Bronchogenic cysts originate from the tracheobronchial bud, which arises from the embryonic foregut. Congenital bronchogenic cysts in the cervical region, especially in the thyroid or perithyroidal area, are extremely rare. Moreover, distinguishing them from other cervical cystic lesions such as thyroglossal duct and branchial cleft cysts and metastatic cervical lymph nodes is difficult preoperatively. In this report, we discuss a case of a 41-year-old woman who presented to us with a history of anterior neck swelling for two weeks with occasional palpitations and bilateral flank pain. On workup, she was diagnosed as a case of multiple neuroendocrine neoplasm type 2A for which she underwent adrenalectomy first followed by total thyroidectomy with central neck dissection and parathyroidectomy. On the final histopathology specimen, an incidental bronchogenic cyst was diagnosed. A bronchogenic cyst is a rare entity, especially in the head and neck region, and can be confused with a metastatic lymph node. Diagnosis is made based on the histopathological examination, which requires surgical excision. The bronchogenic cyst should be considered in the differential diagnosis for midline and lateral neck masses. Bronchogenic cysts originate from the tracheobronchial bud, which arises from the embryonic foregut . It has Congenital bronchogenic cysts are extremely rare in the cervical region, especially in the area around the thyroid gland, and distinguishing them from other cervical cystic lesions such as thyroglossal duct, branchial cleft cysts, and metastatic cervical lymph nodes are difficult preoperatively due to their similar radiological features . TherefoThe patient was a 41-year-old woman who presented to us with a history of anterior neck swelling for two weeks with occasional palpitations and bilateral flank pain. She had a strong family history of medullary thyroid carcinoma (MTC). A neck ultrasound was done, which showed a right thyroid lobe nodule and an enlarged right parathyroid gland , and it was decided to offer her laparoscopic adrenalectomy first, followed by total thyroidectomy with neck dissection and right parathyroidectomy.Surgeries were performed as per the MDT's decision. The patient recovered well postoperatively without any complications. Histopathology after total thyroidectomy with neck dissection and right parathyroidectomy revealed right thyroid lobe MTC, right parathyroid adenoma, and bronchial cyst.Diagnosis of the bronchial cyst was an incidental finding on histopathology as it was not anticipated preoperatively and not recognized during surgery as it was mimicking as level VI lymph nodes. On histopathology, it was referred to as a bronchogenic cyst showing the lining thrown into small folds lined by ciliated lining and underlying fibrous cyst wall Figures , 3.Bronchogenic cysts are uncommon developmental anomalies of the tracheobronchial tree, and they rarely occur in the neck. More than 70 cases of bronchogenic cysts in the head and neck region have been reported in the literature so far . Many brMost frequently unilocular, they contain clear fluid or, less commonly, hemorrhagic secretions or air. These are lined by columnar ciliated epithelium, and their walls often contain cartilage and bronchial mucous glands . It is uThe differential diagnosis for cervical bronchogenic cyst includes thyroglossal duct cyst, branchial cleft cyst, metastatic lymph node, thymic and thyroid cysts, dermoid cyst and lymphangiomas, cystic hygroma, teratoma, and cystic neuroma . In our Large cysts may cause dyspnea, respiratory distress, cough, and dysphagia in some individuals. Occasionally, secondary infection may occur, resulting in sinus tract formation, external drainage of purulent material if the cyst is superficial, or abscess formation if the cyst is deep .A variety of cysts are seen in the head and neck region, and hence histopathological examination is essential for diagnosis. A typical bronchogenic cyst shows ciliated pseudostratified cuboidal to columnar epithelium with an underlying fibrous wall. Sometimes, variations may be seen, such as the presence of cartilage, seromucous glands, and smooth muscle . HoweverCarcinomas arising from bronchogenic cysts have been reported in the literature . These cA bronchogenic cyst is a rare entity especially in the head and neck region, and it can often be confused with a metastatic lymph node. Diagnosis is made on the basis of histopathological examination, which requires surgical excision. The bronchogenic cyst should be considered in the differential diagnosis for midline and lateral neck masses.


Maternal lifestyle is discussed as a modifiable determinant in the prevention of preterm birth. However, previous research on associations between individual lifestyle factors and preterm birth risk is inconclusive. In this secondary analysis, we investigated the associations between several modifiable antenatal lifestyle factors and the odds of preterm birth.This secondary cohort analysis used data from the cluster-randomised controlled “healthy living in pregnancy” (GeliS) trial. Data were collected from early pregnancy to birth with maternity records, validated questionnaires and birth protocols. Women with complete datasets for all covariates were eligible for analysis. Multivariate logistic regression models, adjusted for recognised risk factors, were fitted to determine whether dietary quality, assessed with a healthy eating index (HEI), physical activity (PA) levels and antenatal anxiety/distress influenced the odds of preterm birth. Moreover, the combined association between pre-pregnancy body mass index (BMI) and HEI on the odds of preterm birth was explored. The independent associations of individual dietary components and types of PA on prematurity were assessed by adjusted logistic regression models.p = 0.033), while no associations with either low PA levels or antenatal anxiety/distress were observed. BMI significantly interacted with HEI on the association with prematurity (p = 0.036). Energy % from protein and the intake of average portions of vegetables and cereals were significantly negatively associated with the odds of preterm birth. There was no significant evidence of an association between different types of PA and prematurity.Overall, 1738 women were included in the analysis. A low HEI significantly increased the odds of preterm birth (OR 1.54 (CI 1.04 – 2.30), This cohort analysis revealed that low dietary quality in early pregnancy may increase the chance of giving birth prematurely, while healthier dietary choices may help to prevent preterm birth. More research on pre- and early pregnancy modifiable lifestyle factors is warranted.NCT01958307). Registration date 09 October 2013, retrospectively registered.This trial is registered with the Clinical Trial Registry ClinicalTrials.gov (The online version contains supplementary material available at 10.1186/s12884-022-04513-5. Preterm birth is the leading cause of death in children under the age of five years . GloballThe causes of preterm birth are multifactorial and may be sociodemographic, biological, clinical, social-behavioural and environmental in nature , 8. AlthPrevious studies have investigated potential associations between individual maternal lifestyle factors and the risk of preterm birth, including diet –22, physThe objective of this cohort analysis was therefore to simultaneously investigate the associations between several pre- and early lifestyle risk factors, including dietary quality, PA levels and anxiety/distress, as well as putative socioeconomic and health risk factors on the odds of preterm birth. We additionally examined the potential influence of certain food groups and different types of PA on the odds of preterm birth.The cluster-randomised controlled “Gesund leben in der Schwangerschaft”  (GeliS) trial was embedded in routine prenatal care and aimed at reducing the proportion of women with excessive gestational weight gain (GWG), as defined by the Institute of Medicine (IOM) . Results2 and ≤ 40.0 kg/m2, (2) singleton pregnancy, (3) aged between 18 and 43 years, (4) ≤ 12 weeks of gestation, (5) sufficient German language skills, and (6) provision of written informed consent. Women were not eligible if they had multiple or complicated pregnancies or chronic diseases.In brief, participating midwifery and gynaecological practices from five regions in Bavaria, Germany, recruited pregnant women between 2013 and 2015. Women were eligible for participation if they met the following inclusion criteria: (1) pre-pregnancy BMI ≥ 18.5 kg/mWomen in the control group received standard prenatal care and a leaflet containing general information on healthy lifestyle and breastfeeding. Participants in the intervention group were offered three counselling sessions during pregnancy and one in the postpartum period alongside their routine care visits. Lifestyle counselling was given by previously trained midwives, gynaecologists or medical personnel and comprised personalised advice on recommended GWG, healthy diet, PA and breastfeeding .Data on gestational age at birth were derived from birth records. Preterm birth was defined as a live birth before 37 completed weeks of gestation, including both spontaneous and iatrogenic (induced labor or planned caesarean section) preterm birth. Preterm birth was further categorised into extremely, very, and moderate-to-late preterm born, referring to a gestational age of < 28 weeks, 28 – < 32 weeks, and 32 – < 37 weeks, respectively [th week of gestation. Educational level was classified as low when women graduated from general secondary school or lower.Maternal sociodemographic data were obtained by a screening questionnaire before the 122), overweight (BMI 25.0 – 29.9 kg/m2), and obesity (BMI 30.0 – 40.0 kg/m2)). Maternal weight during pregnancy was measured at each antenatal visit and recorded in maternity records. Early pregnancy GWG was calculated by subtracting the first measured weight in pregnancy (≤ 12 weeks of gestation) from the weight measured at the 16th to 20th week of gestation. Early GWG was further categorised into inadequate, adequate and excessive GWG according to the weekly GWG recommendations from the IOM [Maternal pre-pregnancy weight was likewise collected via the screening questionnaire. The self-reported weight was used to categorise women into pre-pregnancy BMI classes . According to national and international guidelines, women were diagnosed with gestational diabetes mellitus (GDM) if one or more of the following cut-off values was equalled or exceeded: Fasting plasma glucose: 92 mg/dL (5.1 mmol/L), 1 h: 180 mg/dL (10.0 mmol/L), and 2 h: 153 mg/dL (8.5 mmol/L) [Between the 24 mmol/L) , 43.Women were asked to fill out a set of validated questionnaires in early pregnancy (≤ 12 weeks of gestation), covering pre- and early pregnancy lifestyle factors, including dietary and PA behaviour, smoking status, and mental health. Mothers who smoked during early pregnancy were classified as current smokers. Data on dietary intake over the last month were collected using the validated, and slightly modified, food frequency questionnaire (FFQ) originally developed by the Robert Koch Institute in Berlin, Germany, and applied in the German Health Interview and Examination Survey for Adults (DEGS) study . This quData on PA behaviour were obtained using the Pregnancy Physical Activity Questionnaire (PPAQ), which has been slightly adapted to fit German habits . The PPAData on maternal mental health were collected using the German version of the Patient Health Questionnaire-4 (PHQ-4). A score of ≥ 3 on a scale of maximum 12 points indicates symptoms of anxiety and depression .Women with available information on preterm birth and complete data for all of the covariates listed above were included in the analysis. Participants who dropped out during pregnancy, as well as women with missing or invalid lifestyle data due to over- or underreporting, were excluded from analysis see Fig. , data ofBaseline characteristics were stratified according to preterm birth status and are presented as means and standard deviations (SD) or frequencies and proportions. Differences between the groups were assessed by Chi-squared test for categorical and by Kruskal-Wallis test for continuous variables.Multivariate logistic regression models were used to examine associations between potential predictors and the odds of preterm birth. