To explore the relationship between common air pollution and common birth defects, and to provide reference for the prevention of birth defects.2), fine particulate matter 2.5(PM2.5), nitrogen dioxide(NO2), ozone(O3), carbon monoxide(CO) and the occurrence of common birth defects such as congenital heart disease, facial cleft, and finger deformity.We conducted a case-control study in Xiamen, a city in southeastern China from 2019 to 2020. Logistics regression was used to analyze the relationship between sulfur dioxide(SO2 significantly increased the risk of birth defects such as congenital heart disease, cleft lip and/or cleft palate, and ear deformity in the first and second months of pregnancy.SO2 significantly affects the occurrence of birth defects in the first two months of pregnancy.Exposure to common air pollutants increases the risk of birth defects, and SO Birth defects also known as congenital malformations or congenital diseases, is due to external environmental factors, genetic factors or both lead to embryonic growth, differentiation in the process of structural, functional, metabolic abnormalities . With th3, PM2.5, PM10 can increase the incidence of respiratory infections, asthma, coronary heart disease, birth defects and other diseases, eventually leading to increased mortality  of Xiamen University Women’s and Children’s Hospital, including maternal age, parity, nationality, pregnancy disease, infant gestational age, birth weight, gender, birth defect category, and so on . This st2, PM2.5, NO2, O3, and CO to obtain hourly average data and calculate monthly average data. We took the last menstrual time as the starting time of exposure  monitored common air pollutants such as SOexposure . For preexposure . The geoexposure , 16.Inclusion criteria: 1. Regular prenatal examination and resident population in Xiamen; 2. Birth defect group was diagnosed by doctors during pregnancy or childbirth with birth defect diseases; 3. The control group was a healthy fetus with full-term normal birth weight, and no abnormalities were found by imaging physicians, obstetricians, and neonatologists.Exclusion criteria:1. No regular prenatal examination or floating population in Xiamen; 2. There were low birth weight, macrosomia, birth defects in the control group; 3. There are clear genetic diseases in the birth defect group, such as Down syndrome, Turner syndrome or other chromosomal and genetic abnormalities; 4. The duration of pregnancy in the birth defect group did not exceed 3 months.Descriptive analysis was performed on the occurrence of common air pollutants and common birth defect diseases, and the social demographic characteristics of the birth defect group and the control group were compared by Chi-square test. Mann-Kendall trend test was used to analyze the time trend of air pollutant concentration. Pearson test was used to analyze the correlation between air pollution concentration and birth defects. The variance inflation factor (VIF) was used to verify the collinearity between air pollutants and birth defect diseases. When VIF > 10, it was suggested that there was collinearity and relevant factors could not be included in the analysis .2, PM2.5, NO2, O3, and CO was regarded as an independent variable. Factors such as age, nationality, parity, and pregnancy disease were used as covariates. Finally, logistic regression was used to analyze the correlation between common air pollutants and common birth defects. The incidence of birth defects (/ten thousand) = the number of related birth defects/the number of perinatal infants × 10,000. Epidata3.1 was used to collect data, Arcmap10.3 was used to analyze and process air pollution data, and pollutant distribution map was made. R4.04 was used for relevant statistical analysis. Bilateral test was used, and P < 0.05 indicated that the difference was statistically significant.The occurrence of birth defects such as congenital heart disease, finger deformity, and ear deformity was regarded as a binary dependent variable. The exposure concentration of air pollutants such as SOX2 = 4.38, P < 0.05, indicating that the difference between fetuses of different genders was statistically significant. There were 824 cases (68.21%) of full-term infants with gestational age greater than 37 weeks. Chi-square test X2 = 41.87, P < 0.05, indicating that there was statistical significance between different gestational weeks. There were 79 cases (6.51%) of gestational diabetes during pregnancy. Chi-square test X2 = 19.5, P < 0.05, indicating that gestational diabetes during pregnancy was statistically significant , finger deformity , cleft lip and (or) cleft palate , ear deformity  and other diseases . In the nificant .2, NO2, O3, PM2.5 and CO from January 1, 2019 to December 31, 2019  in Xiamen City monitored the real-time changes of air pollutant concentrations such as SO31, 2019 . It can t months .2 and O3 in the birth defect group were 5.88 ug/m3 and 58.46 ug/m3, respectively, which were higher than those in the healthy control group. The mean concentrations of NO2, PM2.5 and CO in the control group were higher than those in the birth defect group. The rank sum test of SO2 concentration in the birth defect group and the control group showed that Z = −0.87, P = 0.38, the difference was not statistically significant. Other pollutants P < 0.05, indicating that the difference in the concentration of O3, NO2, CO and PM2.5 between the birth defect group and the control group was statistically significant  cleft palate, external ear deformity and air pollution such as SO2 during the first and (or) second trimesters of pregnancy increases the incidence of all birth defects, congenital heart disease, cleft lip and (or) palate, and external ear malformations. In the first month of pregnancy and the second month of pregnancy, every 10ug/m3 increase in SO2 will lead to an increase of 21%, 35% and 31%, 33% in all birth defects and congenital heart disease, respectively. In the second month of pregnancy, for every 10 ug/m3 increase in SO2, the cOR of cleft lip and (or) cleft palate was 1.37,95% CI = . The maternal age, nationality, parity, pregnancy disease and other factors were brought into the analysis as covariates, and aOR = 1.498,95% CI = . In the first month of pregnancy, for every 10 ug/m3 increase in SO2, the incidence of ear malformations increased by 65%, and aOR = 1.613 after covariate adjustment, the change was not significant. The remaining pollutants CO, NO2, O3 and PM2.5 will have positive effects on different birth defect diseases in the first three months of pregnancy, but have little effect on birth defect diseases  cleft palate, finger deformity and external ear deformity in the first three months of pregnancy. Among them, SO2 has a greater impact on the occurrence of cleft lip and (or) cleft palate and external ear malformations in the second month of pregnancy. For every 10 ug/m3 increase in SO2, the occurrence of cleft lip and/or cleft palate and external ear malformations will increase by 73% and 150%, respectively. After covariate adjustment, aOR was 1.968 and 2.347, respectively. The remaining pollutants CO, NO2 and O3 will have positive effects on different birth defect diseases in the first three months of pregnancy, but have little effect on birth defect diseases  expression, mitosis, cell respiration, glycolic acid metabolism and proteasome and other biological processes, leading to congenital spinal cord defects  gene polymorphisms, the higher the risk of congenital heart disease  promoter in umbilical cord blood, leading to adverse pregnancy outcomes  of cleft lip and (or) cleft palate in the first month of pregnancy was the same as our results . A case-regnancy . Shuang regnancy . Wang linclusion .2 concentration, the aOR and 95%CI was 1.15 , while O3 did not have this relationship , which was the same as our conclusion  in this paper, the monitoring time is long, and the coverage area is wide, which provides the accuracy of the air pollution value exposed by the children. Fifth, this study covers the relationship between multiple pollutants and multiple birth defects. Finally, during the novel coronavirus epidemic in this study, according to the regional isolation measures, pregnant women spend most of their time resting at home and are forced to wear masks in public places, which increases the rationality of the location exposure matching of air pollution data in this paper , 43.Our study is based on data from monitoring sites, but most of the time maternal rest at home, studies have shown that indoor air pollutants such as smoking, coal, mold exposure can also increase the risk of birth defects, premature birth, low birth weight, which will affect the accuracy of the results –47. The


