Reproductive and developmental safety evaluation of Thymelaea hirsuta (L.) leaves aqueous extract in Wistar albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The popularity of herbal medicine is expanding globally due to the common belief that herbal products are natural and nontoxic. Thymelaea hirsuta leaves are traditionally used for the treatment of recurrent abortion in humans and animals. However, a lack of safety evaluation of the plant, particularly in pregnant women, raises serious concerns regarding its potential embryotoxic effects. AIM OF THE STUDY: Therefore, the present study investigated the safety of Thymelaea hirsuta leaves aqueous extract (THLE) during pregnancy and lactation following maternal rat treatment. MATERIALS AND METHODS: THLE phytochemical compounds were identified using high-performance liquid chromatography (HPLC). THLE was orally administered to pregnant rats and lactating dams at dosages of 0, 250, 500, and 1000 mg/kg/day. At the end of the study, dam s' and pups' body weights, serum biochemical and hematological indices, and histopathological changes were investigated. For the fetal observation and histopathological changes were also evaluated. RESULTS: Our findings revealed that THLE is rich in different phenolic and flavonoid compounds. However, biochemical and hormonal parameters such as ALT, AST, and prolactin were significantly increased in dams treated with a higher dosage of THLE when compared to the control dams (P ≤ 0.05). Additionally, external, visceral and skeletal examinations of fetuses revealed a marked increase of malformation rates in treated fetuses. CONCLUSIONS: The results revealed that higher oral dosing of THLE during pregnancy could affect embryonic development in rats, while lower doses are safe and can be used during pregnancy and lactation to attain its beneficial effects.

Transcription factor-based transdifferentiation of human embryonic to trophoblast stem cells.

During the first week of development, human embryos form a blastocyst composed of an inner cell mass and trophectoderm (TE) cells, the latter of which are progenitors of placental trophoblast. Here, we investigated the expression of transcripts in the human TE from early to late blastocyst stages. We identified enrichment of the transcription factors GATA2, GATA3, TFAP2C and KLF5 and characterised their protein expression dynamics across TE development. By inducible overexpression and mRNA transfection, we determined that these factors, together with MYC, are sufficient to establish induced trophoblast stem cells (iTSCs) from primed human embryonic stem cells. These iTSCs self-renew and recapitulate morphological characteristics, gene expression profiles, and directed differentiation potential, similar to existing human TSCs. Systematic omission of each, or combinations of factors, revealed the crucial importance of GATA2 and GATA3 for iTSC transdifferentiation. Altogether, these findings provide insights into the transcription factor network that may be operational in the human TE and broaden the methods for establishing cellular models of early human placental progenitor cells, which may be useful in the future to model placental-associated diseases.

Prevention of Recurrent Spontaneous Preterm Delivery Using Probiotics (Clostridium butyricum, Enterococcus faecium, and Bacillus subtilis; PPP Trial): Protocol for a Prospective, Single-Arm, Nonblinded, Multicenter Trial.

BACKGROUND: The rate of recurrent spontaneous preterm delivery (sPTD) ranges between 27% and 34% and is 22.3% in Japan. Although it currently remains unclear whether probiotics prevent sPTD, retrospective studies recently reported a reduction in the rate of recurrent sPTD with the administration of probiotics including Clostridium spp., which induce regulatory T cells that play an important role in maintaining pregnancy. OBJECTIVE: The objective of this trial is to evaluate the preventative effects of available oral probiotics, including Clostridium butyricum, on recurrent sPTD. METHODS: This is a prospective, single-arm, nonblinded, multicenter trial in Japan. The sample size required for this trial is 345 pregnant women with a history of sPTD, considering a clinically significant reduction in the relative risk of 30% (risk ratio=0.7). The primary endpoint is the rate of recurrent sPTD at <37 weeks of gestation. The secondary endpoints are the rate of sPTD at <34 weeks of gestation, the rate of recurrent sPTD at <28 weeks of gestation, the ratio of intestinal Clostridium spp. (detected by next-generation sequencing), and bacterial vaginosis (using the Nugent score). RESULTS: The trial procedures were approved by the Clinical Research Review Board of Toyama University Hospital (SCR2020008) on March 31, 2021. The trial was registered on the Japan Registry of Clinical Trial website on April 28, 2021. Recruitment began on May 1, 2021, and the trial is estimated to finish on March 31, 2025. CONCLUSIONS: The findings will clarify the rate of recurrent sPTD following probiotic administration including Clostridium butyricum. Outcomes from this trial will inform clinical practice and guide future randomized controlled trials. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs041210014; https://jrct.niph.go.jp/latest-detail/jRCTs041210014. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/59928.