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Four models with different sets of categorical and equivalent linear covariates were fitted. Model 1 included group assignment, maternal age, and pre-pregnancy BMI as covariates. Model 2 additionally assessed the influence of early inadequate or excessive GWG and nulliparity on the odds of preterm birth. Model 3 further comprised low education and smoking status. For the fully adjusted Model 4, low HEI, low PA and antenatal anxiety and distress were added. We further explored the potential combined association of HEI and BMI on the odds of preterm birth by including their interaction term into the fully adjusted categorical Model 4. Further logistic regression models were fitted to examine the influence of individual dietary and PA variables on the odds of preterm birth, adjusting for group assignment, maternal age, parity, and pre-pregnancy BMI.Exploratory subgroup analyses of the multivariate logistic regression models were performed to assess the associations between the aforementioned covariates and the odds of spontaneous and iatrogenic preterm birth.p value of < 0.05 was considered statistically significant. Due to the exploratory nature of this analysis, no adjustment for multiple comparisons was perfomed.All analyses were performed using SPSS software . A Among 2286 enrolled women in the GeliS study, 2174 women were potentially eligible for the current analysis  had a preterm birth, of whom 100 (5.8%) were classified as moderate to late preterm, 12 (0.7%) as very preterm, and 2 (0.1%) as extremely preterm. Of the 112 women who gave birth to a preterm infant with additional information on the type of birth, 77 (68.8%) had a spontaneous and 35 (31.3%) had an iatrogenic preterm birth  (Table p = 0.055). The proportion of mothers with a low HEI score was higher among those with a preterm birth, as compared to those with a full-term birth . All other sociodemographic, health and lifestyle factors were comparable between groups (Table Table p = 0.033). There was no significant evidence of an association between pre-pregnancy BMI, excessive or inadequate GWG, low PA, antenatal anxiety/distress, smoking or low education and the odds of preterm birth  and the odds of preterm birth across Models 2 to 4 .In an exploratory analysis a significant interactive association between pre-pregnancy BMI and HEI on the odds of preterm birth was observed (p = 0.037) , Overall, the Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) were lower across categorical as compared to linear models (data not shown). Lower information criteria indicate a better fit of the model .p = 0.029) and across linear Models 1 to 4 (Model 4: OR 1.12 (1.04 – 1.22), p = 0.004)  , p = 0.030). E% from both carbohydrates in general and from saccharose tended to increase the odds of preterm birth, without evidence of a robust association .Table p = 0.023) and by 29% (p < 0.001), respectively. Consumption of dairy products yielded a similar trend (p = 0.078). No further food groups were significantly associated with the odds of preterm birth (Table Among food groups, vegetable intake and cereal intake, per average portion, lowered the odds of preterm birth by 25% p = 0.02 and by 2There was no evidence of associations for total PA or any of the different types of PA, including household, occupational, sports, transportation or inactivity with the odds of giving birth to a preterm infant Table .This secondary analysis of pooled data from the GeliS cohort investigated the simultaneous associations between several modifiable and non-modifiable pre- and early pregnancy, sociodemographic, health and lifestyle factors and the risk of preterm birth. The findings suggest that women with a low HEI in early pregnancy have a higher risk of giving birth to a preterm infant. An exploratory analysis further elucidated that there was a significant combined association between low dietary quality and higher pre-pregnancy BMI on the risk of preterm birth. More specific associations between selected dietary factors and preterm birth risk revealed that E% from protein and the intake of vegetables and cereals reduced the odds. None of the other modifiable risk factors, including low PA and anxiety or distress in pre- and early pregnancy, were significantly associated with the risk of prematurity.The causes of prematurity are still largely unknown, which makes the identification of early risk factors highly relevant for clinical practice. Within the last few decades, research has focused on identifying maternal sociodemographic and health characteristics as risk factors for preterm birth. Our data confirmed that advanced age and nulliparity increase the risk for preterm birth, as already noted previously . SubgrouBesides maternal sociodemographic and health characteristics, lifestyle factors are discussed to play a crucial role in preventing preterm birth. So far, published research focused on analysing lifestyle factors independently. However, factors might interact with each other, which emphasizes to explore the combined associations of predictors on preterm birth risk.Recent observations of lower preterm birth rates during the lockdown phases of the ongoing COVID-19 pandemic suggest that drastic changes to women’s lifestyles may emerge as possible contributory factors –61. BesiIn addition to maternal mental health, diet and PA have been discussed to influence preterm birth risk. In line with our findings, recent systematic reviews , 62, 63 Inconsistencies in findings related to dietary parameters and their contribution to the risk of preterm birth may be attributable to differences in dietary assessment methods, timing of assessment, methodological approaches and heterogeneity in population characteristics, which makes a general comparison between study results difficult.The potential of PA as another modifiable risk factor for preterm birth risk is not yet fully understood. We did not observe any association between low PA and the odds of preterm birth in the combined model estimate. While some of the previous studies explicitly described leisure time PA/overall PA to reduce preterm birth risk , 65, othOur findings should be interpreted in light of some limitations. Despite using validated questionnaires to assess maternal lifestyle, self-reported data could have introduced reporting bias. Although we used a validated FFQ, we acknowledge that the calculated E% is only an estimate and may not be completely accurate. Although we adjusted for a variety of non-modifiable and modifiable covariates in our multivariate models, residual confounding by other risk factors, such as ethnicity or a history of preterm birth, cannot be excluded. We are aware that some of the reported OR for the influence of specific food groups are rather small and their clinical relevance has to be interpreted with caution. As the data are taken from a well-educated sample of women from a single federal state, generalising our findings to the broader German population may be limited. The lack of more detailed information on the ethnicity of the study participants is a clear limitation which needs to be acknoweledged. The exclusion of women with complicated or multiple pregnancies, which are known to have an increased risk for preterm birth , could eThis comprehensive analysis has several strengths that merit particular attention. This study adds to the evidence the simultaneous consideration of modifiable and non-modifiable maternal determinants in pre- and early pregnancy on the odds of preterm birth. Moreover, few research groups have examined so far whether pre- and early pregnancy lifestyle factors play a role in increasing the risk for preterm birth. Dietary quality was rated with a HEI. This tool might be advantageous over previous approaches, such as dietary pattern analyses, as it was based on national recommendations. The GeliS study considered women of several BMI classes, which enabled us to identify a combined association between pre-pregnancy BMI and HEI on the odds of prematurity. Our study was conducted within the German routine care system and thus allowed the collection of data from medical records with minimal inconvenience to the participants and, consequently, low drop-out rates.Preterm birth is a global health issue, for which the causes are still largely unknown. Our findings suggest that a low dietary quality is associated with an increased risk of preterm birth, while a healthier diet may contribute to prevent prematurity. Further research on early modifiable risk factors is needed to develop prevention strategies. Cohort data allowing a pre- and within-pandemic comparison may be additionally valuable for further elucidation.Additional file 1: Table S1 Preterm incidence in intervention and control group. Table S2 Characteristics of eligible and included participants. Table S3 Proportions of spontaneous and iatrogenic preterm births. Table S4 Associations between sociodemographic, health and lifestyle factors and the odds of preterm birth – models including linear covariates. Table S5 Associations between sociodemographic, health and lifestyle factors and the odds of iatrogenic preterm birth – models including categorical covariates. Table S6 Associations between sociodemographic, health and lifestyle factors and the odds of iatrogenic preterm birth – models including linear covariates. Table S7 Associations between sociodemographic, health and lifestyle factors and the odds of spontaneous preterm birth – models including categorical covariates. Table S8 Associations between sociodemographic, health and lifestyle factors and the odds of spontaneous preterm birth – models including linear covariates.