Neuropsychiatric disorders (NDs) are a diverse group of pathologies, including schizophrenia or bipolar disorders, that directly affect the mental and physical health of those who suffer from them, with an incidence that is increasing worldwide. Most NDs result from a complex interaction of multiple genes and environmental factors such as stress or traumatic events, including the recent Coronavirus Disease (COVID-19) pandemic. In addition to diverse clinical presentations, these diseases are heterogeneous in their pathogenesis, brain regions affected, and clinical symptoms, making diagnosis difficult. Therefore, finding new biomarkers is essential for the detection, prognosis, response prediction, and development of new treatments for NDs. Among the most promising candidates is the apolipoprotein D (Apo D), a component of lipoproteins implicated in lipid metabolism. Evidence suggests an increase in Apo D expression in association with aging and in the presence of neuropathological processes. As a part of the cellular neuroprotective defense machinery against oxidative stress and inflammation, changes in Apo D levels have been demonstrated in neuropsychiatric conditions like schizophrenia (SZ) or bipolar disorders (BPD), not only in some brain areas but in corporal fluids, i.e., blood or serum of patients. What is not clear is whether variation in Apo D quantity could be used as an indicator to detect NDs and their progression. This review aims to provide an updated view of the clinical potential of Apo D as a possible biomarker for NDs. In the past decades, there has been growing interest in the study of neuropsychiatric disorders (NDs) since they have become the first cause of disability and the second cause of death worldwide . A EuropFrom a clinical point of view, there are several circumstances that could be behind the neuropsychiatric symptoms, including metabolic alterations, the consumption of poisons/toxins, and general medical conditions such as neoplasm, trauma or infections . This coThe apolipoprotein (Apo) family is a specialized group of proteins that associates with lipids and mediates several steps in lipid metabolism. So far, there are 22 known members of the family but only Apo E , Apo J , and ApoApo D is an “atypical” apolipoprotein since its molecular structure revealed that it belongs to the lipocalin superfamily ,22. HumaAt the molecular level, Apo D shows the lipocalin characteristic ligand binding structure, which classifies it as a kernel lipoprotein able to bind arachidonic acid (AA), cholesterol, and steroids. No specific ligand has been identified, but Apo D binds with high affinity to AA, progesterone, and retinoic acid, whereas with reduced affinity to pregnenolone and some eicosanoids ,33,34. MApo D expression is regulated by various factors as its promoter region contains several response elements . In vitro experiments have shown that the gene is under the control of serum-responsive elements during cellular growth arrest . Apo D iThe mammalian brain is one of the organs of major expression for Apo D, but this lipocalin is also expressed in the peripheral nervous system during regeneration and remyelination . As a liIn the human CNS, Apo D is located in perivascular cells, astrocytes, oligodendrocytes, and some neurons in both physiological and pathological conditions ,46. Of nDuring the last decades, numerous in vitro ,53,54,55Analyses of CSF from patients with chronic inflammatory demyelinating polyneuropathy and Guillain–Barré Syndrome revealed an increase in Apo D content . SimilarFinally, Apo D has also been associated with other neurodegenerative lesions, as it has been shown in different experimental models of stroke, entorhinal cortex lesions, or maternal hyper and hypothyroidism ,60.Current evidence strongly suggests the increase of Apo D expression in NDs such as Schizophrenia (SZ), Bipolar Disorders (BPD), Major Depressive Disorders (MDD), or Autism Spectrum Disorder (ASD), a group of diseases that shares some cardinal pathological features including oxidative stress, excitotoxicity, myelin dysfunction, cholesterol imbalance, and apoptosis, and where it seems to play a fundamental role as a neuroprotective protein. The existing lack of biomarkers for the effective and early detection of NDs makes it necessary to search for new predictive molecules, and, in this sense, Apo D could be a good candidate. An updated view of the role of Apo D as a potential biomarker for different NDs, summarized in SZ is a severe and long-term brain condition characterized by changes in how a person thinks, perceives, and interprets reality that affects approximately 20 million individuals globally . Major sTaking this into consideration, Thomas et al., in 2001, described, for the first time, a selective increase of Apo D quantity in some brain areas of patients with SZ . They toFurthermore, Apo D high levels have also been found in a study that looked for biomarkers of psychosis risk in blood. In fact, Apo D has been identified, together with matrix metalloproteinase 7, as the only two molecules of 117  that showed a significant difference between people with clinical high-risk symptoms who developed psychosis and those who, despite presenting symptoms, did not do so . A meta-The differences in the results of the mentioned studies could be explained by different factors such as the analysis methodologies, the number of subjects, the phase of the disease, or the medication. Once again, data about pharmacological treatments of patients is interesting since it has been shown that some drugs, like haloperidol (HAL), reduce Apo D expression in the hippocampus, piriform cortex, and caudate-putamen, while others, such as risperidone (RISP) or olanzapine (OLZ), produce the opposite effects in rat brain . In factIn the CSF, Apo D has been identified as a potential biomarker for cerebral amyloid angiopathy , chronicWhile it is true that due to the invasiveness of the techniques, using Apo D as a biomarker for diagnosing SZ in brain tissue or CSF does not provide an advantage over other biomarkers, the ability to detect changes in Apo D levels with just a blood sample and a protein profiling assay places it in an advantageous position compared to other molecular markers whose detection involves methodologically complex and expensive assays, such as RNA sequencing.BPDs are a group of chronic mental health conditions that cause abnormal shifts in mood, ranging from extreme highs (mania) to extreme lows (depression) episodes . BPDs afThe study of the Apo D brain levels in post-mortem samples of BPD subjects, in the same areas as the authors did previously for SZ, demonstrated differences between the two NDs . In the p < 0.050) [In regard to the potential of Apo D as a serum biomarker for BPD, results found in the literature are quite contradictory. Dean and co-workers, in 2008, using ELISA immunological assays, did not observe differences in Apo D levels between BPD vs. SZ patients or their controls . Interes< 0.050) . Similar< 0.050) . In thisNotwithstanding, it is important to remember that Apo D conformation is not the same in the post-mortem brains and in plasma, and, consequently, their behavior may be completely different. Thus, a systematic review and a meta-analysis on MS-based proteomics applied to human peripheral fluids to assess potential biomarkers of BPD showed that Apo D is present in plasma and serum, and it was among the 258 proteins differentially expressed in blood-related samples  when studying BPD patients vs. controls . FinallyMDD or clinical depression is a ND characterized by a persistent low mood, feelings of sadness, and loss of interest that condition the daily functioning and quality of life of patients . It is cThe MDD pathophysiology includes dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, neurotransmitter metabolism disorder, oxidative stress, and neuroinflammation , processThe study of Lee et al., performed by liquid chromatography–tandem mass spectrometry and label-free quantification in plasma from BPD and MDD subjects, took into account the effects of medication over protein expression  and demonstrated that Apo D expression was not affected for any of the antipsychotic drugs. However, it was negatively associated with the total scores of the Hamilton depression rating scale (HAM-D) and with the anhedonia/retardation and guilt/agitation scores of this scale . In factClinical evidence suggests that some people suffering from MDD attempt suicide. It has been reported that alterations in cholesterol levels could play a crucial role in suicidal behavior, as shown by the significant association between (i) low levels of peripheral circulating cholesterol in patients with suicidal and violent conduct ,107, andIn the last decade, there has been an increasing interest in the use of secreted membrane vesicles, collectively called extracellular vesicles (EVs), as potential diagnostic tools for NDs ,111,112.In view of the potential role of Apo D as a biomarker for SZ, BPD, or MDD, some laboratories are focusing on this protein but in other NDs, namely ASD, anxiety, and addictions.ASD is a complex neurodevelopment condition that can manifest with deficits in social communication, restricted interest, and repetitive behaviors. The estimated prevalence of ASD has been increasing in the past two decades, mainly affecting children under 3 years of age, although symptoms may improve over the adult’s life . The mulLipid peroxidation, abnormalities in prostaglandin metabolic pathways, oxidative stress, and alterations in the formation and maintenance of synaptic structures have been associated with the pathogenesis of ASD, so Apo D could play a role in this pathology due to its ability to interact with AA, as already mentioned in this review . On the The origin of some anxiety disorders could be traced as early as the three first weeks after birth. In mammals, enhanced postnatal care during this period operates by suppressing microglial inflammation, and is associated with reduced anxiety . Mice laCritically, there are noticeable variations between studies examining Apo D levels in patients with addictions to different substances, i.e., drugs of abuse, cigarettes, or alcohol. As we mentioned previously, Apo D levels could be modulated by some medical drugs ,77,82. MMost of the studies in this field have centered on alcohol and smoking effects. Variations in Apo D gene levels were first reported in 2000 in a study with tissues from the superior prefrontal cortex of alcoholic subjects using four different microarrays . NotwithRegarding other substances of abuse, references in the literature are scarce, but it has been observed that morphine also upregulates the Apo D gene in the lateral hypothalamus of wt mice vs. those KO for mu opioid receptor after a chronic treatment . FinallyIn the CNS, Apo D acts not only as a lipid carrier  but also seems to be a neuroprotective molecule in oxidative stress situations, as well as necessary for the correct myelination process. It is clear that Apo D levels (protein or gene) are altered in several NDs . Of noteFuture perspectives in this field of research necessarily involve more studies about the presence of Apo D in human fluids in different NDs to establish an expression pattern that could be used as a biomarker to help in the diagnosis of these pathologies but also to consider Apo D as a neuroprotective molecule that could help in the treatment of NDs due to its antioxidant and anti-inflammatory properties.