Potential candidate maternal serum miRNAs for the diagnosis of fetal congenital heart disease.

Congenital heart disease (CHD) is one of the most significant birth defects leading to infant mortality worldwide. Circulating microRNAs (miRNAs) are emerging as novel biomarkers for the detection of cardiovascular diseases. In this study, we aimed to investigate the role of maternal serum miRNAs expression as biomarkers in the diagnosis and prediction of children with CHD. High-throughput sequencing of peripheral blood from pregnant women with abnormal and normal fetal hearts identified 1939 differentially expressed miRNAs, the first 11 of which were selected as predictive biomarkers of CHD. The expression of miRNAs in more clinical samples was then quantitatively verified by reverse transcriptase polymerase chain reaction and the correlation between abnormal miRNAs and CHD was analyzed. Two miRNAs (hsa-miR-3195 and hsa-miR-122-5p) were found to be significantly down-regulated in pregnant women with fetal CHD. By further bioinformatics analysis, we predicted that hsa-miR-3195 and hsa-miR-122-5p could induce CHD by influencing biometabolic processes. hsa-miR-3195 and hsa-miR-122-5p may serve as novel non-invasive biomarkers for prenatal detection of fetal CHD.

The molecular mechanism of ferroptosis-induced spontaneous abortion based on bioinformatics approach.

Spontaneous abortion (SA) is a prevalent placental dysfunction, and ferroptosis may play a crucial role in placental dysfunction and the development of SA. In this study, we employed data mining and analysis techniques to investigate the biological mechanism of SA induced by ferroptosis, resulting in the identification of a total of 79 ferroptosis-related genes in SA were identified. Among them, 3 co-expression modules of ferroptosis risk genes, ten significant functions and six biologically significant pathways were obtained 61 pairs of differentially expressed miRNA-ferroptosis factor relationships were identified, and WIPI1 and GSN were expressed at significantly higher levels in SA. This is extremely helpful for future research on SA.

Impact of maternal protein restriction on the proteomic landscape of male rat lungs across the lifespan.

The developmental origins of healthy and disease (DOHaD) concept has demonstrated a higher rate of chronic diseases in the adult population of individuals whose mothers experienced severe maternal protein restriction (MPR). Using proteomic and in silico analyses, we investigated the lung proteomic profile of young and aged rats exposed to MPR during pregnancy and lactation. Our results demonstrated that MPR lead to structural and immune system pathways changes, and this outcome is coupled with a rise in the PI3k-AKT-mTOR signaling pathway, with increased MMP-2 activity, and CD8 expression in the early life, with long-term effects with aging. This led to the identification of commonly or inversely differentially expressed targets in early life and aging, revealing dysregulated pathways related to the immune system, stress, muscle contraction, tight junctions, and hemostasis. We identified three miRNAs (miR-378a-3p, miR-378a-5p, let-7a-5p) that regulate four proteins (ACTN4, PPIA, HSPA5, CALM1) as probable epigenetic lung marks generated by MPR. In conclusion, MPR impacts the lungs early in life, increasing the possibility of long-lasting negative outcomes for respiratory disorders in the offspring.

Plasma proteomic signature of neonates in the context of placental histological chorioamnionitis.

BACKGROUND: Placental histological chorioamnionitis (HCA) is recognised as a significant risk factor for various adverse neonatal outcomes. This study aims to explore if the inflammatory protein levels in neonates were associated with HCA. METHODS: All women with singleton births from February 2020 to November 2022 were selected and divided into three groups based on maternal placental pathology results: the HCA-stage 1 group (n=24), the HCA-stage 2 group (n=16) and the control group (n=17). Olink Target 96 Inflammation Panel was used to detect the levels of 92 inflammation-related proteins in the plasma of newborns from all three groups within 24 hours after birth. We compared the protein profiles through differential protein expression analysis. RESULTS: A total of six inflammation-related proteins exhibited significant differences between the HCA-stage 1 and the control group. Specifically, TRANCE and CST5 were significantly upregulated (p=0.006, p=0.025, respectively), whereas the expression of IFN-gamma, CXCL9, CXCL10 and CCL19 was significantly downregulated (p=0.040, p=0.046, p=0.007, p=0.006, respectively). HCA-stage 2 newborns had significantly elevated levels of CD5 and CD6 and decreased IFN-gamma, CXCL10 and CCL19 in comparison to controls. These differential proteins were significantly enriched in positive regulation of cytokine activity, leucocyte chemotaxis and positive regulation of T-cell activation pathway-related Gene Ontology terms. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that viral protein interaction with cytokine and cytokine receptor, interleukin-17/NF-kappa B/toll-like receptor/chemokine signalling pathway, and cytokine-cytokine receptor interaction exhibited significant differences. Spearman analysis demonstrated a significant positive connection between the levels of CD6 and CD5 proteins, not only in neonatal leucocytes but also in maternal leucocytes. Additionally, CD6 was found to be associated with neonatal birth weight. CONCLUSIONS: In conclusion, placental histological changes associated with chorioamnionitis appear to influence the expression of inflammatory proteins in offspring. Notably, CD6 and CD5 proteins may potentially contribute to the pathogenesis of HCA-related neonatal diseases.

