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.

Effect of mild gestational diabetes mellitus on histological, ultrastructural, and quantitative morphometric alterations of rat fetal liver.

Objectives: Gestational diabetes mellitus (GDM), one of the most common metabolic disorders in pregnancy, impacts maternal and fetal health. This study was designed to assess the effects of mild GDM on the histology, ultrastructure, and morphometry of fetal liver tissue. Materials and Methods: In this experimental study, twenty pregnant rats were randomly allocated into control and streptozotocin (STZ)-induced diabetic groups. Mild hyperglycemia was induced by intraperitoneal injection of STZ (40 mg/kg/bw) on the 5th day of gestation. At day 19 of gestation, fetal livers were separated and subjected to histological, transmission electron microscopic, and quantitative morphometric examinations. Results: In the GDM group, PAS staining was positive, revealing scattered eosinophilic inclusions in some hepatocytes. Masson trichrome staining was also positive and showed some fibrous tissue as fine fibers in the portal spaces that extended to the central vein. Reticulin staining in the GDM group was focally positive in the areas of fibrosis and the portal spaces. Ultrastructural examination showed pyknotic nuclei, karyolysis, degranulation and vesiculation of the rough endoplasmic reticulum, and degeneration of mitochondria in the GDM group. The morphometric examination demonstrated that the mean area of hepatocytes was significantly lower in the GDM group than in the control group (P<0.05). Moreover, the mean diameter of the central vein and the density of megakaryocytes were significantly higher in the GDM group than in the control group (P<0.05). Conclusion: Uncontrolled mild GDM induced the histological, ultrastructural and morphometric alterations in the fetal liver.

Anti-D Alloimmunization in Index Pregnancy after Appropriate Rho(D) Immune Globulin Injection in Two Obese Rh-Negative Patients.

Background The rhesus factor D (RhD)-negative patients who give birth to an RhD-positive newborn or who are otherwise exposed to RhD-positive red blood cells are at risk of developing anti-D antibodies. These antibodies may cause hemolytic disease of the fetus and newborn (HDFN). During pregnancy, prevention of alloimmunization is completed with a Rho(D) immune globulin (RhIg). Cases We report two cases, where obese patients developed alloimmunization, with high neonatal titers, after appropriate RhIG prophylaxis during the index pregnancy. Conclusion Our cases demonstrate cases of anti D-alloimmunization in an index pregnancy, with high neonatal titers. Both patients are obese, with BMI > 35 mg/m 2 . Key Points RhIG can be administered via intramuscular or intravenous formulations. Overall, it appears that both formulations are equally effective. The optimal administration, especially with obese women, is not clearly established.Our cases demonstrate that obesity is a risk factor for failure of RhIG, and could lead to an increase in HDFN.

A challenging case of hemolytic disease of the fetus and newborn (HDFN) due to anti-Ku in a K0 (Kellnull) mother.

Hemolytic disease of the fetus and newborn (HDFN) due to an antibody in the Kell blood group system can be associated with severe fetal anemia. This case report details the challenges of managing a Kellnull mother with anti-Ku that affected her fetus/newborn. A gravida 4 para 3 woman at term underwent an emergency lower caesarean section because of fetal distress. The baby was intubated because of low oxygen saturation. An urgent request for a hematology workup showed severe anemia and erythroblastosis fetalis. Unfortunately, no compatible blood was found, and the baby died. The case was referred to the National Blood Centre, and anti-Ku was confirmed in a sample sent from the mother. When she presented with her fifth pregnancy, meticulous planning was used to manage this pregnancy. Her family screening revealed one brother with a matching phenotype. Three blood donations were planned for the brother-for freezing, for intrauterine transfusion, and for standby during delivery. Serial anti-Ku titrations of maternal samples were performed, and the fetus was monitored for anemia through middle cerebral artery Doppler scans. Although the anti-Ku titers reached as high as 1024, fetal anemia was never diagnosed. The neonate was delivered safely but was diagnosed with severe pathologic jaundice and anemia secondary to HDFN and congenital pneumonia. The baby was transfused with K0 packed red blood cells and later discharged to home.