P < 0.05). After adjusting for all the risk factors included in this study, restricted cubic spline analyses found that the PLR and the hsCRP level were positively associated with the risk of APO. The levels of PLR and hsCRP in the third trimester are related to the occurrence of APO in women with GDM, and high levels of PLR and hsCRP may indicate the occurrence of APO.Gestational diabetes mellitus (GDM) is a major complication of pregnancy. GDM is associated with a higher risk of adverse pregnancy outcomes (APO). The purpose of this study was to assess the association between third-trimester platelet to lymphocyte ratio (PLR) and high-sensitivity C-reactive protein (hsCRP) concentration and the risk of APO in GDM pregnant women. This study selected 406 non-elderly gestational diabetes patients diagnosed in the Renmin Hospital of Wuhan University from May 2021 to February 2023 as the research objects. According to the presence or absence of APO, they were divided into an APO group (n = 171) and a non-APO group (n = 235). Logistic regression model to evaluate the correlation between PLR and hsCRP and APO in women with GDM; Restricted cubic spline analyses was used to explore nonlinear correlations between PLR or hsCRP and the risk of APO; ROC curve analysis of the diagnostic performance of PLR and hsCRP for APO in women with GDM. APO occurred in 171 of the 406 included participants. Compared with the non-APO group, patients in the APO group had higher PLR and hsCRP levels. The incidence of APO was positively associated with PLR and the hsCRP level in each logistic regression model ( Women with a history of GDM had increased rates of metabolic syndrome and cardiovascular events compared with women without a history of GDM5. At the same time, studies have shown that about 10% of women develop diabetes soon after giving birth, and the rest have a 20–60% incidence of diabetes within 5–10 years in the absence of specific diabetes interventions7. GDM is associated with adverse pregnancy outcomes (APO), including preterm delivery, stillbirth, macrosomia, small for gestational age infant, and large for gestational age infant10.Gestational diabetes mellitus (GDM) refers to a variable degree of abnormal glucose metabolism that occurs for the first time during pregnancy and is detected. It is the most common pregnancy-related metabolic disorder, occurring in about 7% of all pregnancies, and is usually detected in the second and third trimesters14.The causes of APO in pregnant women with GDM are unclear, but may be related to insulin resistance (IR), genetic susceptibility, disorders of the insulin signaling system, decreased pancreatic islet B cell secretory function, chronic inflammation, various placental hormones  and various adipocytokines  in pregnant women are related to many factors16. PLR has emerged as an informative marker, revealing changes in platelet and lymphocyte counts due to acute inflammation and prothrombotic states. Serum hsCRP, as an inflammatory mediator that rises sharply in plasma during inflammatory response, can play a regulatory role during inflammatory response by enhancing the phagocytic function of phagocytes and activating complement18. Numerous studies have confirmed that PLR and hsCRP are potential biomarkers for spontaneous preterm birth, miscarriage, and fetal growth restriction23. This study aimed to determine whether third trimester PLR and hsCRP are associated with APO in patients with GDM.Both platelet-to-lymphocyte ratio (PLR) and high-sensitivity C-reactive protein (hsCRP) are commonly used indicators to reflect the inflammatory state of the body. Previous studies have shown that platelets release a variety of inflammatory mediators to participate in immune inflammatory responses through autocrine or paracrine methods, and at the same time directly chemotactic immune cells to aggregate and infiltrate into damaged tissues24, if one or more blood glucose values were equal to or exceed the defined cutoff values, namely, fasting blood glucose levels < 5.1 mmol/l and blood glucose levels of < 10.0 mmol/l, < 8.5 mmol/l during the first and second hours. The exclusion criteria were those patients (1) who presented with cardiogenic shock, heart valve disease; (2) who presented with uremia or have had kidney transplantation; (3) who suffer from severe liver disease, cancer, autoimmune diseases, blood system diseases, or infectious disease and (4) those who used anti-inflammatory drugs within four weeks.We used a retrospective study design to evaluate the association between PLR and serum hsCRP levels and the risk of subsequent and APO in women with GDM. All participants were recruited consecutively between May 2021 and February 2023 at Renmin Hospital of Wuhan University in Obstetrics and Gynecology. All participants were diagnosed with GDM and under 35 years old. All women who were not diagnosed with diabetes before 24 weeks of gestation underwent a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation. GDM was diagnosed using the criteria of the International Diabetes and Pregnancy Study Group (IADPSG)The research protocol has been approved by the Ethics Committee of the Renmin Hospital of Wuhan University, and the research has been carried out in accordance with the Helsinki statement. Almost all patients or their relatives signed written informed consent before the study.Detailed medical histories and physical examination results were obtained from all included patients. The following baseline data from blood sample examinations were recorded from the first visit of the patients: age (years), gestational weeks, Pre-pregnancy BMI, maternal family history of diabetes, history of hypertension, preeclampsia, and the use of insulin. Pregnancy weight gain (kg) was counted after the end of pregnancy.Adverse pregnancy outcomes  and/or large for gestational age infant (LGA)) was used as the criteria to define cases.At the time of the patient's admission, medical staff collected 5 ml of procoagulant blood and 2 ml of ethylenediaminetetraacetic acid (EDTA) anticoagulated venous whole blood from the cubital vein. The procoagulant blood was placed at room temperature for 30 min. After the blood coagulated, it was centrifuged at 3500 r/min (1 369 × g) for 5 min. The upper serum was collected in an Eppendorf tube and stored in the refrigerator at − 80 °C for later use. A Siemens Advia 2400 automatic biochemical analyser  was used to determine serum Glu(glucose) and hsCRP. Johnson & Johnson Vitros 350 dry-biochemical analyzer  was used to detect the urinary protein level. A SysmexCA-7000 system  was used to detect the RBC (Red blood cell count), Hb(hemoglobin), RDW (Red blood cell distribution width), WBC (White blood cell count), NEU (Neutrophil count), LYM (lymphocyte count), MONO(monocyte count), PLT (Platelets), MPV (Mean platelet volume), PDW (Platelet distribution width).Analyses were done with SPSS 23.0 and Python 3.9.7. PLT was the continuous variables that obeyed a normal distribution, so they are described by mean ± standard deviation. Age, gestational weeks, BMI, Glu, Urinary protein, RBC, Hb, RDW, WBC, NEU, LYM, MONO, MPV, PDW, NLR (Neutrophil–lymphocyte ratio), LMR (Lymphocyte-monocyte ratio), PLR, hsCRP, which did not obey the normal distribution and are expressed as interquartile range. The two-independent-sample t test or the Mann–Whitney U test were used to compare groups on the averages of continuous variables. The chi-square test t was used to compare the percentages of categorical variables between APO group and non-APO group. Simple and multiple logistic regression were used to explore the relationship between PLR and hsCRP and APO. Restricted cubic spline analyses were used to explore the nonlinear correlation between the PLR or the hsCRP and the risk of APO. ROC curve analysis of the diagnostic performance of PLR and hsCRP for APO in women with GDM.The authors are accountable for all aspects of the work to ensure that issues related to the accuracy or completeness of any part of the work are properly investigated and resolved. This study was approved by the Medical Ethics Review Committee of Renmin Hospital of Wuhan University, China. All participants signed an informed consent form in accordance with the policies of the Renmin Hospital of Wuhan University Ethics Committee.APO occurred in 171 of the 406 included participants. Compared with patients without APO, patients with APO were more likely to suffer from preeclampsia. In addition, the values of LYM, PLT, NLR, PLR and hsCRP in the APO group were higher than those in the non-APO group, while the LMR were lower than non-APO group : 1.872 (1.057–3.316), P = 0.032), PLR (OR (95% CI): 1.013 (1.006–1.019), P < 0.001), and hsCRP levels (1.046 (1.022–1.070), P = 0.001) were risk factors for APO in GDM patients  of their risk of APO, taking patients in the fourth PLR quartiles as a reference Table . SimilarRestricted cubic spline analyses found that after adjusting for all confounding factors included in this study, the risk of APO increases with increased levels of PLR and hsCRP in the third trimester Fig. .Figure 2As shown in Fig. This study is the first to identify PLR and hsCRP levels as potential risk factors for APO in pregnant women with GDM. This correlation persisted after adjusting for confounders.28. GDM not only increases the risk of APO such as preeclampsia, polyhydramnios, macrosomia, and fetal distress, but also increases the incidence of long-term cardiovascular disease in both mother and child generations10. Early intervention in women with GDM can improve the occurrence of adverse maternal and fetal outcomes. Therefore, identifying high-risk patients with APO and intervening them are of great significance for the prevention and treatment of APO in pregnant women with GDM.GDM is one of the most common complications during pregnancy, with an incidence of 5–6% to 15–20% in different parts of the world, and the incidence is still increasing, mainly related to obesity, sedentary lifestyle and increasing pregnancy age33. In addition, there is mounting evidence connecting them to the progression of GDM and its complications. Wang et al.34 found a significant increase in PLR among pregnant women in the GDM group through analysis of blood indicators in 1440 early pregnant women. Moreover, their research has shown that PLR in early pregnancy is an independent risk factor for GDM. In a similar study, Fashami et al.35 found a significant increase in PLT values and PLR in the GDM group during the second trimester of pregnancy. The findings of the Maged et al. study have shown that hsCRP is an important early predictor of GDM36. A prospective study of women with gestational age less than 10 weeks confirmed that women with the highest serum concentration of CRP were three times more likely to develop GDM than women with the lowest serum concentration of CRP37. In addition, the results of a study conducted by Ozugz et al.38 showed that during the 1-year follow-up evaluation, the hsCRP in the GDM group was significantly higher than that in the control group, and the carotid intima-media thickness was significantly greater than that in the control group. They defined GDM as a transient metabolic syndrome and a subclinical inflammatory state associated with elevated hsCRP levels. Previous studies mainly focused on the correlation between PLR and hsCRP and the prevalence of GDM, but there were few studies on their association with APO in pregnant women with GDM. This study analyzed the blood parameters of 406 pregnant women with GDM in the third trimester of pregnancy, and found that there was a significant correlation between the levels of PLR and hsCRP and the occurrence of APO in GDM pregnant women.Numerous studies have demonstrated that PLR, and hsCRP are potential inflammatory biomarkers for rheumatoid arthritis, endocrine disease, cardiovascular disease, and tumors41. Both PLR and hsCRP are commonly used indicators to reflect the inflammatory state of the body. Platelets are rich in pro-inflammatory agents and can release highly active microparticles, which are related to the inflammatory state of the body. In vitro and in vivo studies have elucidated the origin of activated circulating platelets, which display numerous membrane receptors and release a variety of bioactive substances from their granules that can modulate cellular interactions and contribute to immune, inflammatory, and thrombotic diseases44. P-selectin-mediated interaction of platelets with T lymphocytes reduces lymphocyte proliferation and modulates the release of inflammatory factors, leading to activation of the inflammatory response46. As a sensitive indicator of non-specific inflammation, hsCRP mainly inhibits the activity of insulin receptor tyrosine kinase and phosphorylates insulin receptor substrates, resulting in the disorder of the body's material metabolism, thereby aggravating IR50.The reasons for the prevalence of APO are not fully understood, and previous studies have found that inflammation is associated with APO in pregnant women with GDMThis study has several limitations. First, due to the small sample size, other risk factors for APO were not stratified. Second, although we found elevated levels of PLR and hsCRP in GDM pregnant women in the third-trimester APO group, we were unable to collect any data on PLR and hsCRP levels in the disease during the first and second trimesters. Blood samples obtained longitudinally during pregnancy may add more comprehensive data to understand the value of PLR and hsCRP levels during disease development.In short, the levels of PLR and hsCRP in the third trimester are related to the occurrence of APO in women with GDM, and high levels of PLR and hsCRP may indicate the higher risk of the occurrence of APO. If the association and related mechanisms between PLR and hsCRP with APO in patients with GDM are confirmed in future research, potential interventions to improve maternal and infant outcomes can be expected.