Proteomic analysis and in vivo visualization of extracellular vesicles from mouse oviducts during pre-implantation embryo development.

Pre-implantation embryonic development occurs in the oviduct during the first few days of pregnancy. The presence of oviductal extracellular vesicles (oEVs, also called oviductosomes) is crucial for pre-implantation embryonic development in vivo as oEVs often contain molecular transmitters such as proteins. Therefore, evaluating oEV cargo during early pregnancy could provide insights into factors required for proper early embryonic development that are missing in the current in vitro embryo culture setting. In this study, we isolated oEVs from the oviductal fluid at estrus and different stages of early embryonic development. The 2306-3066 proteins in oEVs identified at the different time points revealed 58-60 common EV markers identified in exosome databases. Oviductal extracellular vesicle proteins from pregnant samples significantly differed from those in non-pregnant samples. In addition, superovulation changes the protein contents in oEVs compared to natural ovulation at estrus. Importantly, we have identified that embryo-protectant proteins such as high-mobility protein group B1 and serine (or cysteine) peptidase inhibitor were only enriched in the presence of embryos. We also visualized the physical interaction of EVs and the zona pellucida of 4- to 8-cell stage embryos using transmission electron microscopy as well as in vivo live imaging of epithelial cell-derived GFP-tagged CD9 mouse model. All protein data in this study are readily available to the scientific community in a searchable format at https://genes.winuthayanon.com/winuthayanon/oviduct_ev_proteins/. In conclusion, we identified oEVs proteins that could be tested to determine whether they can improve embryonic developmental outcomes in vivo and in vitro setting.

Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities.

OBJECTIVE: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies. METHODS: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines. RESULTS: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON, L1CAM, KMT2D, and ASPM. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses. CONCLUSION: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

Reducing maternal infection after assisted vaginal birth in a diverse and deprived population.

Postpartum maternal sepsis is a leading cause of maternal mortality and morbidity. A single dose of prophylactic antibiotics following assisted vaginal births has been shown to significantly reduce postpartum maternal infection in a landmark multicentre randomised controlled trial, which led to its national recommendation. This project aimed to improve the local implementation of prophylactic antibiotics following assisted vaginal births to reduce postnatal maternal infections.Using a prospectively collated birth register, data were collected retrospectively on prophylactic antibiotics administration and postnatal maternal infection rates after assisted vaginal births at the Sandwell and West Birmingham Hospitals National Health Service Trust in North-West Birmingham of the UK. The data were collected from routinely used electronic health records over three audit cycles (n=287) between 2020 and 2023.A mixed-method approach was used to improve the use of prophylactic antibiotics: (1) evidence-based journal clubs targeting doctors in training, (2) presentations of results after all three audit cycles at our and (3) expedited a formal change of local guidelines to support prophylactic antibiotics use.Prophylactic antibiotic administration increased from 13.2% (December 2021) to 90.7% (July 2023), associated with a reduction in maternal infection rates (18.2% when prophylaxis was given vs 22.2% when no prophylaxis was given). However, we observed a gradual increase in the overall postnatal maternal infection rates during the project period.Our repeat audit identified prophylactic antibiotics were regularly omitted after deliveries in labour ward rooms (59.3%), compared with 100% of those achieved in theatre. After further interventions, prophylactic antibiotics administration rates were comparable between these clinical areas (>90%) in 2023.Together, we have demonstrated a simple set of interventions that induced sustainable changes in practice. Further evaluation of other modifiable risk factors and infection rates following all deliveries is warranted in view of the gradual increase in the overall postnatal maternal infection rates.