Maternal diet during pregnancy and adaptive changes in the maternal and fetal pancreas have implications for future metabolic health.

Fetal and neonatal development is a critical period for the establishment of the future metabolic health and disease risk of an individual. Both maternal undernutrition and overnutrition can result in abnormal fetal organ development resulting in inappropriate birth size, child and adult obesity, and increased risk of Type 2 diabetes and cardiovascular diseases. Inappropriate adaptive changes to the maternal pancreas, placental function, and the development of the fetal pancreas in response to nutritional stress during pregnancy are major contributors to a risk trajectory in the offspring. This interconnected maternal-placental-fetal metabolic axis is driven by endocrine signals in response to the availability of nutritional metabolites and can result in cellular stress and premature aging in fetal tissues and the inappropriate expression of key genes involved in metabolic control as a result of long-lasting epigenetic changes. Such changes result is insufficient pancreatic beta-cell mass and function, reduced insulin sensitivity in target tissues such as liver and white adipose and altered development of hypothalamic satiety centres and in basal glucocorticoid levels. Whilst interventions in the obese mother such as dieting and increased exercise, or treatment with insulin or metformin in mothers who develop gestational diabetes, can improve metabolic control and reduce the risk of a large-for-gestational age infant, their effectiveness in changing the adverse metabolic trajectory in the child is as yet unclear.

International expert consensus statement on physiological interpretation of cardiotocograph (CTG): First revision (2024).

The first international consensus guideline on physiological interpretation of cardiotocograph (CTG) produced by 44 CTG experts from 14 countries was published in 2018. This guideline ensured a paradigm shift from classifying CTG by arbitrarily grouping certain features of the fetal heart rate into different "categories", and then, randomly combining them to arrive at an overall classification of CTG traces into "Normal, Suspicious and Pathological" (or Category I, II and III) to a classification which is based on the understanding of fetal pathophysiology. The guideline recommended the recognition of different types of fetal hypoxia, and the determination of features of fetal compensatory responses as well as decompensation to ongoing hypoxic stress on the CTG trace. Since its first publication in 2018, there have been several scientific publications relating physiological interpretation of CTG, especially relating to features indicative of autonomic instability due to hypoxic stress (i.e., the ZigZag pattern), and of fetal inflammation. Moreover, emerging evidence has suggested improvement in maternal and perinatal outcomes in maternity units which had implemented physiological interpretation of CTG. Therefore, the guideline on Physiological Interpretation of CTG has been revised to incorporate new scientific evidence, and the interpretation table has been expanded to include features of chorioamnionitis and relative utero-placental insufficiency of labour (RUPI-L).

Campylobacter fetus Plasmid Diversity: Comparative Analysis of Fully Sequenced Plasmids and Proposed Classification Scheme.

Campylobacter fetus is an animal pathogen that contains 2 mammal-associated subspecies: Campylobacter fetus subsp. fetus (Cff) and Campylobacter fetus subsp. venerealis (Cfv) including its biovar intermedius that exhibit different biochemical traits and differences in pathogenicity. Although plasmids are important in the horizontal transfer of antimicrobial resistance genes and virulence factors, C. fetus plasmids are understudied. Here, the closed sequences of 12 plasmids from Spanish C. fetus isolates were compared with the publicly available DNA sequences of C. fetus plasmids and other members of the Campylobacterales order. Sizes of C. fetus plasmids from Spanish isolates ranged between 4 and 50 kb and most of them (10/12) were potentially conjugative. Comparative analysis of the plasmids' gene content revealed a close genetic relationship between the plasmids of C. fetus isolated in Spain and those from other geographical regions, while being clearly distinct from plasmids of other Campylobacter species. Furthermore, C. fetus plasmids were grouped into two main clusters regardless of their geographic location or lineage. The distribution pattern of relaxase, replicase, and single-stranded DNA binding SSB protein encoding genes showed a clustering comparable to that resulting from plasmid whole gene content analysis, suggesting its potential use for the classification of C. fetus plasmids. Most of the larger plasmids harbored mobile genetic elements. These results can help to better understand the evolutionary dynamics and pathogenic implications of C. fetus plasmids.