To determine the relationship between prior obstetrical history and gestational age at delivery in a twin pregnancy.Retrospective cohort study using the United States Society for Assisted Reproductive Technology Clinic Outcomes Reporting System database.Clinic-based data.Patients undergoing in vitro fertilization (IVF) in the United States with live delivery of twins.None.The main outcome measures are median gestational age at delivery and rate of preterm delivery (before 37 weeks).The median gestational age at delivery of IVF-conceived twins was 36.3  weeks for nulliparous women, 35.9  weeks for parous women with a prior preterm birth, and 36.7  weeks for parous women without a prior preterm birth. The rate of preterm delivery was 61% for nulliparous women, 70% for parous women with a prior preterm birth, and 55% for parous women without a prior preterm birth.Parous women without a history of preterm delivery had lower rates of preterm delivery in a subsequent twin pregnancy than nulliparous women. Nulliparous women had lower rates of preterm delivery compared with parous women with a history of preterm delivery. Despite recent trends in practice patterns toward the performance of more single embryo transfers, multiple embryo transfer is still often performed to maintain pregnancy rates. In 2018, in the United States, approximately 13% of deliveries after in vitro fertilization (IVF) with autologous oocytes were twins or higher-order multiples  cycles in the United States. The data were collected through voluntary submission, verified by SART, and then reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493). The SART maintains HIPAA-compliant business associate agreements with reporting clinics. In 2004, after a contract change with the Centers for Disease Control and Prevention, SART gained access to the SART CORS data system for research purposes. The data in the SART CORS are validated annually, with select clinics having on-site visits for chart review based on an algorithm for clinic selection . During This study included patients aged 20 to 50 with a live twin delivery in the SART CORS database with cycles from 2012 to 2017. Cycles were excluded if there was a single embryo transfer, monochorionic gestation, use of a gestational carrier, or pregnancy after a transfer of an embryo created from a frozen oocyte. The initial dataset obtained included 55,272 pregnancies. A total of 24,536 pregnancies were excluded for unrecorded gravidity or parity, fetal weight data not recorded, gestational age data not recorded, recorded gestational age less than 23 weeks 0 days or greater than 41 weeks 6 days, or average fetal weight less than 250 grams or greater than 5500 grams. Data from the remaining 30,736 pregnancies were included in the primary analysis . The SARThe gestational age at delivery and average birth weight were nonnormally distributed. The unadjusted analysis of outcomes was performed using Fisher’s exact test for categorical data and the Wilcoxon rank-sum test for continuous data. There were 93 instances of unknown fetal sex, and these were recorded as male/female because this was the most frequent combination.P<.05) between nulliparous and parous groups were considered for evaluation as confounders. These characteristics included age, fetal sex, prior spontaneous abortion, use of autologous oocytes, use of one or more fresh embryos, the number of fetal heartbeats detected, use of preimplantation genetic testing, maternal ethnicity, and infertility diagnosis (P< .20 (and an absolute difference of at least 1% between nulliparous and parous groups for ethnicity and infertility) were included in the preliminary model as shown in Two logistic regression models were built, one for the rate of preterm delivery and the other for rate of low average birth weight . We used the methods described by Hosmer and Lemeshow for the purposeful selection of covariates . Demograiagnosis . CovariaP>.05 and no expected clinical significance.The preliminary model consisted of all the variables identified on univariate analysis that differed between nulliparous and parous groups and were associated with preterm delivery or low birth weight in nulliparous patients. We then fit multivariable models (one model for preterm delivery and another model for low birth weight) containing all the identified variables and assessed the significance of each variable in the multivariable model. The final model was determined by removing variables that were insignificant in the multivariable model based on a For preterm delivery (before 37 weeks), there were no changes from the preliminary to the final model. All predictors were statistically significant except for the use of preimplantation genetic testing (PGT) and White ethnicity, which were left in the model because of potential clinical significance. The interaction between parity and age was not significant and was not included in the final model. The final model  for pretFor low average birth weight (< 2500 grams), there were also no changes from the preliminary to the final model. All predictors were statistically significant except for the use of PGT, diminished ovarian reserve, and unexplained infertility. These were left in the model because of potential clinical significance. The interaction between parity and age was not significant and was not included in the final model. The final model  for low P=.16) or low average birth weight (P= .24). A P<.01 was considered statistically significant for comparisons of outcomes between nulliparous and parous groups.Hosmer and Lemeshow overall goodness of fit tests did not show evidence of poor fit for predicting the risk of preterm delivery  was 60.7% for nulliparous women compared with 56.7% for parous women  was 56.8% for nulliparous women compared with 44.8% for parous women . The rate of low birth weight (less than 2500 grams) was 56.8% for nulliparous women, 55.9% for parous women with a prior preterm birth, and 43.2% for parous women without a prior preterm birth. There was no significant difference in the low-birth-weight rate between nulliparous and parous women with prior preterm birth  was 60.7% for nulliparous women, 69.6% for parous women with a prior preterm birth, and 54.8% for parous women without a prior preterm birth (adjusted We report obstetrical outcomes of parous women based on parity number in There are some differences in gestational age and birth weight based on obstetrical history, but these are small compared with the increased risk of preterm delivery in twins compared with singletons. Parous women with twins delivered at a median gestational age of 36.6 weeks compared with 36.3 weeks for nulliparous women. Parous women with a history of prior preterm birth delivered at a median gestational age of 35.9 weeks compared with 36.7 weeks for parous women without prior preterm birth . AlthougPerhaps the most useful frame of reference for risk stratification is the rate of extreme prematurity. Nulliparous women with twins delivered before 32 weeks 10.2% of the time and before 28 weeks 3.3% of the time. Corresponding rates were 11.8% and 4.0% for parous women with a prior preterm birth and 6.3% and 1.8% for parous women without a prior preterm birth . Using tThere are two strengths of this study related to the analysis of the SART CORS dataset. First, this study represents the use of IVF data to answer an obstetrical question. Second, precise gestational age is challenging to determine outside an IVF context. The SART database contains precise information about the date of conception and delivery. This analysis may encourage other investigators to use IVF data to study other obstetrical scenarios where precise pregnancy dating is important for the analysis.Second, although not the main aim of this study, we did find vanishing gestations to be associated with higher rates of preterm delivery and low birth weight in the remaining twin pregnancies. In nulliparous women, the rate of preterm delivery of twins was 67.0% when 3 or 4 fetal heartbeats were initially seen compared with 60.6% when only two heartbeats were seen on initial ultrasound . These dIn conclusion, parous women carrying twins without a history of preterm delivery had lower rates of preterm delivery and low birth weight than did either nulliparous women or parous women with a history of prior preterm birth. Whereas the differences in rates are statistically significant, the magnitude of the differences is small compared with the differences in rates of preterm delivery and low birth weight between singleton and twin pregnancies in general.