Identifying microbiome-based changes and biomarkers prior to disease development in mother and child, with a focus on gestational diabetes mellitus: protocol for the DANish Maternal and Offspring Microbiome (DANMOM) cohort study.

INTRODUCTION: The human gut microbiota is associated with gestational diabetes mellitus (GDM), which imposes a risk of developing long-term health problems for mother and child. Most studies on GDM and microbiota have been cross-sectional, which makes it difficult to make any conclusions on causality. Furthermore, it is important to assess if a dysbiotic microbiota is passed from the mother to the child, and then being at risk of developing metabolic health problems later in life. The DANish Maternal and Offspring Microbiome study aims to identify gut microbiota-related factors involved in metabolic dysfunction in women with GDM and their offspring. Importantly, the study design allows for early detection of biological changes associated with later development of metabolic disease. This could provide us with unique tools to support early diagnosis or implement preventative measures. METHODS AND ANALYSIS: Pregnant women are included in the study after the 11-14 weeks' prenatal ultrasound scan and followed throughout pregnancy with enrolment of the offspring at birth. 202 women and 112 children have been included from North Denmark Regional Hospital and Aalborg University Hospital in Denmark. Mother and child are followed until the children reach the age of 5 years. From the mother, we collect faeces, urine, blood, saliva, vaginal fluid and breast milk samples, in addition to faeces and a blood sample from the child. Microbiota composition in biological samples will be analysed using 16S rRNA gene sequencing and compared with demographic and clinical data from medical charts, registers and questionnaires. Sample and data collection will continue until July 2028. ETHICS AND DISSEMINATION: The study protocol has been approved by the North Denmark Region Committee on Health Research Ethics (N20190007). Written informed consent is obtained from all participants prior to study participation. Study results will be published in international peer-reviewed journals and presented at international conferences. The results will also be presented to the funders of the study and study participants.

Neonatal birth asphyxia and associated factors among newborns delivered and admitted to NICU in selected public hospitals, under Addis Ababa City Administration Health Bureau, Addis Ababa, Ethiopia, A cross-sectional study.

BACKGROUND: In developing countries birth asphyxia is a major cause of neonatal morbidity and mortality. Despite the implementation of various strategies and interventions to combat neonatal mortality rates, birth asphyxia remains the main public health concern in Ethiopia. Moreover, limited studies have been conducted, especially in the study area and there are no multicenter analyses available to generate evidence for action. Therefore, this study aimed to assess the burden and associated factors of birth asphyxia among newborns in the selected public hospitals of the Addis Ababa City Administration Health Bureau. METHODS: Three hundred forty-three mother-child pairs who used delivery services and gave birth in the selected public hospitals were included in the study, and institution based cross sectional study design was employed. A systematic random sampling technique was used to select the study participants. A pretested, structured interviewer administered questionnaire was used to collect the data. The physician's/health care professionals diagnosis of an Apgar score less than 7 within the first five minutes of life led to the confirmation of the diagnosis of birth asphyxia. SPSS version 24 was used for analysis after the data were exported from Epi Info version 7.2. Multivariate logistic regression analysis included variables which had P-values less than 0.25 in the bivariable logistic regression analysis. The study findings were expressed using adjusted odds ratio with a 95% confidence interval, and P-value less than 0.05 was used to declare the statistical significance. RESULTS: The magnitude of birth asphyxia was found to be 17.1% [95% CI; (13.2-21.5)] at the first 5 min. In the multivariable logistic regression analysis cord accident [AOR = 6.24: 95% CI; (1.24-31.32)], prolonged duration of labor [AOR = 2.49: 95% CI; (1.93-10.89)], and meconium-stained amniotic fluid [AOR = 3.33: 95% CI; (1.73-6.41)] were the predictors of birth asphyxia. CONCLUSIONS: The findings of this research indicate that birth asphyxia is a prevalent neonatal problem at the study area. Therefore, the Addis Ababa Health Bureau must prioritize integrated mitigation interventions targeting high-risk pregnancies to achieve national and international commitment to sustainable changes in newborn health.

Uncovering the hidden health burden: a systematic review and meta-analysis of iron deficiency anemia among adolescents, and pregnant women in Pakistan.