On the child data birth, for each mass unit (kg) increase, the probability of having a cleft child decrease (odds ratio = 0.435). (4) Conclusions: In this study, only maternal body mass index and maternal age found statistical differences in the risk of having a cleft child. In the children’s initial data, the cleft group found a higher risk of having a lower birth weight but no relation was found regarding length and head circumference.(1) Background: The etiology of orofacial cleft (OC) is not completely known but several genetic and environmental risk factors have been identified. Moreover, a knowledge gap still persists regarding neonatal characteristics. This study evaluated the effect of parental age and mothers’ body mass index on the risk of having an OC child, in a matched year and sex group . Additionally, birth data were analyzed between groups. (2) Methods: 266 individuals born between 1995 to 2015 were evaluated: 133 OC individuals  and 133 control . A logistic model was used for the independent variables. ANOVA or Kruskal-Wallis tests were used for comparison between the OC phenotypes. (3) Results: Regarding statistically significant parental related factors, the probability of having a cleft child decreases for each maternal year increase (odds ratio = 0.903) and increases for each body mass index unit (kg/m Orofacial clefts (OC) are one of the most common craniofacial malformations, with an international prevalence in newborns of 14 per 10,000 live births worldwide . The preThe etiology of OC is not completely known but several genetic and environmental risk factors have been identified. Previous studies have clarified the importance of epidemiologic knowledge, especially in (1) assessing the burden of OC in order to plan public health resources; (2) knowing the causes of OC, which stimulates research on primary prevention and treatments to improve the quality of care . The genEven though there are several studies about OC etiological factors in the literature, there is a gap regarding neonatal characteristics. Several studies showed that OC children are lighter and smaller than healthy controls but with inconsistent results ,23. DespThis study aims to evaluate the effect of possible parental related influencing factors on the development of cleft lip and/or palate as well as the differences in birth data. Therefore, this study used child recruitment with standardized methods in order to obtain a homogeneous sample regarding age, sex, and sociodemographic factors. Moreover, length and head circumference at birth will be measured in addition to birth weight. The purpose of this study was to test the hypothesis that the risk of having a cleft child increased with parental age or maternal BMI, and also to compare the differences in birth data  between cleft children and healthy controls (non-cleft group).This retrospective case-control study was approved by the Ethics Committee of the Faculty of Medicine of University of Coimbra (Reference: CE-072/2020). The study was handled in accordance with the Declaration of Helsinki.The study group included parents from children (born between 1995–2015), with non-syndromic OC, being rehabilitated at the Institute of Orthodontics, Faculty of Medicine, University of Coimbra (FMUC), regardless of sex or place of birth. The control group included individuals without clinical alterations or craniofacial defects. To minimize bias, controls were matched according to year of birth and sex. Both groups had similar socio-economic backgrounds.Data were collected through two sources: (1) medically recorded data—parents were requested to send the pre-natal care logbook and all medical record during the pregnancy; (2) maternal self-reported information.A structured questionnaire was also distributed to the parents of both groups after the clinical visit, avoiding any harm to the patients. The questionnaires were deployed always by the same examiner (I.F.) after being properly trained for the activity. Before fulfilling the questionnaire, parents were asked to read the enclosed list as a memory aid with the most common maternal diseases during pregnancy and pregnancy supplements. From both groups, the parents who did not consent to participate in the study or who did not answer the questionnaire sufficiently, parents with consanguineous marriages, and children with syndromic OC were excluded.-Sociodemographic—age of parents and child; child’s sex.-Obstetrical data—alcohol intake, smoking, drugs, and pregnancy supplements used, diseases diagnosed before and during pregnancy and exposure to carbon monoxide, recorded by gestational month; early pregnancy body mass index.-Child birth data—presence and phenotype of cleft, birth weight, birth length, and head circumference at birth.The questionnaire included retrospective parent and patient information. Variables were divided in three groups:After matching the control group to the OC group, the final sample consisted of 266 individuals . All parAll analyses were performed using the Statistical Package for the Social Sciences, version 26.0 for Windows . The significance level chosen was 0.05.Descriptive statistics for the quantitative variables were obtained using mean, standard deviation values, and 75th and 25th percentiles. Categorical variables were expressed as absolute and relative frequency.The comparison between the groups was performed using Fisher’s exact test for gender , and for the quantitative variables, the Mann-Whitney test was used when a violation of the normality assumption was verified through the Shapiro-Wilk test.To assess the risk factors, a logistic model was adjusted using as independent variables parental age, maternal BMI, and birth data . The logistic model was evaluated using the Naguelkerke’s R2 and by measuring the area under the ROC curve. The null hypothesis of the statistical analysis (the logistic regression) is that no risk factors exist.Comparison between the different phenotypes of cleft was performed using the ANOVA test or the Kruskal-Wallis test when the normality assumption was not observed. Tukey’s post-hoc tests were performed, after verifying the significant ANOVA test.In total, 266 eligible cases were identified in the FMUC between 1995 and 2015, among them 133 were orofacial cleft and 133 were control group.p = 1.00) between groups .p < 0.001). The model obtained explains about 17% of the variance (R2Naguelkerke = 0.169) and presents an accuracy of 63.2% which is compared with 50% obtained in the null model. Three independent variables  found statistical significance using the logistic model (2) increase, the probability of having a cleft child increases 1.14 (OR = 1.14). The child-birth data showed that for each mass unit (kg) increase at birth, the probability of having a cleft child decreases 0.4 (OR = 0.435). The area under the ROC curve for the probabilities obtained by the logistic model was 0.699 .Regarding parental related factors, it was found that (1) for each maternal year increase, the probability of having a cleft child decreases 0.9 (OR = 0.903) and (2) for each BMI unit (kg/mp = 0.573).No association between maternal age and BMI index on the risk of having a child with a cleft was found (p = 0.023) with a statistical difference in cleft lip .The purpose of this study was to evaluate the effect of parental age and mothers’ BMI on the risk of having a child with OC. Possible interaction of mother risk factors is also investigated. Moreover, birth data of cleft children were analyzed to assess the differences between patients with OC and healthy controls. Of the six study variables, three variables  found statistically significant differences using the logistic model (p = 0.747) in all age groups study, including mothers 35 years of age or older [The current study suggests that for each maternal year increase, the probability of having a cleft child decreases 0.9 (OR = 0.903) but no statistical differences were found regarding paternal age. The association between the risk of having cleft and parental age does not have a consensus in the literature ,28,29. Hor older ,31. Berg2) increase, the probability of having a cleft child increases 1.14 (OR = 1.14). These findings are consistent with the results of three meta-analyses that found an association between overweight women and orofacial clefts with a similar odds ratio for cleft palate and for unilateral cleft lip and palate [p = 0.023) with a statistical difference in cleft lip (p = 0.04) [A positive association between BMI and orofacial cleft was also found: for each BMI unit  . The mecp = 0.573). This result is unexpected because ageing is associated with an increase in abdominal white adipose tissue and fat deposition in skeletal muscle, which significantly affect insulin sensitivity [Despite the average associations regarding maternal age and maternal BMI, no exploration of possible interaction in both risk factors has been done. Thus, this is the first study that intends to verify this relation, revealing that no association can be established between these two factors (sitivity . Moreovesitivity .p < 0.001), suggesting that for each increase in mass unit (kg) at birth, the probability of having a cleft decreases 0.4 (OR = 0.435). This finding is consistent with the Wyszynski et al. study, which verified that cleft palate patients with or without lip involvement had slightly lower birth weight  [Regarding child birth data , all variables presented a lower mean in the cleft group compared with non-cleft individuals. However, only birth weight found statistical differences using the logistic model (ctively) . Becker ctively) . These actively) ,23. Despctively) .The main limitation of the present study was the analysis of the different types of orofacial clefts because the division of data into subgroups results in very small numbers, especially in cleft lip where the prevalence is lower. This may explain why only BMI showed differences statically significant among the different types of cleft studied. Additionally, unmeasured confounding factors cannot be excluded even though the model obtained presents an accuracy of 63.2%. This study has several strengths compared with the published literature: (1) both groups had similar socio-economic backgrounds; (2) controls (non-cleft group) were individually matched to each case regarding age and sex; (3) a geneticist participated in the diagnosis of the cleft group, avoiding including syndromic patients; and (4) data birth were recorded by medical professionals.This study highlights the complexity in identifying the risk factors for having orofacial cleft, especially when trying to detect differences between phenotypes. In some countries all over the world, healthcare systems cannot afford treatment for cleft lip and palate. Identification of strategies to modify risk factors for non-syndromic OC (such as being overweight) is the first step toward primary prevention . As stroIn this homogenous population-based study, maternal body mass index and maternal age was found to affect the risk of having a cleft child. However, the association of these two factors does not increase the risk. In the children’s initial data, the cleft group found a higher risk of having a lower birth weight but no relation was found regarding length and head circumference. This trial and further studies will allow the incorporation of the findings into preconception counseling health care programs for women of reproductive age.