To evaluate the timing of antenatal steroid administration and associated medical interventions in women with imminent preterm birth.We performed a prospective observational study at a single tertiary center in Germany from September 2018 to August 2019. We included pregnant women who received antenatal steroids for imminent preterm birth and evaluated the interval from administration to birth. 120 women with antenatal steroid application were included into our analysis. Descriptive statistics were performed to analyze factors influencing the timing of antenatal steroids and to evaluate additional medical interventions which women with imminent preterm birth experience.Of the 120 women included into our study, 35.8% gave birth before 34/0 weeks and 64.2% before 37/0 weeks of gestation. Only 25/120 women (20.8%) delivered within the optimal time window of 1–7 days after antenatal steroid application. 5/120 women (4.2%) only received one dose of antenatal steroids before birth and 3/120 (2.5%) gave birth within 8 to 14 days after antenatal steroids. Most women gave birth more than 14 days after steroid application . Women with preeclampsia (60%), PPROM (31%), and FGR (30%) had the highest rates of delivery within the optimal time window. Women of all timing groups received additional interventions and medications like antibiotics, tocolytics, or anticoagulation.Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially for women with symptoms of preterm labor and bleeding placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions. Preterm birth is affecting 11% of all children born globally . To imprMost published trials addressing the timing of steroid application analyze cohorts with preterm delivery after ANS retrospectively or solely evaluate neonatal outcome –13. Thatn = 1), the time from the last injection of steroids until birth was used. In a second step, we formed two groups for further statistical analysis: the optimal timing group  and the non-optimal timing group (only one dose and birth more than 7 days after ANS). The indications for ANS administration were divided into six subgroups: (1) PPROM, (2) preterm labor , (3) FGR, (4) preeclampsia and HELLP syndrome , (5) placenta previa/vaginal bleeding, and 6) others (not matching 1–5). The indication for ANS was made by the attending obstetrician. For the preterm labor group, we use a cervical length of 15 mm as a cut-off for indicating ANS based on German guidelines [We performed a prospective observational study at a tertiary center in Germany from September 2018 to August 2019. We included women who received ANS for suspected imminent preterm birth at our institution. Women under the age of 18 years, women who could not speak German, and women who received ANS outside of our hospital were excluded. After written informed consent was obtained, perinatal data of pregnant women who received antenatal steroids for imminent preterm birth were collected. If patients did not give birth at our hospital, we contacted them by phone to collect perinatal outcome data. We evaluated the ANS–birth interval and classified the patients into four study groups: incomplete ANS (only 1 dose of steroids), optimal timing , suboptimal timing (birth 8 to 14 days after the first dose), and ineffective timing (birth more than 14 days after the first dose). In our hospital, betamethasone  was used for ANS as a standard throughout the whole study period. If there was a second cycle of ANS, which was not common .Descriptive statistics using percentages for perinatal parameters and corresponding timing of ANS were carried out. For categorical variables Pearson’s Chi-square test or Fisher’s exact test and for continuous variables Mann–Whitney n = 5/120) received only one dose of betamethasone and gave birth afterward. 20.8% received a complete course of ANS and delivered within the optimal time window of 1–7 days after the first dose and 2.5% gave birth 8–14 days after the first dose of ANS. Most of the patients who received ANS (72.5%) gave birth more than 14 days later.Between September 2018 and August 2019, we approached 164 women who received ANS for suspected imminent preterm birth and asked them to participate in the study. 32 women declined consent, 5 women did not meet the inclusion criteria, and 5 women were lost to follow-up as they gave birth in another hospital and could not be contacted. We included 120 mother–infant pairs into our analysis . 54.7% of the patients had a preterm birth and 21.1% delivered before 34 weeks of gestation in the non-optimal timing group.Based on the described intervals, we formed two groups for further analysis: the optimal timing group with The indications for ANS administration were distributed differently between the two groups (see Table n = 65), only 11% gave birth within the optimal time window after ANS and 88% stayed pregnant for more than 14 days after steroids. The mean ANS–birth interval was 39.7 days for this group. The smallest group of placenta previa/bleeding showed the most unfavorable timing. All patients stayed pregnant for more than 14 days after ANS. In a one-way ANOVA, the differences in the mean ANS–birth intervals for the six indication groups reached statistical significance (p < 0.001).Figure n = 116). The mean total duration of the hospital stay was 11.7 days. 35 patients did not leave the hospital between ANS and birth (29.2%), all others went home after ANS. The mean total duration of the hospital stays for patients who went home between ANS and birth was 9.9 days (SD 11.6). The largest group of pregnant women who delivered more than 14 days after ANS (n = 87) stayed in the hospital for a mean of 12.4 days. Most of them went home between ANS and birth (92.0%). Most women who were treated for suspected imminent preterm birth received additional interventions and medications besides ANS: 31.7% were treated with antibiotics, 70.8% with tocolytics, 80.8% with anticoagulation, 16 women were treated with a pessary or cervical stitch cerclage, and 51.7% received vaginal progesterone. The rates of interventions were not statistically different between the study groups except for progesterone, which was most common in the group of patients who gave birth more than 14 days after ANS, as it included a lot of women with preterm labor. Thus, most women from the ineffective group, which did not benefit from ANS, had high rates of interventions.The overall preterm birth rate of our cohort was 64.2% and 44/120 patients (36.7%) gave birth before 34/0 weeks. 13 patients from the ineffective timing group gave birth before 34 weeks. Their mean GA at ANS was 25.8 weeks and at birth was 30.9 weeks. The mean ANS–birth interval for this group was 37.1 days. Most patients receiving ANS were hospitalized . Only 10.7% of them gave birth within the optimal therapeutic window. The mean cervical length at ANS was 13.1 mm. In 38 women, an additional biomarker test was done to evaluate the risk for spontaneous preterm birth (PartoSure®). We found 6 positive and 32 negative test results. None of the patients with a positive biomarker test gave birth within 7 days. Two patients who had a negative result gave birth within 1 week. One was a patient who delivered 7 days after the start of ANS (and the biomarker test) in 25/5 weeks and had a cervical length of 20 mm at admission. The other one gave birth 3 days after the start of ANS (and the biomarker test) in 29/3 weeks with a cervical length of 14 mm at admission. The sensitivity of the biomarker test in our cohort was 0 and the specificity 83.3%. The positive likelihood ratio was 0 and the negative likelihood ratio was 0.01. Concerning the cervicometry, a cut-off value of 15 mm is used in our clinic as a threshold for the indication of ANS. 45 women with preterm labor had a cervical length below 15 mm, and only 5 of them gave birth within 7 days. Of the 20 women with a cervical length of 15 mm or more, 3 gave birth within 1 week. Hence, the 15 mm cut-off value for cervicometry had a sensitivity of 62.5% and a specificity of 29.8% in our cohort. The positive likelihood ratio was 2.17 and the negative likelihood ratio  – 2.06. 52/65 women in the preterm labor group received tocolysis. Only 8 of them gave birth within 14 days (15.4%).More than half of the women of our cohort received ANS for suspected preterm labor  gave birth more than 14 days after ANS, resulting in an ineffective timing. Women with preeclampsia, PPROM, and FGR had the highest rates of delivery within the optimal time window. In the largest group of women with signs of preterm labor, only 11% gave birth within the optimal time. Most women treated with ANS were hospitalized and received additional interventions and medications besides ANS like antibiotics, tocolytics, anticoagulation, vaginal progesterone, and pessary or cervical stitch cerclage. Even the mother–infant pairs from the ineffective group, who did not benefit from ANS, had high rates of interventions. Thus, inaccurate prediction of the individual preterm birth risk led to untimely and unnecessary interventions in our cohort.n = 630), women from the group with hypertensive disorders were most likely to give birth within the optimal time window (62%) [n = 431), 41% of the women gave birth within 7 days after ANS administration. Women with preterm labor and PPROM or vaginal bleeding were more likely to give birth within the optimal time window in their cohort, which is contrary to our data. The authors report a higher risk for an adverse neonatal outcome when the ANS–birth interval exceeded 7 days [n = 1008) included all women, who received ANS during the study period, similar to our design. 45.5% of them gave birth within 7 days, which is higher than in our cohort. The group of women with vaginal bleeding had the lowest rate of deliveries with optimal timing of ANS (13.6%) compared to 61.5% in the group with maternal indications, which is comparable to our data [Antenatal steroids are an important therapeutic tool to reduce neonatal morbidity and mortality in the case of preterm birth –9. Althoow (62%) . Similard 7 days . A retroour data . In thein = 1356) found no difference in the frequency of delivery within the optimal window after introducing a rescue cycle [To improve the timing of ANS and consecutively improve neonatal outcome, guidelines allow a second cycle of steroids, if the risk for preterm birth continues to be high 7–14 days after the first cycle –4. Howevue cycle . Repeat ue cycle , 20, andue cycle , 22. Thep < 0.001). Only 59.1% of the infants were born preterm in the non-optimal timing group versus 100% of the optimal timing group. Hence, the need for respiratory support was a lot lower in the non-optimal timing group.Looking at the neonatal outcome of the two study groups, it might seem surprising at first sight that infants from the optimal timing group had lower APGAR scores as well as a higher need for CPAP and intubation than the non-optimal timing group (see Table A reliable prediction of preterm birth is necessary for the appropriate timing of ANS. As preterm birth is a syndrome caused by various conditions, its precise prediction within the next 7 days remains a clinical challenge . For theWe are aware of strengths and limitations of our study. A major strength is the prospective design, which includes all women receiving ANS even if they did not deliver preterm. Most international trials do not include this group and underestimate the exposed mother–infant pairs who do not benefit from ANS. By choosing the prospective design, we were able to give a complete estimate of the ineffective group. To our knowledge, this is the first analysis of this kind for a German population. We are aware of some limitations. One limitation is the relatively small cohort size, and a second one is the single-center design of our study. As standards of care and patient characteristics differ between regions and hospitals, our results may not be fully transferable to other populations, although they are in line with international data.Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially, for the large group of women with symptoms of preterm labor and women with bleeding due to placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions.