INTRODUCTION: Iron deficiency anemia (IDA) is the most prevalent diet-related disorder and mainly affects women and children. To determine the trend of anemia incidence in Pakistan, a current review was carried out. This review aimed to estimate the prevalence of anemia among pregnant women and adult/adolescent nonpregnant women in Pakistan and to provide a 15-year trend analysis. MATERIALS AND METHODS: Studies were identified by searching PubMed, Google Scholar, Scopus, and Science Direct, complementing this digital exploration, and a manual review of reference lists from previously published prevalence studies was performed to enhance the scope of relevant articles. A total of twenty-seven population-based anemia studies on adolescent/adult females and pregnant women published in Pakistan from January 1st-2007 until December 2021 were included. Systematic data extraction was facilitated through the implementation of a standardized and rigorously pretested data extraction checklist. For the subsequent analysis, the sophisticated capabilities of R statistical software were harnessed. The I2 test was used to assess heterogeneity among studies, and the pooled prevalence of anemia was calculated. RESULTS: The final analysis included 27 research articles as well as two extensive National Nutrition survey reports, NNS 2011 and NNS 2018. The forest plot of sixteen studies on pregnant women revealed that the overall pooled prevalence of anemia among pregnant females in Pakistan was 70.4% (95% CI: 0.619, 0.789), and the forest plot of eleven studies on non-pregnant adolescent and adult females reported the pooled prevalence was 54.6% (95% CI: 0.422, 0.669). Subgroup analysis among pregnant women based on region, trimester and socioeconomic status revealed that the highest anemia incidence was observed in Punjab (77.4%). Similarly, females in the second trimester reported a higher prevalence of anemia 78% (95% CI, 0.556 1.015), and the status-wise group with a mixed background reported a higher prevalence 72.8% (95% CI, 0.620 0.835). According to the subgroup analysis, eleven studies of adult nonpregnant groups of mixed socioeconomic status reported a higher prevalence of 56.9% (95% CI, 0.292 0.845). CONCLUSION: In Pakistan, anemia, is widespread among pregnant women and nonpregnant adolescent/adult females. A deeper understanding of anemia in Pakistani women is necessary for targeted interventions and policy decisions to predict demographic shifts.

The role of microRNAs in pregnancies complicated by maternal diabetes.

With the global prevalence of diabetes increasing, more people of reproductive age are experiencing hyperglycaemic pregnancies. Maternal Type 1 (T1DM) or Type 2 (T2DM) diabetes mellitus, and gestational diabetes mellitus (GDM) are associated with maternal cardiovascular and metabolic complications. Pregnancies complicated by maternal diabetes also increase the risk of short- and long-term health complications for the offspring, including altered fetal growth and the onset of T2DM and cardiometabolic diseases throughout life. Despite advanced methods for improving maternal glucose control, the prevalence of adverse maternal and offspring outcomes associated with maternal diabetes remains high. The placenta is a key organ at the maternal-fetal interface that regulates fetal growth and development. In pregnancies complicated by maternal diabetes, altered placental development and function has been linked to adverse outcomes in both mother and fetus. Emerging evidence suggests that microRNAs (miRNAs) are key molecules involved in mediating these changes. In this review, we describe the role of miRNAs in normal pregnancy and discuss how miRNA dysregulation in the placenta and maternal circulation is associated with suboptimal placental development and pregnancy outcomes in individuals with maternal diabetes. We also discuss evidence demonstrating that miRNA dysregulation may affect the long-term health of mothers and their offspring. As such, miRNAs are potential candidates as biomarkers and therapeutic targets in diabetic pregnancies at risk of adverse outcomes.

[A prospective birth cohort study on the association between gestational blood pressure and neurodevelopment in 2-year-old children].

Objective: To investigate the association between gestational blood pressure and neurodevelopment in 2-year-old children. Methods: Based on the"Wuhan Healthy Baby Birth Cohort", 3 754 mother-infant pairs were enrolled in this study. Based on multiple blood pressure measurements during pregnancy, the mean, cumulative, and variability of blood pressure throughout the entire pregnancy and each trimester were calculated. Blood pressure variability was evaluated using standard deviation (SD), coefficient of variability (CV), and variability independent of mean (VIM). Follow-up testing of neurodevelopment in infants and young children at the age of two was conducted to obtain the Mental Development Index (MDI) and the Psychomotor Development Index (PDI). The multivariate linear regression and generalized estimation equation were used to analyze the association between gestational blood pressure data and neurodevelopmental index. Results: The age of 3 754 pregnant women was (29.1±3.6) years, with a pre-pregnancy BMI of (20.9±2.7) kg/m² and a gestational age of (39.3±1.2) weeks. The birth weight of 3 754 children was (3 330.9±397.7) grams, and the birth length was (50.3±1.6) centimeters. The results of the multivariate linear regression analysis showed that after adjusting for relevant confounding factors, the mean blood pressure, cumulative blood pressure, standard deviation of blood pressure, coefficient of variation of blood pressure, independent blood pressure variability of systolic blood pressure, diastolic blood pressure, and pulse pressure throughout pregnancy were negatively associated with the MDI and PDI scores of 2-year-old children. The analysis results of the generalized estimation equation showed that after adjusting for relevant confounding factors, the average systolic blood pressure in the first, second, and third trimesters was negatively associated with MDI/PDI. The negative association between cumulative blood pressure and MDI/PDI was only found in the first trimester. The negative association between blood pressure variation during pregnancy and MDI/PDI was mainly concentrated in the second and third trimesters. Conclusion: There is a negative association between gestational blood pressure and the neurodevelopmental index of 2-year-old children.