A polypropylene (PP) film is usually used as a dielectric material in capacitors as well as cables. However, PP films may degrade because of the combined effect of temperature and electric field. In an earlier study, plain PP films and PP films loaded with nano-metric natural clay were studied under sinusoidal (AC) electric fields at power frequency and temperatures above the ambient. To better understand the electrical characteristics of PP film under various conditions, the objective of this study is to determine the time-to-breakdown of the plain PP and PP filled with 2% (wt) natural nano-clay when subjected to time-invariant (DC) electric fields at elevated temperatures. In order to achieve this objective, the effects of uniform as well as non-uniform electric fields were compared at the same temperature for the PP film. In this study, experimental results indicated that the time-to-breakdown of all PP films, plain or filled with nano-clay, decreases with the increase in electric field intensity, non-uniformity of the electric field, and temperature. It was also found that the time-to-breakdown of PP film filled with 2% (wt) natural nano-clay under DC electric field is longer and less sensitive to temperature. Furthermore, when compared with the results under the uniform electric field, PP film filled with 2% (wt) nano-metric natural clay indicates shorter time-to-failure under non-uniform DC electric fields. Finally, the morphology of the samples was observed by digital camera, optical micrography, and SEM, to better understand the mechanism of the breakdown. For its economic development, the ever-increasing demand for electrical energy in China requires the upgrading of electrical energy infrastructure, especially with the incorporation of renewables sources such as wind and solar energy. A high-voltage direct current (HVDC) transmission systems is one of the most important candidates to reliably deliver large amounts of energy over thousands of miles . When elPolymeric materials are often used as insulation materials in cables in high-voltage applications. As one of the most widely used polyethylenes (PE) ,4,5, theIn an earlier study, plain PP films and PP films loaded with nano-metric natural clay were studied under sinusoidal (AC) electric fields at power frequency and temperatures above the ambient. However, to the best of our knowledge, there is very little information about the behavior of PP and its nano-composites with natural clay under time-invariant electric fields (DC). It has been shown that in solid dielectrics, the development of charge and the breakdown phenomenon are significantly different under time-invariant (DC) electric fields than under sinusoidal electric fields.High temperature may lead to the degradation of electrical insulation ,19. EspeIn this work, the same samples were tested under combined DC fields and thermal stresses. Experiments were carried out under different degrees of homogeneity of the electric field. Furthermore, the mechanism of insulation failure can be fully understood by observing the morphology of the experimental samples. The objectives of this study are to have a more comprehensive understanding of various phenomena and electrical properties in polymer-based materials when subjected to DC electric fields, and to lay a solid foundation of these materials before they are applied to real applications in power equipment.®20A, [Al1.67 Mg0.33 (Na0.33)]Si4 O10 (OH)2) filled PP films were labeled as the other group. The dimension of samples was 50 mm × 50 mm with a thickness of 135 μm with a variation of ±10%.Preparation of the PP film and its nano-composites tested in this work are the same as in our previous studies ,21. The In the specially made experimental tank, as shown in Two groups of stainless-steel electrodes were used in the experiment to compare the results under different electric field conditions. The parameters and side view of the electrodes during the measurement are given in detail in As shown in During each test, when the temperature was stable at the pre-set level, the sample was subjected to DC electric fields of 40 kV/mm, 50 kV/mm, and 60 kV/mm, respectively. The leakage current was measured by a digital multimeter  with an accuracy of better than 0.25%.The time-to-breakdown, which means that the time from the beginning of voltage application to the breakdown (failure) of the sample, was recorded at each temperature and electric field. Five samples were used for each test. The time-to-breakdown of both unfilled isotactic PP films and nano-modified PP films decreased with the increase in electric field intensity at a fixed temperature; the results can be found in It is worth noting that, at the same electric field intensity, the time-to-breakdown of unfilled PP film at 92 °C was longer than that of the nano-modified PP film at 72 °C. This phenomenon is consistent with the discovery under AC field , and canAt 60 kV/mm, the time-to-breakdown of PP film and its nano-composite at three different temperatures is shown in Due to the symmetrical molecular structure, the crystallinity of isotactic PP is higher than that of non-isotactic pp. In the filled PP films, the presence of nanoparticles has a negative effect on the crystallinity of PP. Moreover, the temperature field provides external energy, which increases the molecular thermal motion. The polymer matrix and nano-clay filler have different motion activity, making the filled PP more unstable than the plain PP at the same temperature. As a result, the lifespan of PP films filled with nano-clay, which has a higher molecular mobility, is shorter than that of the plain samples under combined electric and temperature fields. Under different electric fields, dielectric polarization has different performance. The comparison of the experimental results of PP films filled with 2 wt % nano-clay under DC electric field and AC electric field is shown in The aging of the polymer was greatly accelerated by high temperature and high electric field intensity. It can be seen from The above results indicated that the PP film is more prone to failure under the AC field. This could possibly be because of the internal energy loss due to the rate of the charge of polarization processes in the dielectric under AC electric fields. When the material is subjected to DC voltage, only the leakage conduction loss dominated the internal energy loss of the dielectric. However, under AC voltage, there is polarization loss in addition to the leakage conduction loss. More energy loss of the polymer under AC field accelerates the temperature elevation inside the material, which further intensifies the thermal motion of the molecules. Admittedly, the nano-clay fillers in the samples have different physical and chemical properties from the polymer matrix. Subsequently, the enhanced thermal motion of all molecules in the PP film will destroy the diffused ionic layer between the clay flakes and the polymer matrix. As a result, a large number of clay flakes peel off from the polymer matrix, which accumulate and collide with the polymer molecules. Therefore, the weak point is more likely to be produced in the PP film, which will lead to the breakdown under AC voltage.In addition, due to the different polarization performances under different electric fields, the PP film subjected to time-invariant (DC) electric fields has lower molecular mobility than that of the PP film subjected to sinusoidal (AC) electric fields.The surface morphology of the breakdown-point obtained by digital camera, optical microscope, and scanning electron microscope (SEM) of PP film filled with 2 wt % nano-clay under the combined electric and temperature field is shown in The failure of polymers in the long-term combined electric and temperature field is a time-dependent phenomenon as well as a process of thermal breakdown. The temperature field provided further energy for the internal energy loss and accelerates the aging of materials. Compared to the breakdown-point of samples after being tested under DC electric field, it is indicated that the breakdown-point of samples after being tested under AC electric field has bigger size, shown in Based on the comparison of the results under different electric field formations, it is found that the nano-modified PP film has a longer lifespan under DC electric field at a fixed experimental condition. This provides more possibilities for the application of PP in DC power equipment. However, the distribution of the electric field in the insulating material under actual operating conditions is extremely complex, and the non-uniform electric field distribution is often encountered. Consequently, in order to fully understand the characteristics of PP under DC electric field, experiments under different electric field uniformity were carried out. The results are shown in Experimental results showed that the time-to-breakdown of nano-modified PP film shortens with the increase of the non-uniform DC electric field intensity. Similarly, when the applied voltage is constant, the time-to-breakdown shortens with the increase of the temperature. Therefore, the breakdown characteristics of the material under the non-uniform electric field are also similar to those under the uniform electric field. Experimental results in In the uniform electric field, the breakdown of the sample may occur at any position between the electrodes. However, when the non-uniform electric field was applied, the breakdown always occurs at the tip of the conical electrode where the electric field intensity is much higher than other locations. Consequently, in practical application, improving the electric field distribution on the polymers is an effective way to extend the lifespan of the insulation system.The maximum leakage current before breakdown was recorded in the DC experiment, and it is found that the value of the leakage current under the non-uniform electric field is 248.0 μA which is approximately 4.5 times of that under uniform electric field (65.6 μA), as can be seen in Under a long-term DC electric field, the current through the experimental circuit is mainly the leakage current through the sample. No polarization current can be measured. Before the failure of the material, the amplitude of leakage current is extremely small and is even lower