In this study, an association between the mother’s occupations with preterm and small-for-gestational-age (SGA) births was investigated using national data in Japan, and individual-level birth data from the Report of Vital Statistics: Occupational and Industrial Aspects in the 2015 fiscal year were used. Preterm and SGA birth rates were calculated for each of infant characteristics, and relative risk of each type of maternal occupations (categorized into 12 types) for the outcomes was estimated using a log binomial regression model.Data of 997,600 singleton births were analyzed. Among maternal occupations, preterm birth rate was highest among carrying, cleaning, packaging, and related workers (5.65%) and lowest among security workers (4.24%). SGA birth rate was highest among manufacturing process workers (5.91%) and lowest among security workers (4.00%). We found significantly elevated risks for preterm birth among manufacturing process workers compared with unemployed mothers, and significantly elevated risks for SGA birth compared with unemployed mothers were observed among sales workers, service workers, and manufacturing process workers. In contrast, security workers had a significantly decreased risk for SGA birth compared with unemployed mothers.The online version contains supplementary material available at 10.1186/s13104-023-06539-0. Preterm birth and small-for-gestational-age (SGA) in infants is a major adverse birth outcome. SGA rate differs largely depending on regions and tends to be high in developing countries , 2. AlthIt is known that some characteristics of mothers, such as maternal age, smoking habits, and maternal socioeconomic status, are risk factors of adverse birth outcomes –14. In JTo address this goal, we used the Vital Statistics data in Japan to investigate the association between maternal occupations and preterm and SGA births.We obtained nationwide individual-level data of the Report of Vital Statistics: Occupational and Industrial Aspects in the 2015 fiscal year from the Japanese Ministry of Health, Labor, and Wealth. Use of the data for research was permitted by the Ministry based on Article 33 of the Statistics Act. The survey for the report is conducted every 5 years, and the data include infants which were born between April 1, 2015 and March 31, 2016. The Report corresponds to the Vital Statistics with occupational and industry information. Vital Statistics is a survey by the Japanese government, and information from the birth certificates of all over the country are gathered by the Ministry of Health, Labor, and Wealth. It is mandatory for a parent to submit birth certificates of their children to a municipality within 14 days after childbirth. The birth certificate is a self-administered questionnaire, while health-related information, such as birthweight and gestational age, are written by physicians or midwives at the time of childbirth. The same data have been analyzed in previous studies in Japan , 24, andPreterm birth was defined as gestational age below 37 weeks. SGA is often defined as a birth weight below the 10th percentile of the sex- and gestational age-specific standard reference value , 25. In We tallied the number of births, preterm births, and SGA births and preterm and SGA birth rates for each infant characteristic. We defined six disjoint groups for maternal age , three groups for gestational age , and three groups for birth weight . Parity for infants was categorized into primiparous and multiparous. Maternal nationality was classified into Japanese and non-Japanese. Chi-square test was conducted between each of the birth characteristics and each of the outcomes. In addition, the relative risk of preterm and SGA birth for each type of occupation was calculated using a log binomial regression model with other characteristics as covariates. The log binomial regression model is a method used for calculating the relative risks for binary data , 29. UneComplete-case analysis was conducted in the chi-square test and the regression analysis for dealing with missing data. In addition, multiple imputation was used as a sensitivity analysis for dealing with missing data in the regression analysis . All staFigure Table Table Supplementary Table An association between the adverse birth outcomes and maternal occupations was revealed from an analysis of nationwide Vital Statistics data in Japan. Specifically, we have found that the risk of preterm and SGA births varied depending on maternal occupations. We now discuss the possible reasons for those associations.Regarding the mother’s occupation, it was suggested that the risk for manufacturing process workers was the highest. The elevated risk for adverse birth outcomes among manufacturing process workers might indirectly reflect the prevalence of lower socioeconomic status among Japanese female manufacturing process workers. It is known that, in Japan, the proportion of university graduates is relatively low and the proportion of junior high school or elementary school graduates is relatively high for manufacturing process workers in the occupational classifications among women aged 20–49 years old . The assOne strength of this study is that we used a large set of nationwide birth data for the analysis, and the study results represent nationwide trends in Japan. In particular, the association between maternal occupations and SGA and preterm birth is demonstrated for the first time using nationwide Vital Statistics. We specifically highlighted a higher risk of preterm birth and SGA for mothers employed as manufacturing process workers. This finding has important implications. First, future studies are needed to investigate the causes for the observed association. Second, there is a need for implementing effective prevention measures to lower the risk of adverse birth outcomes. Adjusting the work load or improving working conditions might be needed to lower those risks for pregnant manufacturing process workers. A call for attention in working places or prenatal care for pregnant women with those occupations might help. Finally, providing health guidance targeted to husbands of pregnant women whose occupations have higher risk of adverse birth outcomes might be also effective.One limitation of this study is the lack of data on women’s behaviors or physical characteristics, such as smoking status, BMI, utilization of prenatal care, chronic diseases, and working hours, that are known risk factors for adverse birth outcomes. Another limitation is the indirect inference of maternal educational level or physical characteristics because of the absence of such data in the dataset we analyzed. Socioeconomic status indicators of a mother, such as educational level or household income were not available in the data, and we could not fully differentiate the effect of maternal occupations from that of maternal socioeconomic status. Thus, to properly account for those factors that the survey does not collect, an epidemiological study designed to target those factors needs to be conducted in the future.Below is the link to the electronic supplementary material.Supplementary Material 1


Objective To determine the prevalence of inadequate birth interval and its associated factors in the BRISA study.Methods Cross-sectional study using data from the BRISA cohort. Birth interval was categorized into “adequate” (≥ 2 years or < 5 years between births), “short interval” (< 2 years) and “long interval” (≥ 5 years). The analysis of the factors associated with short and long birth intervals used multinomial logistic regression.Results The prevalence of adequate birth intervals was 48.3%, of long intervals, 34.6%, and of short intervals, 17.1%. Skin color, age, education level, economic status, type of delivery, number of prenatal visits, parity, blood pressure, diabetes, and anemia  proceeded to the final model. The variable ≥ 3 births  was associated with short intervals. Age < 20 years old  or ≥ 35 years old , ≥ 6 prenatal visits , ≥ 3 births , and gestational diabetes  were associated with long intervals.Conclusion Older mothers were more likely to have long birth intervals, and higher parity increases the chances of short birth intervals. Furthermore, gestational diabetes and adequate prenatal care presented higher chances of having adequate birth intervals, indicating that health assistance during pregnancy is important to encourage an adequate interval between gestations. The World Health Organization (WHO) recommends waiting between 18 to 24 months, but < 5 years, after a live birth before attempting another pregnancy.Research has shown that long and short interpregnancy intervals are independently associated with an elevated risk of adverse maternal, perinatal, and infant health outcomes.Literature on this topic has tended to focus on the consequences of short and long birth intervals for perinatal outcomes. The effects of birth spacing on maternal mortality and morbidity have received less attention. Therefore, relatively little is known about its consequences and associated factors.Short interpregnancy intervals are associated with increased adverse maternal health outcomes, such as risk of premature rupturing of membranes, preterm birth, uterine and placental bleeding, and gestational diabetes,The length of birth interval is influenced by socioeconomic, demographic, and reproductive health factors. In this respect, studies have shown that factors related to short intervals include low socioeconomic status, postpartum stress, unstable lifestyles, and access to health services, while advanced maternal age, maternal illness, infertility, unplanned pregnancy, and family and social break-ups are potential factors associated with long intervals. These factors can influence maternal health independently of their effect on birth interval.Studies have also investigated the influence of prenatal care on maternal and reproductive health and, by association, the relationship between this factor and birth interval.Among women in Africa, inadequate birth spacing was rated as more risky for women's health than other pregnancy-related events, like contraceptive methods.In view of the above, it is essential to gain a deeper understanding of the factors influencing birth intervals and the association between these intervals and maternal morbidity. The aim of the present study was, therefore, to determine birth intervals and to investigate the socioeconomic and reproductive health factors and maternal morbidities associated with inadequate birth intervals in São Luís, state of Maranhão, in the northeastern region of Brazil.A cross-sectional population-based study was conducted using data on hospital births in São Luís from the BRISA birth cohort. The present study was conducted in 10 public and private hospitals and maternity facilities in the municipality of São Luís using a representative sample (one-third) of births in these facilities in 2010. The total sample comprised 5,067 births after the exclusion of stillbirths and twins.A stratified sampling design was used, in which the size of each stratum was proportional to the number of births in each maternity facility. The births from each maternity facility were selected systematically from a list of all births that occurred in the facility sorted in chronological order, using a sampling interval of three and a random starting