[Prenatal screening and prenatal diagnosis clinical laboratory diagnostic pathway].

Congenital defects and genetic diseases in the fetus are the focus of prenatal screening and prenatal diagnosis. Obstetrics and gynecology, pediatrics, medical imaging (ultrasound and magnetic resonance imaging), clinical laboratory, pathology, and other disciplines are mostly involved in this multidisciplinary work on maternal and infant health care, which aims to prevent birth defects in strict accordance with laws, regulations, and pertinent industry standards, such as the Notice of the National Health Commission on Issuing the Basic Standards for Prenatal Screening Technical Medical Institutions and the Basic Standards for Prenatal Diagnosis Technical Medical Institutions (Guowei Maternal and Child Letter [2019] No. 297). To further support the implementation of prenatal screening and diagnosis work and streamline workflow, this study has compiled the timing, inspection, and testing procedures of various projects in each link from the standpoint of the disease clinical laboratory diagnostic pathway. This approach improves communication amongst various disciplines in prenatal screening and diagnosis work and offers clinical service quality, and it also helps improve the standard of the birth population and prevent and controll severe birth defects.

Semi-parametric benchmark dose analysis with monotone additive models.

Benchmark dose analysis aims to estimate the level of exposure to a toxin associated with a clinically significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop a novel approach for calculating benchmark dose lower limits based on an approximate pivot for the nonlinear equation solved by the estimated benchmark dose. The favorable properties of this approach compared to the Delta method and a parameteric bootstrap are discussed. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from six NIH-funded longitudinal cohort studies. Software to reproduce the results in this paper is available online and makes use of the novel semibmd  R package, which implements the methods in this paper.

Exploring low back and pelvic pain challenges: Administrative insights into prevalence during pregnancy among 2016-2021 South Carolina Medicaid beneficiaries.

BACKGROUND: Musculoskeletal changes occur during pregnancy; one-half of pregnant women experienced low back pain and/or pelvic pain during pregnancy. Prescription opioid use for Medicaid enrolled pregnant women has increased dramatically due to severe low back pain/pelvic pain. OBJECTIVES: This study aimed to explore the prevalence of low back pain/pelvic pain and related risk factors among a broader population. DESIGN: This is a retrospective cohort study. METHODS: This study utilized de-identified Medicaid claims data provided by the South Carolina Revenue and Fiscal Affairs Office, including individuals who gave birth between 2016 and 2021 during pregnancy. Low back pain/pelvic pain and a group of musculoskeletal risk factors were identified with International Classification of Diseases v10. Comparisons were made for the prevalence of low back pain and pelvic pain between those with pregnancy-related musculoskeletal risk and those without. RESULTS: Among 167,396 pregnancies, 65.6% were affected by musculoskeletal risk factors. The overall prevalence of low back pain was 15.6%, and of pregnancy-related pelvic pain was 25.2%. The overall prevalence for either low back pain or pelvic pain was 33.3% (increased from 29.5% in 2016 to 35.3% in 2021), with 24.6% being pregnancy-induced. Pregnancies with musculoskeletal risk factors were more likely to be diagnosed with low back pain (20.7% versus 5.7%, p < 0.001) or pelvic pain (35.3% versus 6.0%, p < 0.001) than those without. CONCLUSION: This study found a very high prevalence of musculoskeletal risk and a high prevalence of low back pain or pelvic pain, with an increasing trend, among South Carolina pregnancies enrolled in Medicaid during the period 2016-2021. Most of the diagnosed low back pain or pelvic pain were pregnancy induced. Musculoskeletal risk factors were associated with low back pain or pelvic pain.