setting key parameters that shape psychedelic experiences also shape birthing experiences. And, as stated previously, it is not only that the set and setting theory has explanatory powers to describe the birthing experience retrospectively. The framing of set and setting also has the power to predict future experience outcomes.There seems to be broad agreement with the familiar slogan that “you cannot control birth” . PerhapsIn the late 1980s, Newton  discusseI hope that the decade of the 1990s will see this knowledge developed and used to help childbearing women [emphasis added]. ..127)].navigate birth to a physiological direction if one does not ignore the birthing woman’s mental state and the environmental and social settings.It seems reasonable that the broad agreement that birth cannot be predicted or controlled without medicalization is related to the common basic assumption that delivery is dangerous and harrowing and that before the era of modern obstetrics, there was nothing that could be done about it from the perspective of the birthing woman herself, aside from being close to potential helpers around the time of birth [see ]. The beThe experience of childbirth does not uniformly emerge in all women in the same way or even in the same women in different births. Far from uniformity, the effects of childbirth are remarkably diverse and sometimes polarized. I suggest that the birth experience depends first and foremost on the set  and the setting .Thus, for example, the birth experience that takes place in a threatening environment for an anxious woman who is afraid of the pain of birth is likely to provoke unpleasant reactions, anxiety, intense pain, and suffering, to the point of complicating the birth and causing post-traumatic effects. On the other hand, a woman who is aware of the issue of pain management in childbirth and seeks to maximize the therapeutic and analgesic effects of the hormones that are part of the birth process, with childbirth taking place in a supportive and pleasant environment, could be expected to have a more positive, even empowering, experience.My hypothesis is that differences in set and setting conditions are what lead to opposite extreme results in the birth experiences of many women, just like differences in set and setting conditions in psychedelic research in the mid-20th century revealed traumatic experiences, on the one hand, and positive and life-changing experiences, on the other. In other words, I suggest a conceptual shift. Instead of thinking in terms of “control” regarding childbirth, it would be better to think in terms of “design and navigation.” Instead of trying to control childbirth by hyper-medicalization of it, we should design the birth set and setting to provide optimal conditions for the birth experience and thereby navigate birth. immediately to the set and setting key parameters, because birthing has intensive feedback loop dynamics. Thus, concerning optimal management of the birth process, set and setting are crucial factors we must deal with. If my hypothesis is valid, then the science of consciousness and philosophy of mind can promote the science of birth.The history of psychedelic research directs us to give more attention to how non-physiological factors shape altered states of consciousness and their effects on the mind and body. During childbirth, the woman responds enhance the positive state of consciousness or suppress it. The result is an extreme experience: a positive and life-changing experience compared to a negative or even traumatic one. I believe that this model is ripe for empirical inquiry.The seeming unpredictability and uncontrollability of the birth process and the possibility for unexpected complications should not encourage fatalism. The set and setting concept may significantly advance scientific understanding of the birth process, particularly what promotes healthy birth and what may hinder it. The history of psychedelics’ extreme polar experiences directs us to give more attention as to how non-physiological factors shape altered states of consciousness and their effects on the mind and body. In this paper, I have theoretically demonstrated that a broader understanding of the set and setting key parameters can significantly improve our understanding of human birth.Moreover, the basics of the set and setting theory challenge one of the fundamental and rooted premises of modern obstetrics: that birth progresses as it does purely from a physiological mechanism. But, as stated, women also give birth with their minds, not just their bodies. Thus, physical and social settings have crucial effects on the birth process, and there are empirical studies that validate these kinds of effects. In examining birth experiences, we must re-examine the implications of the altered states of consciousness in childbirth, which respond immediately and flexibly to set and setting key parameters. For optimal management of the birth process, set and setting are crucial factors.The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.The author confirms being the sole contributor of this work and has approved it for publication.