point between one and three. Starting with the random starting point, we counted down the list selecting each third birth until the desired number of births was selected.Data was collected using a standardized questionnaire answered by mothers, preferably in the first 24 hours after birth. Information on prenatal care was obtained from verbal reports of the mothers or from maternity records, when available.The questionnaire was divided into 11 blocks. Blocks C and G contained questions about socioeconomic status and demographic characteristics, and maternal morbidities during pregnancy, respectively, while block H included questions about the current pregnancy and prenatal care.rd trimester, and anemia.The following variables were analyzed: birth interval, skin color, age, economic status, education level, type of delivery, number of deliveries, number of prenatal visits, high blood pressure, diabetes, bleeding in the 3cabocla/morena,” “yellow/oriental,” or “indigenous”). Age was divided into three categories: < 20 years old, 20 to 34 years old, and ≥ 35 years old. Economic status was classified according to the Brazilian Criteria of Economic Classification into groups A, B, C, D, and EBirth interval was calculated by using the difference between the current age of the mother and her age in the last pregnancy. The data were self-reported and were categorized into “adequate” (≥ 2 years or < 5 years between births), “short interval” (< 2 years), and “long interval” (≥ 5 years) based on recommendations proposed by the Report of a WHO Technical Consultation on Birth Spacing.rd trimester, were assessed in relation to the current pregnancy.With regard to reproductive health variables, delivery type was classified as natural birth and cesarean section, while number of deliveries was grouped into 2 deliveries and ≥ 3 deliveries. The number of prenatal visits was defined according to the minimum number recommended by the Brazilian Ministry of HealthFor the present article, the minimum sample size was determined based on an expected prevalence of 50%, precision of 2%, and 95% confidence interval (CI), resulting in 2,396 women. From the total sample of the BRISA study, all women who reported more than one delivery, live birth, and singleton pregnancies were included in this analysis.Data analysis was conducted using the statistical software package Stata 14.0 . A descriptive analysis of the data was conducted to determine the frequencies and percentages of the variables. The analysis of the factors associated with short and long birth intervals used multinomial logistic regression, using the adequate interval as the reference category.Univariate analysis was conducted first to determine unadjusted odds ratios (ORs) adopting a 95% CI. The independent variables that obtained a p-value < 0.20 were included in the multivariate analysis. A significance level of 5% was adopted.In accordance with the provisions of Resolution 196/96 of the National Health Council, the present study was approved by the Ethics Committee of the Hospital Universitário Presidente Dutra (application number 4771/2008–30 and 223/2009).The final sample was comprised of 2,751 mothers who gave birth in maternity facilities in São Luís, state of Maranhão, Brazil . The prerd trimester of pregnancy . For long intervals, a significant association was observed with age < 26 years old  or ≥ 35 years old ; > 9 years of education ; economic status C  or D/E ; cesarean section ; ≥ 6 prenatal visits ; ≥ 3 births ; and gestational diabetes . No significant association was found between the other variables studied .p-value was < 0.2 in the univariate analysis, proceeded to the final model. In the adjusted analysis, only the variable ≥ 3 births  was associated with short intervals. Age < 20 years old , ≥ 6 prenatal visits , ≥ 3 births , and gestational diabetes  were inversely associated with long interval independently. Age ≥ 35 years old  was a factor associated with long birth intervals .The predominance of long intervals was found by other studies, which showed that the prevalence was higher for birth or pregnancy-spacing intervals of > 5 years.st trimester of pregnancy was lower among mothers with short birth intervals.The univariate and multivariate analyses revealed a statistically significant association between the number of prenatal visits and birth intervals, whereby mothers who had at least 6 visits had 58% less chance of having long birth intervals. A study conducted with Arab women in 2012 showed that the number of prenatal visits during the 1The multivariate analysis also showed statistically significant association between age and long birth intervals. Age < 20 years old decreases the chances of long birth intervals, whereas age ≥ 35 years old increases this chance by 43%. The relationship between age and parity is well described in the literature. Often, women with more children are older. Women who have had ≥ 3 births had 29% more chance of having short birth intervals. The negative impact of short birth intervals may only occur in high parity births, usually in older women. This finding is consistent with the concept of maternal depletion as the underlying cause of increased adverse child outcomes.The univariate analysis showed a statistically significant association between diabetes and birth interval. Having gestational diabetes proved to be a factor associated with long and short birth intervals. After adjustment for socioeconomic variables, age, and parity, the association with long intervals was maintained. A systematic review of the effects of birth interval on women's health highlighted a cross-sectional study undertaken in Latin America that did not find a significant association between diabetes and birth interval.No association was found between prevalence of anemia during pregnancy and birth interval. Despite the fact that anemia is common during pregnancy, the findings in the literature are inconclusive.There is emerging evidence that women with long birth intervals are at increased risk for labor dystocia, and that short intervals are associated with increased risks of uterine rupture in women attempting vaginal birth after previous cesarean delivery and uteroplacental bleeding disorders .The high number of women included in the present study and the recruitment strategy increased the possibility of generalization of the findings for women who reside in capitals in the northeastern region of Brazil with similar characteristics.Recent studies indicate the importance of identifying factors associated with birth intervals due to different patterns of association shown for preterm birth compared with maternal outcomes. This suggests that increasing maternal age may have discordant effects on associations between short birth intervals and adverse perinatal and maternal outcomes.rd trimester of pregnancy. The prevalence of adequate birth intervals was higher than that of long and short intervals. However, approximately one third of the participating women had long intervals. A statistically significant association was maintained between the variable ≥ 3 births and short birth interval with multivariate analysis. In this respect, women who were ≥ 35 years old were more likely to have long birth intervals. Age < 20 years old, ≥ 6 prenatal visits, ≥ 3 births, and gestational diabetes decreased the chances of long birth intervals. Moreover, women with gestational diabetes and adequate prenatal care had higher chances of adequate birth interval, indicating that health assistance during pregnancy is extremely important to encourage adequate intervals between gestations.Most of the women in the sample were nonwhite, from economic group C, aged between 20 and 24 years old, had at least 9 years of education, had 2 lifetime births, had natural births, and had at least 6 prenatal care visits. With respect to maternal morbidity, 15.6% of the mothers had high blood pressure, 2.2% had diabetes, 49.5% had anemia, and 9.4% had experienced at least one bleeding episode in the 3


Preterm birth, defined as birth before 37 weeks of gestation, is a major public health concern. It affects about 10% of all newborns globally and is the main cause of infant death and morbidity. Prematurity increases the likelihood of respiratory distress syndrome, cerebral palsy, and developmental abnormalities. Furthermore, premature newborns are at risk of acquiring chronic noncommunicable diseases later in life due to interference with organ system development during the in-utero and perinatal period. Because of the greater risk of long-term repercussions, preterm birth should be considered a chronic disorder, and gestational age and other birth histories should be included in all medical records for patients of all ages, especially when assessing the risk of multiple chronic diseases. Conventional methods for assessing preterm infant development, as well as reliable and precise growth monitoring, can lead to the early detection of growth decline and the adjustment of feeding regimens as needed. Because of its unique composition and useful components, human milk is a powerful tool for mitigating the negative outcomes associated with prematurity. It contains a variety of growth factors that promote the development of organs and systems, counteracting the negative effects of the abrupt interruption of intrauterine development and promoting better outcomes in all altered functions. Despite its multiple benefits, human milk cannot totally restore the lasting damage caused by premature birth. Premature infants cannot be completely overcome by nutrition alone, and yet adequate nutritional intake and human milk feeding are critical to their health and development. It is aIdentifying risk factors and implementing interventions to prevent premature birth and improve outcomes for premature infants is crucial. The risk of having long-term negative outcome increases as gestational age at birth decreases. 54.6% of adults (18–64 years old) born preterm do not develop comorbidities; this percentage falls to 23 percent if we consider adults born before 28 weeks of gestation , air displacement plethysmography (ADP), and bioelectrical impedance analysis (BIA) are commonly used to measure the body composition of premature infants . These mGrowth retardation, characterized by failure to achieve expected growth rates, can result in negative health outcomes, such as impaired neurodevelopment and increased morbidity . The imp5.Human milk feeding is essential for promoting optimal growth and development in infants. It contains a unique combination of macronutrients, micronutrients, and essential developmental factors for infant growth and development . The AmeHuman milk is a potent tool for mitigating some of the negative outcomes associated with prematurity due to its unique composition and functional substances. Enhancing the development and function of preterm infants' immune systems is one of the most notable benefits of human milk for premature infants. Moreover, human milk contains numerous growth factors that promote the maturation of the gastrointestinal tract, thereby facilitating optimal nutrient absorption and digestion . Brain d6.Preterm infants face a variety of health issues, including underdeveloped lungs, kidneys, brain, and cardiovascular system, which can have long-lasting effects on organ structure, metabolism, and susceptibility to chronic diseases later in life. Despite the numerous advantages of human milk, it is essential to recognize that it cannot completely reverse the permanent damage that may result from premature birth. Indeed, nutrition alone cannot thoroughly overcome these obstacles, regardless of the quality of human milk and its functional components.Further studies are required to develop individualized nutritional strategies concerning sex differences between males and females, birthweight, birthweight small for gestational age, impaired placental flows, intrauterine and extrauterine growth restriction, and other comorbidities . Furthermore, novel opportunities such as webinars can support education around the growth and nutrition of preterm infants and remove differences in future outcomes among different centres.We firmly believe that adequate nutritional intake and an individualized approach using human milk feeding are crucial to the health and development of preterm infants . Human m