Structural and Biochemical Characterization of Aminoglycoside Nucleotidyltransferase(6)-Ib From Campylobacter fetus subsp. fetus.

Aminoglycoside antibiotics have played a critical role in the treatment of both Gram-negative and Gram-positive bacterial infections. However, antibiotic resistance has severely compromised the efficacy of aminoglycosides. A leading cause of aminoglycoside resistance is mediated by bacterial enzymes that inactivate these drugs via chemical modification. Aminoglycoside nucleotidyltransferase-6 (ANT(6)) enzymes inactivate streptomycin by transferring an adenyl group from ATP to position 6 on the antibiotic. Despite the clinical significance of this activity, ANT(6) enzymes remain relatively uncharacterized. Here, we report the first high resolution x-ray crystallographic structure of ANT(6)-Ib from Campylobacter fetus subsp. fetus bound with streptomycin. Structural modeling and gel filtration chromatography experiments suggest that the enzyme exists as a dimer in which both subunits contribute to the active site. Moreover, superposition of the ANT(6)-Ib structure with the structurally related enzyme lincosamide nucleotidyltransferase B (LinB) permitted the identification of a putative nucleotide binding site. These data also suggest that residues D44 and D46 coordinate essential divalent metal ions and D102 functions as the catalytic base.

Hemolytic disease of the fetus and newborn-a perspective of immunohematology.

BACKGROUND: Hemolytic disease of the fetus and newborn is a public health problem caused by maternal-fetal incompatibility; no prophylaxis is available for most alloantibodies that induce this disease. This study reviews the literature regarding which antibodies are the most common in maternal plasma and which were involved in hemolytic disease of the fetus and newborn. METHOD: Seventy-five studies were included in this review using a systematic search. Two independent authors identified studies of interest from the PubMed and SciELO databases. MAIN RESULTS: Forty-four case reports were identified, of which 11 babies evolved to death. From 17 prevalence studies, the alloimmunization rate was 0.17 % with 161 babies receiving intrauterine transfusions and 23 receiving transfusions after birth. From 28 studies with alloimmunized pregnant women (7616 women), 455 babies received intrauterine transfusions and 21 received transfusions after birth. CONCLUSION: Rh, Kell, and MNS were the commonest blood systems involved. The geographical distribution of studies shows that as these figures vary between continents, more studies should be performed in different countries. Investing in early diagnosis is important to manage the risks and complications of hemolytic disease of the fetus and newborn.

Increased prevalence of negative pregnancy and fetal outcomes in women with primary adrenal insufficiency. A systematic review and meta-analysis.

Maternal primary adrenal insufficiency (PAI) during pregnancy, due to either Addison disease (AD) or congenital adrenal hyperplasia (CAH), is rare. Only few studies have examined the subsequent important outcomes of maternal glucocorticoid and mineralocorticoid deficiencies during pregnancy upon the fetus and the neonate. Therefore, this systematic review and meta-analysis evaluated the impact of these deficiencies, with data from PubMed/Medline, Cochrane/CENTRAL, and Google Scholar. A total of 31 studies were included for qualitative analysis and 11 for quantitative analysis. Studies examining the prevalence of spontaneous abortion, preterm birth, the occurrence of small for gestational age (SGA) neonates, as well as the neonatal birth weight were included. The systematic review revealed a substantial number of spontaneous abortions, preterm births and SGA neonates in pregnant women with PAI. The meta-analysis showed a mean spontaneous abortion prevalence of 18%, 18% and 17% in women with PAI, AD or CAH, respectively. The mean preterm birth prevalence was 11% when women with AD or CAH were analyzed together, and 13% and 9% in women with AD or CAH, respectively, when these women were analyzed separately. The mean prevalence of SGA neonates was 8% when women with AD or CAH were analyzed together, and 5% and 10% in women with AD or CAH, respectively, when these women were analyzed separately. The mean fetal birth weight was within normalcy in all women with PAI, as well as in women with AD or CAH. In conclusion the executed systematic review of 31 studies followed by a meta-analysis of 11 studies in pregnant women with PAI has shown a greater prevalence of pregnancies with negative outcome (spontaneous abortion, preterm birth) and of negative fetal outcome (SGA) in women with either AD or CAH, as compared to control pregnant women.