than the magnitude of the noise. As the activation energy of the molecules in the material continuously accumulates at an elevated temperature, the physical and chemical properties of polymers are also changing. When the activation energy exceeds the initial barrier of electrical destruction, the breakdown occurs. This process takes more time in DC electric field than in AC electric field. Because in the AC electric field, the increase of activation energy of polymer molecules is not only supported by the temperature field, but also assisted by the polarization current.Different from the experimental results obtained under the uniform electric field as shown in The results of Fourier Transform Infra-Red (FTIR)  shown in According to the kinetic theory of solid strength combined with nonlinear stress-strain dependence , the PP In this paper, the electrical properties of the PP films under DC electric field combined with temperature field are investigated experimentally. One of the important conclusions of this work is that the nano-modified PP film under DC electric field has a longer lifespan compared to the values measured under AC electric field. The main reason for this result is that besides the leakage conduction loss, under AC electric field, the polarization loss plays an important role in the failure process. Whereas, under DC electric field, only the leakage conduction loss dominates the failure process.Similar to the experimental results under AC electric field, the time-to-breakdown of the PP film filled with nano-particles is shorter than that of the unfilled isotactic sample. The failure of polymers in the long-term combined electric and temperature field is a time-dependent phenomenon, in which thermal effects contribute to the breakdown. The temperature field provides further energy for the internal energy loss and accelerates the aging of materials. The carbonization at the breakdown point can be used as one of the characteristics to judge the breakdown type of polymers. When a thermal breakdown occurs, there is obvious carbonization at the breakdown point, but when an electric breakdown occurs, it is difficult to observe the trace of carbonization.Compared with the results under the uniform electric field, the life of the nanocomposite film under the non-uniform DC electric field is shorter. The breakdown of materials is the result of the joint contribution of both the electric field and the temperature field in a uniform electric field. However, the electric field contributes more to the breakdown of materials in the non-uniform electric field.The experimental conclusions provided in this paper are expected to contribute to a better understanding of the electrical properties of polymers and their wider application in HVDC power transmission lines.


The aim of the study is to evaluate the influence of the timing of antenatal steroids (ANSs) on neonatal outcome of very low birth weight infants (VLBWI) born before 30 weeks of gestation in the German Neonatal Network.n = 187, (II) only one dose of betamethasone, ANS-birth interval 0–24 h, n = 70, (III) two doses of betamethasone, ANS-birth interval >7 days, n = 177, and (IV) no antenatal steroids, n = 238. Descriptive statistics and logistic regression analyses were performed for the main neonatal outcome parameters. Group IV (no ANS) was used as a reference.The German Neonatal Network is a large population-based cohort study enrolling VLBWIs since 2009. We included 672 neonates, who were born between January 1, 2009 and December 31, 2019 in our analysis in 10 selected centers. Infants were divided into four subgroups based on the interval between the first steroid administration and preterm birth: (I) two doses of betamethasone, ANS-birth interval: >24 h to 7 days, p < 0.001) and mechanical ventilation , whereas the group of infants that only received a single dose of steroids reflected a subgroup at high risk for adverse neonatal outcomes; an ANS-birth interval of >7 days was still associated with a lower risk for intraventricular hemorrhage  and the need for mechanical ventilation .An ANS-birth interval of 24 h to 7 days after the first dose was associated with a reduced risk for intraventricular hemorrhage (OR 0.17; 95% CI 0.09–0.31, Our observational data indicate that an ANS-birth interval of 24 h to 7 days is strongly associated with a reduced risk of intraventricular hemorrhage in VLBWIs. Further research is needed to improve the prediction of preterm birth in order to achieve a timely administration of antenatal steroids that may improve neonatal outcomes such as intraventricular hemorrhage. Preterm birth affects 10% of all children born worldwide with rates significantly varying between countries and continents –4. SeverThe German Neonatal Network (GNN) is a population-based observational multicenter cohort study of VLBWIs with a gestational age between 22/0 and 36/6 weeks enrolled in 65 German neonatal intensive care units since 2009. After obtaining written informed consent from parents or legal guardians, predefined data on general neonatal characteristics, antenatal and postnatal treatment, and outcome are recorded for each patient on clinical record files at the participating centers. After discharge, datasheets are sent to the study center (University of Luebeck). A physician or study nurse from the central GNN study office (University of Luebeck) with expertise in neonatology monitors the data quality of completed record files through annual on-site visits. As part of the standardized annually monitored documentation, the GNN record files include information on whether ANS was given to the mothers prenatally (no/complete/incomplete). However, an exact documentation of the injection timepoint is not recorded. Therefore, we performed an additional on-site monitoring of the exact timing of maternal ANS application in 10 randomly chosen GNN centers to calculate the ANS-birth interval. During this audit, we monitored maternal medical records of GNN cases with delivery and discharge between January 1, 2009 and December 31, 2019. The additional dataset included dates and times of ANS administration as well as the substance and dosage that were used (betamethasone or dexamethasone) and the number of applications. All recorded data were entered into a database, double checked, and imported into the GNN database at the study center in Luebeck.For the current analysis, we used data collected from VLBWIs born and discharged in GNN centers between January 1, 2009 and December 31, 2019, with a gestational age between 23/0 and 29/6 weeks who received active perinatal care. By performing an extra on-site monitoring to record exact dates and times of maternal ANS administration, we included mother–infant pairs from 10 GNN centers. The centers were chosen by a quasi-randomization based on the accessibility and the possibility of our study team to perform an extra on-site monitoring of maternal charts. All mother–infant pairs, of whom dates and times of ANS administration could be extracted from the patient charts and who fulfilled our inclusion criteria, were included into our analysis. Following international standards, two doses of betamethasone were administered intramuscularly with a dose of 12 mg at an interval of 24 h. To achieve a homogenous cohort and to reduce possible confounding factors, mother–infant pairs who received more than one cycle of ANS or were treated with dexamethasone were excluded. Furthermore, infants with lethal malformations were excluded. Since information on whether ANS were administered is part of the routine GNN documentation , all infants from the 10 GNN centers without ANS who met the inclusion criteria were included as a reference group in our analysis.To evaluate the effects of the timing of ANS on neonatal outcome, four subgroups were defined based on the ANS-birth interval.Group I: Two doses of betamethasone were administered at an interval of 24 h. The ANS-birth interval between the first application of betamethasone and preterm birth was ≤ 7 days and ≥24 h.Group II: Only one dose of betamethasone was administered. Accordingly, the ANS-birth interval was <24 h.Group III: Two doses of betamethasone were administered at an interval of 24 h. The ANS-birth interval between the first application of betamethasone and preterm birth was >7 days.Group IV was the no ANS group (reference): No ANS was administered.staphylococci (CoNS) were isolated as a single pathogen in one peripheral blood culture, two clinical signs and one laboratory sign were required for classification of CoNS sepsis  was defined as a birth weight below the 10th percentile for gestational age according to gender-specific standards for birthweight by gestational age in Germany . InotropS sepsis . BronchoS sepsis . NEC wasS sepsis . Death wS sepsis . PerivenS sepsis . Anencepp-value of <0.05 was considered statistically significant. To address the problem of multiple comparisons, we performed Bonferroni corrections for multivariate analyses in order to avoid statistical Type I errors. Additional information derived from Bonferroni correction is indicated in the Data analyses were performed using the SPSS 26.0 data analysis package . Hypotheses in the univariate analysis were evaluated with Pearson's Chi-square test for categorical variables and Mann–Whitney U-test for continuous variables. After univariate analyses, we performed linear and logistic regression models and included known confounders of neonatal outcomes as independent variables: gestational age per week, gender, multiple birth, mode of delivery, and SGA status. Effect size and 95% confidence intervals (CIs) were calculated. A For primary and subgroup analyses, we used a uniform dataset with available data for all metric parameters. Missing data were not included. For our statistical analyses, we defined the largest group (no ANS) as reference in the regression model.All study parts were approved by the University of Luebeck Ethical Committee and the committees of the participating centers (vote no. 08–022). Informed consent was obtained from all subjects. All methods were carried out in accordance with relevant guidelines and regulations specifically The Declaration of Helsinki, the current revision of ICH Topic E6, the Guidelines for Good Clinical Practice, and the Guidelines of the