Low birth weight is still an important public health problem worldwide. It is a major contributor to neonatal death in developing countries, including Nepal. The government of Nepal has developed and implemented different programs to improve maternal and neonatal health, including baby’s birth weight. However, low birth weight is a major maternal and child health challenge. Maternal factors determining the birth weight of neonates have been poorly assessed in previous studies in Nepal. Thus, this study aims to assess the prevalence and risk factors associated with low birth weight in Nepal. An institution-based descriptive cross-sectional study was carried out in Paropakar Maternity Hospital and Tribhuvan University Teaching Hospital of Kathmandu district among 308 postnatal mothers. The data was collected through the face-to-face interview technique. The data was entered in EpiData 3.1 and exported to Statistical Package and Service Solutions version 21 for analysis. Multivariate logistic regression was used to obtain an adjusted odds ratio, while p-value < 0.05 with 95% Confidence Interval (CI) was considered significant. The findings showed that 15.3% of the children had low birth weight. The mean and standard deviation of childbirth weight was 2.96±0.59 kg. Mothers belonged to Dalit ethnic , Antenatal Care visited three or fewer  and did not comply with Iron and Folic Acid supplementation  were significantly associated with low birth weight. Nearly one in every six children had low birth weight. Maternal health services such as antenatal care and compliance with a recommended dose of maternal micronutrients significantly impact on birth weight. Maternal and neonatal health programs should consider these factors to reduce adverse birth outcomes in Nepal. Birth weight has been one of the predictors of child mortality and morbidity. According to the World Health Organization (WHO), Low birth weight (LBW) live-born infants with a birth weight of less than 2500 grams, irrespective of the gestational age . EpidemiThe global prevalence of low birth weight is estimated to be 15% to 20% of all births representing over 20 million births in a year . There iEvidence suggests that factors such as iron folic acid intake , maternaVarious factors were explored to identify the cause of low birth weight in different countries , 24, 25.A cross-sectional study was conducted among two tertiary hospitals from September 2019 to August 2020 by using quantitative methods.Our study population was postnatal mothers. We included mothers who had singleton pregnancy and recently delivered liv- birth baby admitted in the postnatal ward of Tribhuvan University Teaching Hospital (TUTH) and Paropakar Maternity and Women’s Hospital (PMWH). We excluded the mothers with any serious obstetric or medical conditions, mothers who did not have ANC cards, who had multiple pregnancies, whose last menstrual period was not exactly known, who had a history of some complications like antepartum hemorrhage and neonates with congenital malformations, had medical conditions like Diabetes, Hypertension, cardiac diseases or chronic infections and who required constant medical support and monitoring.Kathmandu Valley, Bagmati Province of Nepal. It covers an area of 413.69 km2 (153 sq mi), and is the most densely populated district. It’s headquarter is Kathmandu Metropolitan City [The study sites were Tribhuvan University Teaching Hospital (TUTH) and Paropakar Maternity and Women’s Hospital (PMWH) of Kathmandu district, Nepal. Kathmandu district is located in tan City . Kathman2pq/d2, considering the prevalence of low birth weight as 23.6% from the previous study conducted at Bharatpur Nepal [A total of 308 mothers were interviewed with equal samples (154) taken from each hospital which was calculated using the formula n = zur Nepal , at 95% We conducted face-to-face interviews among postnatal mothers using a semi-structured questionnaire. We also used the ANC card and Maternity register to confirm the information. The tools were developed based on study objectives through extensive literature review and pretested among 10% of non- sampled population in postnatal ward of TU Teaching hospital. PT, NA and two trained enumerators were involved in data collection from February 20, 2020 to April 7, 2020.Birth weight was reported in grams which was operationalized as a continuous variable. We constructed a binary variable for low birth weight based on the weight of birth <2500 gm as defined by WHO .Independent variables were selected based on previously published studies , 29–31. Sociodemographic factors included age of postnatal mother , ethnicity , education of mother , occupation . Maternal obstetric factors included the height of mother (categorized into less than 145 cm and more than 145 cm), weight gain during pregnancy , gestational age at birth , parity , birth interval (categorized into less than 2 years and more than 2 years), pregnancy intention (categorized into unintended and intended), history of abortion Behavioral factors included tobacco and alcohol use. Diet-related factors included dietary patterns, food taboos during pregnancy. Health service-related factors included ANC visit (categorized into less than 4 visits and more than or 4 visits), intake of deworming (categorized into Yes and No), hemoglobin level recorded at first ANC visit (categorized into less than 11 gm/dl and 11gm/dl or more). Maternal compliance with compliance to iron-folic acid was also assessed. Compliance was defined as the uptake of IFA supplementation by pregnant women daily. The mother was determined to have compliance if she uptakes at least 80% of the recommended dose  , 33. MatData was entered in EpiData version 3.1. After confirming the completeness, data were exported to IBM SPSS Version 21 for further analysis. Univariate analysis was conducted using frequencies, percentages, mean and standard deviation. Multi-collinearity was assessed before logistic regression using the variance inflation factor (VIF). The decision criterion for excluding of variable from the regression model was set out as those with VIF values greater than 10. The goodness of fit the regression model was tested by applying the of Hosmer and Lemeshow chi-square test. Those variables significantly associated in the univariate analysis at 95% confidence level, p-value less than 0.05 were included in the multivariate model. We applied Multivariate logistic regression analysis adjusting for covariates such as ethnicity, IFA compliance, and ANC visit to identify the factors associated with low birth weight. The unadjusted and adjusted odds ratio with 95% confidence intervals were reported. P-value less than 0.05 was considered statistically significant.The ethical review committee approved the study at the Institute of Medicine  E2 076/077) and Nepal Health Research Council . Permission was taken from both hospitals. Participants provided verbal and written consent to participate in the study, which was voluntary and anonymous.Our study found that about one in every seven children had a birth weight of less than 2500 gm. The three factors: (1) ethnicity, (2) Compliance with IFA, and (3) Maternal Antenatal care visits were significantly associated with birth weight of children. The prevalence of low birth weight (15.3%) was slightly lower than the study conducted in Dhulikhel hospital (21.6%) , JanakpuMaternal age is considered as a key factor for the healthy outcome of pregnancy. This study reveals no statistical association between maternal age and low birth weight, which contradicts the study done in tertiary hospitals of Nepal that shows higher risk of delivering low birth weight babies by mothers of age less than 20 years , 30. ThiOur study showed that ethnicity significantly affects a baby’s birth weight. The mothers who belongs to Dalit ethnicity were nearly three times more likely to have low birth weight baby. This finding was consistent with another study conducted in Chitwan, which revealed that mothers belonging to Dalit and Madhesi ethnicity were more likely to have low birth weight baby . SimilarOur study revealed that mothers who did not attend four times or more antenatal services were 2.6 times higher change of low-birth-weight baby compared to those who attend four or more times. In support with this finding, another study conducted in Nepal using nationally representative survey data in 2011 showed that mothers who attend three or fewer ANC visits only were two times more likely to have low birth weight babies . This fiOur study showed that 77.6% of mothers had compliance to iron-folic acid supplementation. A lower finding was seen in a study in Pokhara, Nepal that showed the compliance rate of 58% . The stuLow iron intake causes the poor delivery of iron to the fetus, impair in proper hormonal and neuronal regulation of pregnancy and poor oxygenation of the fetus leading to poor growth and development . Our stuSmoking and alcohol consumption negatively affects the fetus’s growth and development because of their chemical substances . HoweverThis study has certain limitations that should be addressed in future research. The study was based on the health institutions limiting its generalizability in the community setting. Also, the other potential risk factors for low birth weight including micronutrient deficiencies among mothers and exposure to toxins like pesticides and indoor air pollution, were not evaluated, which may have affected the result.This study concluded that about one in seven children had low birth weight. The mothers who belong to Dalit ethnicity, who did not have antenatal visits as per recommended protocol (4 or more times) and mothers who did not comply with iron-folic acid supplementation were likelier to have low birth weight babies. This suggests that disadvantageous ethnic groups should be a focus in national preventive programs for the prevention of risk of delivering low birth weight baby. During ANC visits, priority should be given for providing nutrition education and motivating pregnant women towards IFA compliance focusing on complete ANC visits. Further studies such as case-control, cohort studies might help to bring forward the information on factors associated with the birth weight of children.S1 Data(SAV)Click here for additional data file.S1 File(DOCX)Click here for additional data file.