Intra-abdominal retroperitoneal fetus in fetu: A case report.

Fetus in fetu (FIF) is a rare abnormality where a vertebrate parasitic fetus develops inside the body of another normally developing fetus. It is distinct from teratomas, tumors composed of cells from multiple germ layers and have malignant potential. Symptoms of FIF arise from the mass effect, causing abdominal distension, feeding difficulties, and pressure effects on organs. FIF is commonly found in the retroperitoneal region but can also occur in other locations. It often includes certain organs such as the vertebral column, limbs, central nervous system, gastrointestinal tract, vessels, and genitourinary tract. Early diagnosis of FIF by ultrasound, computed tomography, and magnetic resonance imaging can improve patient outcomes. Surgical resection is the primary treatment approach, aiming to alleviate symptoms, and molecular analysis helps differentiate FIF from malignant teratomas. Regular follow-up is necessary due to the potential recurrence of teratomas.

Fetus descent simulation with the active uterine contraction during the vaginal delivery: MRI-based evaluation and uncertainty quantification.

Finite element models ranging from single to multiscale models have been widely used to gain valuable insights into the physiological delivery process and associated complication scenarios. However, the fetus descent simulation with the active uterine contraction is still challenging for validation and uncertainty quantification issues. The present study performed a fetus descent simulation using the active uterine contraction. Then, simulation outcomes were evaluated using theoretical and in vivo MRI childbirth data. Moreover, parameter uncertainty and propagation were also performed. A maternal pelvis model was developed. The active uterine contraction was modeled using a transversely isotropic Mooney-Rivlin material. Displacement trajectories were compared between simulation, theoretical and in vivo MRI childbirth data. Monte Carlo (M.C) and Polynomial Chaos Expansion (PCE) methods were applied to quantify uncertain parameters and their propagations. Obtained results showed that fetal descent behavior is consistent with the MRI-based observation as well as the theoretical trajectory (curve of Carus). The head downward vertical displacement ranges from 0 to approximately 47 mm. A reduction of 50% in uterine size was observed during the simulation. Three high-sensitive parameters (C1,C2,Ca0) were also identified. Our study suggested that the use of the active uterine contraction is essential for simulating vaginal delivery but the global parameter sensitivity, parameter uncertainty, and outcome evaluation should be carefully performed. As a perspective, the developed approach could be extrapolated for patient-specific modeling and associated delivery complication simulations to identify risks and potential therapeutic solutions.

Maternal physical activity in healthy pregnancy: Effect on fetal oxygen supply.

AIM: We review evidence for effects of physical activity before and during gestation on the course of pregnancy and ask if there are circumstances where physical activity can stress the fetus due to competition for oxygen and energy substrates. RESULTS: We first summarize physiological responses to exercise in nonpregnant people and known physiological adaptations to pregnancy. Comparing the two, we conclude that physical activity prior to and continuing during gestation is beneficial to pregnancy outcome. The effect of starting an exercise regimen during pregnancy is less easy to assess as few studies have been undertaken. Results from animal models suggest that the effects of maternal exercise on the fetus are transient; the fetus can readily compensate for a short-term reduction in oxygen supply. CONCLUSION: In general, we conclude that physical activity before and during pregnancy is beneficial, and exercise started during pregnancy is unlikely to affect fetal development. We caution, however, that there are circumstances where this may not apply. They include the intensive exercise regimens of elite athletes and pregnancies at high altitudes where hypoxia occurs even in the resting state.