Council for International Organization of Medical Sciences, the World Health Organization .n = 187 received two doses of ANS 24 h to 7 days before preterm birth (group I), n = 70 infants had only one dose of ANS (group II), and n = 177 VLBWIs were treated with an ANS-birth interval of >7 days  were characterized by improved respiratory characteristics and superior postnatal adaptation when compared with infants with one dose of betamethasone or no ANS . During p < 0.001], more than three times as frequent in infants with a single dose of betamethasone  and almost twice as frequent in group III  when compared with infants in group I . IVH was almost four times as frequent in infants without ANS .In our cohort, 6.1% of the VLBWIs died during the primary hospital stay. Mortality was lower in group I (4.8%) and group III (4.5%) compared with group IV (8.0%) and group II (7.1%), but the difference did not reach significance . There wp < 0.001). An ANS-birth interval of more than 7 days proved to be protective against IVH with a higher OR than that for group I , whereas a single dose of betamethasone did not affect the IVH risk . When adjusted for main confounders, timely administration of ANS did not affect the infants' overall mortality . Furthermore, logistic regression models demonstrated that ANS-birth interval of 24 h to 7 days is protective against the need for mechanical ventilation  but not BPD. Single doses of ANS did not have a protective effect on neonatal outcome in our cohort. An ANS-birth interval >7 days (group III) was associated with lower risks for IVH and mechanical ventilation but not BPD and PVL.In logistic regression models, we adjusted our results for main confounders of adverse neonatal outcomes, such as gestational age, male gender, multiple delivery, delivery mode, and SGA status . The no p < 0.001) and >7 days  remained associated with a reduced risk for all grades of IVH, whereas single-dose betamethasone did not affect the IVH risk . In the alternative model, mortality remained unaffected, and the risk for mechanical ventilation during primary stay was significantly reduced in group I  and group III  and not in group II .To address further potential confounders reflecting disease severity at birth and reasons of preterm birth, we performed an alternative logistic regression model in which we additionally included the parameters Apgar <7 and primary intubation that were derived from univariate analyses  12–24 h; n = 28, (c) 24–48 h; n = 44, (d) 48 h to 7 days; n = 143, (e) 7–14 days; n = 92, (f) >14 days; n = 85, (e) no ANS; n = 238. Our alternative logistic regression model was adjusted for gestational age, gender, multiple birth, delivery mode, SGA, preeclampsia, pathological Doppler/IUGR, amnion infection syndrome, Apgar <7, and primary intubation as surrogate measure for complicated clinical course. A time interval of 48 h after first dose of betamethasone (complete cycle of ANS) to 7 days (168 h) after the first dose was associated with a lower risk for IVH  as well as a time interval of 7–14 days . No associations between the IVH risk and the time interval were observed in the three subgroups with an ANS-birth interval <48 h  and the subgroup of infants in group f (>14 days). However, data must be interpreted with caution due to the low sample sizes in the subgroups.In a second alternative model, we tested our primary outcome (IVH) in subgroups with different cutoffs for the ANS-birth interval in order to address clinical situations, where prolongation of the pregnancy for a couple of hours  seems feasible: (a) 0–12 h; p < 0.001) and severe IVH . An ANS-birth interval >7 days prior birth was also associated with a reduced risk intraventricular hemorrhage and the need for mechanical ventilation, whereas in the group of infants with a single dose of steroids, an independent association between ANS and neonatal outcomes was not measurable.In this multicenter cohort of the German Neonatal Network, we hypothesize that VLBWIs, whose mothers have received two doses of ANS with a timing of >24 h to 7 d before birth, have a reduced risk for intraventricular hemorrhage and mechanical ventilation during primary hospital stay. We suggest a protective effect of an ANS-birth interval of 24 h to 7 days on all grades of IVH  and reported reduced risks for mortality and severe neonatal brain injury, which decreased 1 week after steroid application . They demonstrated better survival in extremely preterm infants (22 to 26 weeks), if ANS were applied 24 h to 7 days before preterm birth  that defined the same timing groups as we did. A higher risk for RDS was shown in the groups with an ANS-birth interval >7 days, a single dose, and no ANS, but—similar to our results—they did not observe mortality differences. IVH was only analyzed within a composite adverse outcome, which was not different between the groups. Battarbee et al. performed a large retrospective secondary analysis of two multicenter studies on mother–infant pairs with mainly spontaneous preterm birth before 34/0 weeks  , which mrm birth  but did /0 weeks . InfantsIn conclusion, there are several factors that could explain the differences between ANS effects in the studied populations: First, the gestational age of included infants plays a major role as earlier gestational ages come with a higher risk for adverse outcomes and, therefore, a potentially greater benefit from ANS. Second, mortality rates in the different cohorts range from as low as 6.1% in our cohort to 30% in a US cohort . Hence, n = 238/672). The proportion of infants without ANS between 23 and 30 weeks in the whole GNN is 7.5%, and in the 10 selected centers, it is 7.2%. For our statistical analyses, we defined the largest group (no ANS) as reference in the regression model. Furthermore, this subcohort represents a relatively homogenous group as it does not imply variation in ANS timing. We are aware that this group includes more emergency deliveries; thus, we adjusted our regression models for birth mode . Third, our cohort was too small to further subdivide our subgroups. The cutoffs for timing groups are set very differently by international study groups, which might explain a part of the conflicting results. To address this aspect, we calculated an alternative regression model including smaller subgroups. An ANS-birth interval of 48 h to 7 days was associated with a lower risk for IVH than an ANS-birth interval of 7–14 days. No associations between the IVH risk and the time interval were observed in the three subgroups of an ANS-birth interval of <48 h and the subgroup of infants >14 days. However, the numbers in the groups for this calculation were small. Another limitation is the fact that we only present data on short-term outcomes. Mortality could possibly be underestimated due to very early deaths if parents were not approached for consent soon enough after birth. VLBWIs without active perinatal care are not part of the GNN. The suggested influence of ANS timing on long-term neonatal outcomes  and by the Local Ethics Committees of all participating centers has been granted. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.IF and VB: study concept, design, and drafting of the manuscript. All GNN sites: acquisition of data. IF and WG: statistical analyses. IF, LM, HB, BG, AH, MA, CR, IR, AR, CH, EH, WG, and VB: analysis, interpretation of data, and critical revision of the manuscript for important intellectual content. WG: obtained funding and study supervision. All authors contributed to the manuscript revision and approved the final version.The GNN is funded by the German Ministry for Education and Research (BMBF-grant-nos: 01ER0805 and 01ER1501). The sponsor had no role in (1) the study design; (2) the collection, analysis, and interpretation of data; (3) the writing of the report; and (4) the decision to submit the paper for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Although prevalence of low birth weight has increased in the last 3 decades in Japan, no studies in Japanese women have investigated whether birth weight is associated with the risk of pregnancy complications, such as pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM).We used data from the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT), a population-based cohort study in Japan that launched in 2011. In the main analysis, we included 46,365 women who had been pregnant at least once, for whom information on birth weight and events during their pregnancy was obtained using a self-administered questionnaire. Women were divided into five categories according to their birth weight, and the relationship between birth weight and risk of PIH and GDM was examined using multilevel logistic regression analyses with place of residence as a random effect.Compared to women born with birth weight of 3,000–3,999 grams, the risk of PIH was significantly higher among women born <1,500 grams , 1,500–2,499 grams , and 2,500–2,999 grams . The risk of GDM was significantly higher among women born 1,500–2,499 grams , albeit non-significant association among women in other birthweight categories.We observed an increased risk of PIH among women born with lower birth weight albeit non-significant increased risk of GDM among Japanese women. Thus, being born small may have a negative impact on not only their own health but the next generation’s health, as it is well known that fetuses that are exposed to maternal pregnancy complications in utero have higher risk of metabolic disease in later life.13–16Studies show that the influence of being born with low birth weight has non-negligible influence on the individual. It increases the risk of infant and child mortality and morbidity including allergies and mental disorders, and recent studies suggest long-term influences that persist into adolescence and adulthood. Large epidemiological studies have shown robust evidence that being born with low birth weight is associated with risk of chronic disease, such as hypertension, diabetes mellitus, and coronary artery disease in later life.8,17–19 Japan has seen a unique trend compared to other countries, as prevalence of low birth weight has increased in the last three decades.20 Investigating the extent to which being born with lower birth weight influences the risk of pregnancy complications would be of great