Major reduction in occurrence of anti-c and anti-E in pregnancy after more than 10 years of preventive matched transfusion with most benefit for c-matching.

Extension with cE-matching of the transfusion policy for women under 45 years to prevent alloimmunization and hemolytic disease of the foetus and newborn (HDFN) was evaluated. After implementation of cEK-matching, anti-c occurrence decreased from 46.8 to 30.4 per 100 000 pregnancies (RR 0.65, 95% CI 0.54-0.79), while anti-E occurrence decreased from 122.1 to 89.9 per 100 000 pregnancies (RR 0.74, 95% CI 0.66-0.84). The c-negative women showed a higher anti-E occurrence before cEK-matching and a more pronounced decline with the new policy. This indicates that cEK-matched transfusion effectively reduces alloimmunization, and that a cK-matched approach could prevent most transfusion-related alloimmunization and HDFN.

Association of vitamin A with gestational diabetes and thyroid disorders in pregnancy and their influence on maternal, fetal, and neonatal outcomes.

Gestational diabetes mellitus (GDM) and thyroid disorders during pregnancy pose significant health concerns, impacting a substantial number of mothers globally. Globally, about 14% of pregnant women develop GDM, while thyroid disorders impact approximately 2%-3%. Both conditions contribute to adverse outcomes, including gestational hypertension, excessive fetal growth, and heightened perinatal morbidity. The central focus of this literature review is to examine the relationship between vitamin A, a crucial fat-soluble micronutrient in fetal development, and the occurrence of GDM and thyroid disorders during pregnancy. The primary research question investigates the association between vitamin A, GDM, and thyroid disorders, analyzing their combined impact on maternal, fetal, and neonatal outcomes. The review underscores the potential of vitamin A to modulate the risk and outcomes of GDM and thyroid disorders during gestation, emphasizing its role in GDM development and resolution and its influence on thyroid function in pregnancy.

Expanding MNS1 Heterotaxy Phenotype.

MNS1 (meiosis-specific nuclear structural protein-1 gene) encodes a structural protein implicated in motile ciliary function and sperm flagella assembly. To date, two different homozygous MNS1 variants have been associated with autosomal recessive visceral heterotaxy (MIM#618948). A French individual was identified with compound heterozygous variants in the MNS1 gene. A collaborative call was proposed via GeneMatcher to describe new cases with this rare syndrome, leading to the identification of another family. The first patient was a female presenting complete situs inversus and unusual symptoms, including severe myopia and dental agenesis of 10 permanent teeth. She was found to carry compound heterozygous frameshift and nonsense variants in MNS1. The second and third patients were sibling fetuses with homozygous in-frame deletion variants in MNS1 and homozygous missense variants in GLDN. Autopsies revealed a complex prenatal malformation syndrome. We add here new cases with the ultra-rare MNS1-related disorder and provide a review of all published individuals.

Unraveling the effects of prenatal anesthesia on neurodevelopment: A review of current evidence and future directions.

Human brain development is a complex, multi-stage, and sensitive process, especially during the fetal stage. Animal studies over the last two decades have highlighted the potential risks of anesthetics to the developing brain, impacting its structure and function. This has raised concerns regarding the safety of anesthesia during pregnancy and its influence on fetal brain development, garnering significant attention from the anesthesiology community. Although preclinical studies predominantly indicate the neurotoxic effects of prenatal anesthesia, these findings cannot be directly extrapolated to humans due to interspecies variations. Clinical research, constrained by ethical and technical hurdles in accessing human prenatal brain tissues, often yields conflicting results compared to preclinical data. The emergence of brain organoids as a cutting-edge research tool shows promise in modeling human brain development. When integrated with single-cell sequencing, these organoids offer insights into potential neurotoxic mechanisms triggered by prenatal anesthesia. Despite several retrospective and cohort studies exploring the clinical impact of anesthesia on brain development, many findings remain inconclusive. As such, this review synthesizes preclinical and clinical evidence on the effects of prenatal anesthesia on fetal brain development and suggests areas for future research advancement.