value to understand the population burden of the observed increases in low birth weight. Thus, we targeted a population of Japanese women within the context of a large Japanese cohort study and examined the association between birth weight and risk of pregnancy complications, namely pregnancy-induced hypertension (PIH) and gestational diabetes (GDM).However, all studies to date have primarily been in populations of European ancestry, even though there may be differences in effect size by race.21 Briefly, the JPHC-NEXT study considered 261,939 men and women aged 40–74 years registered into the resident registration system of the seven target prefectures as its target population. Self-administered questionnaires were distributed to this population; participants were also asked to participate in bio-specimen collection and longitudinal follow-up. The questionnaire included items asking about their own birth weight, pregnancy history, medical history as well as lifestyle. Among 61,539 women who completed the questionnaire, 55,303 women had given birth at least once (after excluding 18 women who responded having their first child under the age of 10 years). After exclusion of participants who did not provide their birth weight, 46,365 women remained for the main analysis.This analysis utilized data from the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT), a population-based cohort study launched in 2011 comprising seven prefectures of Japan with the main aim to elucidate the risk factors for lifestyle-related disease and contribute to the development of personalized healthcare.All participants gave their written informed consent at the time of recruitment. The study protocol was approved by the Institutional Review Board at the National Cancer Center on April 11, 2018 (No. 2017-250) as well as at each collaborating institution of the regional areas. The analysis protocol was approved by the Institutional Review board at the National Center for Child Health and Development on June 4, 2018 (No. 1847).Two major complications related to pregnancy, PIH and GDM, were considered as the primary outcomes for this study. Data on self-reported medical history of PIH and GDM ? yes/no; Have you experienced eclampsia? yes/no; Have you ever been told that your blood sugar is high while you were pregnant? yes/no) were collected from the questionnaires.2), family history of diabetes and hypertension (father or mother), having an older brother or sister , and educational attainment , according to previous studies.8,10 Additionally, we considered smoking status at two timepoints as potential confounding factors; maternal smoking at first pregnancy and passive smoking around 10 years old . As the participants had a wide range of birth years and place of residences for which prevalence of our outcomes could have varied, we considered those as confounders as well.The primary exposure of interest was self-reported birth weight with possible response categories including: <1,500 grams, 1,500–2,499 grams, 2,500–2,999 grams, 3,000–3,999 grams, and >4,000 grams. Possible confounding variables considered when examining the effect of birth weight on risk of pregnancy complications were age at first pregnancy, height (quartile cut-points), body mass index (BMI) at 20 years .22 The base model (Model 1) included birth year considering potential influence on both birth weight and outcome. In model 2, we included demographics of the mother as potential confounders. Since we did not have direct information regarding the mothers of the pregnant women except for family history of hypertension, we used the following variables as proxies: number of siblings as proxy for the mother’s parity, height of women as a proxy for height of the mothers, passive smoking status as a child as proxy of the mothers smoking status during pregnancy, and education as proxy of the mothers social economic status during pregnancy. The third model (Model 3a) additionally considered factors (and their proxies) of the pregnant women known to be strongly related to pregnancy outcomes: age at first pregnancy as proxy for age at pregnancy, and current smoking status as proxy for smoking status during pregnancy. For this model, interaction between age at first pregnancy and birth year were included as the interaction was statistically significant. Finally, the last model (Model 3b) included BMI at age 20 years to evaluate whether this may play a mediating role in the association between birth weight and pregnancy complications.Multilevel logistic regression analyses was performed with place of residence (seven prefectures) as the random effect to estimate the association between birth weight and odds of pregnancy complications. To examine the influence of confounding by various co-variables, four nested models were considered. We tested for independence between confounders upon including all variables and included an interaction term when significant interaction was present . We performed multiple imputation by chained equation on 25 datasets for which the completed analysis results were consolidated into one inference using Rubin’s combination rules.23 Two sensitivity analyses were conducted. Because missing birth weight data was not negligible and differed by birth weight (imputed results suggested those born with more extremely high or low birth weights were more likely to remember their birth weight category), the first was conducted on a fully imputed dataset where all variables, including birth weight, were imputed among all women who had a pregnancy . To confirm the robustness of the primary analysis, the second was conducted among all women who had a pregnancy with no missing data for all variables considered in the analysis .We conducted our main analysis on women who had self-reported birth weight and at least one pregnancy . There were moderate levels of missing data for other variables including passive smoking (8.6%), BMI at age 20 years (5.5%), education (1.9%), age at first delivery (0.9%), and height (0.7%); thus, we performed imputation on all variables except for birth weight and refer to this as the partially imputed dataset , and considered a two-sided n = 55,303) datasets as well as those without any missing data  are shown in We considered 46,365 women who had a pregnancy and provided data on their birth weight. Maternal demographics by each category of birth weight are shown in Table n = 46,365) are described in Table The prevalence of PIH and GDM by each category of birth weight, as well as odds ratios for PIH and GDM compared to the reference category , based on the partially imputed dataset , further larger studies regarding the effect between higher birthweight and PIH risk are anticipated.The association between macrosomia and future hypertension requires future research. A previous meta-analysis found women born macrosomia are at higher risk of hypertension at adolescence but at reduced risk for hypertension as an adult.9,10,12 we failed to detect a significant increase in risk for women born at lower birth weight  compared to women born at 3,000–3,999 g, although we detected a significantly higher risk for GDM among women born 1,500–2,499 g. One plausible reason could be the small number of women in this category  and lack of power to detect a true association. Further research on larger samples is anticipated.While previous studies in Europe and United States showed increased risk for GDM among women with lower birth weight,8,10,12 Future studies investigating the individual contributions of shorter gestation and smaller fetal growth on risk of pregnancy complications are warranted. Second, birth weight was collected in a retrospective manner and was self-reported. While a small study in Japan suggested self-reported birth weight categories may correlate with actual birth weight,29 larger studies in other countries have shown that self-reported birth weight tends to be inaccurate and thus could cause recall bias, so self-reported birth weight should be used with caution.30,31 Furthermore, we retrieved pregnancy characteristics, including PIH and GDM, in a retrospective manner as well. Although some studies have showed the validity of self-reported GDM and PIH,32,33 this could have led to misclassification. These misclassification issues of both the exposure and outcomes are likely to be non-differential in nature and may have resulted in an underestimate of the association. Additionally, clinically standardized definitions of GDM and PIH have undergone minor changes. As for PIH, from 1986 to 2005, PIH was defined as women with one or more of the following symptoms between 20 weeks of gestation and 6 weeks postpartum; hypertension (≥140 mm Hg), proteinuria, and edema. In 2005, a modified definition was implemented as follows; women who developed hypertension (≥140 mm Hg) or those with chronic hypertension who developed proteinuria, between 20 weeks of gestation and 6 weeks postpartum. As for GDM, no national guideline to screen or diagnose GDM existed until 1984, when the Japan Society of Obstetrics and Gynecology recommended the use of a 75 g oral glucose tolerance test to diagnose GDM according to one or more of the following criteria; fasting blood sugar >100 mg/dL, 1-hour 75 g oral glucose tolerance test (OGTT) >180 mg/dL, and 2-hour 75 g OGTT >150 mg/dL. Studies that utilize birth weights and pregnancy complications obtained by potentially more accurate methods, such as official records by healthcare provider, may help to add clarity to this area of investigation.Our study utilized a large population cohort, allowing us to undertake a rigorous analysis that considered a broad range of possible confounders while maintaining adequate statistical power. To our knowledge, this is the largest study examining the association between birth weight and subsequent risk of pregnancy complications among Asian women. Nonetheless, this study had limitations. First, information on women’s own gestational age at birth was not available. Low birth weight can be due to shorter gestation and/or smaller fetal growth, and recent studies suggest their influences on future health may differ.In conclusion, among a large population of Japanese women, we observed that those born at lower birth weights had a subsequent increased risk of PIH during their own pregnancy.


Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children’s health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA : 1.57, 2.88), PTB , LBW  than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions. Pregnancy-induced hypertension (PIH) is defined as hypertension (blood pressure ≥ 140/90 mmHg) with or without proteinuria ≥300 mg/24 h) emerging after 20 weeks of gestation. Furthermore, PIH is defined as a new onset proteinuria (≥300 mg/24 h) in hypertensive women exhibiting no proteinuria before 20 weeks of gestation [4 h emergMaternal age, primiparity, Body Mass Index (BMI), multiple pregnancies, previous history of HDP, gestational diabetes mellitus, preexisting hypertension, preexisting type 2 diabetes mellitus, preexisting urinary tract infection, family history of hypertension, type 1 and type 2 diabetes, anti-phospholipid syndrome and systemic lupus erythematosus are non-modifiable risk factors of HDP ,5. HDP cEurope and the US have seen an increase in the ratio of overweight and obese women; however, Japan has seen a dramatic increase in the ratio of underweight women, especially between women in their 20s and 30s from the desire to lose weight ,16,17. UAlthough the different causes for the increasing trends of adverse birth outcomes such as SGA, PTB, and LBW internationally and in Japan are unclear, studies have suggested that pregnancy at an older age, obesity, smoking during pregnancy, alcohol consumption, and HDP have been identified as risks . To daten = 2093)  . In totap) ≥300 mg/24 h without exceeding 2.0 g/24 h or 3 + dipstick. The severe HDP (H) refers to blood pressure ≥160/110 mmHg and proteinuria (P) exceeding 2.0 g/24 h or 3 + dipstick [After enrolling in the study, the participants completed a self-administered questionnaire, which consisted of information on parental characteristics. Questions on maternal age, height, weight, education, occupation, medical history, maternal smoking, and alcohol consumption during and before the first trimester, paternal smoking history, and use of any assisted reproductive technologies were asked. The medical record consisted of information about gestational days at delivery, live-birth, single or multiple births, sex, and birth weight of the infant. The medical history of HDP was obtained from medical records. We used Japanese standard definition of HDP and subclassified the symptoms based on severity. The mild HDP (h) refers to blood pressure ≥140/90 mmHg but <160/110 mmHg after 20 weeks of gestation, and proteinuria (Blood samples collected from participants during the third trimester of gestation were frozen at −80 °C. Cotinine measurement was carried out using the highly sensitive enzyme-linked immunosorbent assay (ELISA) technique. The limit of detection was 0.12 ng/mL. Non-detectable cotinine concentrations were assigned a half value of the detection limit (0.06 ng/mL) before the statistical analysis. The detailed experimental procedure has been discussed in our previous study ,29. We uOur study discussed four birth outcomes as follows: SGA, term-SGA, PTB, and LBW. SGA was defined as newborns smaller in size than expected for their gestational age, expressed as a weight below the 10th percentile for the gestational age according to the condition of parity and the sex of the infant . Term-SGA descriptive analysis was performed to present the demographic and socio-personal information of the mothers. Binary logistic regressions were performed to evaluate association between maternal characteristics and HDP, maternal characteristics and birth outcomes, and HDP and birth outcomes with adjustment for the following covariates: maternal age, parity, smoking during the first trimester, and alcohol consumption during the first trimester. The confidence interval (CI) was set at 95%, with a level of significance at 0.05. All statistical analyses were conducted using IBM SPSS Statistics for Windows software version 22.0 .Out of 18,833 mothers, 363 mothers developed HDP. There was a significant difference between the birth weight of infants, gestational age, and type of pregnancy among mothers with HDP compared to mothers without HDP. Similarly, there was a significant difference in age, BMI, parity, and fertility treatment for this pregnancy among mothers with HDP as compared to mothers without HDP. The characteristics of infants and mothers are presented in The crude model showed that term-SGA was associated with mothers with low BMI, smoking habits before and during pregnancy, drinking habits before pregnancy, and active smokers as per plasma cotinine levels during the third trimester. The adjustment model did not show any association of term-SGA with the smoking habit, smoking habit before pregnancy, and drinking habits compared to the crude model.LBW was significantly associated with older age, low BMI, twin pregnancy, smoking habit during pregnancy, drinking habit before pregnancy, those who underwent fertility treatment for this pregnancy, those who underwent IVF, and active smokers as per plasma cotinine levels during the third trimester.This study has tried to understand the risk factors of HDP, and the association between maternal characteristics and HDP on birth outcomes such as SGA, term-SGA, PTBs, and LBW. HDP was found to be associated with SGA (2.13 OR), PTB (3.48 OR), and LBW (3.57 OR). Our findings are similar to previous studies, which have suggested a higher risk of perinatal outcomes among women with HDP ,34. TherHDP and its subtypes are one of the major risk factors for the development of cerebral, renal, cardiovascular disease (CVD) in the mothers in later phase of life . Similar2) and are at risk of delivering LBW infants and SGA infants [2) showed a strong association with SGA, term SGA, PTB, and LBW. Low weight gain before and during pregnancy causes inadequate nutrient supply to the fetus and can induce poor head circumference growth in newborns [The prevalence of LBW deliveries in high-income countries is lower (7%) as compared to low-income countries (12–25%) . Additio infants ,46,47. Onewborns . This coAn Italian population-based study revealed that low maternal education was a risk factor for PTB, LBW, and SGA . No suchOur study showed a strong association between twin and multiple pregnancies and HDP. Previous studies have shown an increased risk for gestational hypertension, preeclampsia, and eclampsia in twin pregnancies compared to singleton pregnancies in primiparous and multiparous women . SimilarThis study showed a strong association of fertility treatment, mainly IVF, with PTB and LBW. Several studies have shown the risk of preterm delivery and LBW babies among women conceiving after fertility treatment ,56. The The smoking rate among females in Hokkaido is 16.1%, which is higher than the national average for women (9.5%) and highest among all prefectures in Japan . The smoThere was an association between SGA, term-SGA, and LBW babies among mothers who habitually drank alcohol before pregnancy. However, we did not find any association between alcohol consumption before pregnancy and during the first trimester and preterm delivery risk. This might have occurred because our alcohol consumption data were based on questionnaires, and not on direct observation or volume calculation. A Japanese study found that maternal alcohol consumption during pregnancy was significantly associated with an increased PTB risk but did not show any relationship with LBW and SGA ,65. A meA Japanese national survey conducted over 55 years (1961–2016) has shown a steady decrease in systolic blood pressure levels among all age groups of men and women, but not in the diastolic blood pressure levels requiring different population-based strategies to manage and prevent hypertension .The strength of this study is its prospective birth cohort study design comprising 18,833 mother-infant pairs. In this study, we calculated the HDP from the medical records, which is a highly reliable report. We measured cotinine levels during the eighth month of pregnancy, as maternal smoking during the third trimester was related to birth size reduction. However, this study has some limitations. The participants who had HDP were relatively small , which might have led to an underestimation of the results. The study participants were pregnant women who had visited hospitals or clinics within the Hokkaido prefecture only. The pre-pregnancy weight, maternal smoking and alcohol consumption habit were self-reported by the respondents, which might have caused biasness. As we did not have participants with chronic hypertension, they were not included in the analysis. In addition, the reported risk of gestational diabetes mellitus, type 2 diabetes mellitus, family history of hypertension, and preexisting urinary tract infection were not assessed in this study.Our study showed that mothers with HDP had increased odds of giving birth to babies with SGA, PTB, and LBW than mothers with normotensive pregnancy. Therefore, women of reproductive age need to be made aware of different risk factors through physician visits, health education, and various community interventions related to public health. Risk assessment before pregnancy, management of modifiable risk factors, and medical history monitoring should be implemented as per national guidelines to reduce further complications among pregnant mothers with HDP. It is crucial to remember that these risk factors can cause maternal and neonatal complications in mothers with HDP. Our study recommends future studies on Japanese mothers with HDP to demonstrate an association between characteristics and birth outcomes, considering the mediating effects of different confounding variables.