Protective effect of quercetin on lipopolysaccharide­induced miscarriage based on animal experiments and network pharmacology.

Spontaneous abortion (SA) occurs in woman of child­bearing age, jeopardizing their physical and mental health. Quercetin is a natural flavonoid, which exhibits a variety of pharmacological activities. However, the role and mechanisms of quercetin in SA still need to be further explored. Animal experiments were performed to examine the effect of quercetin in treating SA. Institute of Cancer Research mice were injected with lipopolysaccharide into the tail vein on the 7th day of gestation to establish a SA model. Gavage was performed during days 3­8 of gestation with high­, medium­ and low­dose of quercetin. Then the effect of quercetin on embryos was evaluated. Animal experiment showed that quercetin could remarkably reduce the embryo loss rate and increase the mean weight of surviving embryos to some degree. Furthermore, network pharmacology was employed to explore the underlying mechanisms of quercetin in the treatment of SA. Several databases were used to collect the targets of SA and quercetin. Protein­protein interaction network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to elucidate the interactions between SA and quercetin. The relative mRNA expressions of several targets in uterine were detected by quantitative reverse transcriptase polymerase chain reaction (RT­qPCR). Network pharmacology indicated that the effects of quercetin in treating SA were mainly related to hormone response and the modulation of defense response and inflammatory response, involving signaling pathways such as PI3K­Akt, VEGF, MAPK and core targets such as AKT1, albumin, caspase­3. RT­qPCR showed that quercetin could up­regulate AKT1, MAPK1, PGR, SGK1 and down­regulate ESR1, MAPK3. The results showed that quercetin may modulate multiple signaling pathways by targeting core targets to prevent and treat SA.

Perceived self-efficacy to teach comprehensive abortion care among nursing and midwifery faculty in higher learning institutions in Rwanda: A mixed method study.

INTRODUCTION: Comprehensive abortion care is an emerging intervention being integrated into nursing and midwifery curricula. Yet, no studies have been conducted in Rwanda to determine whether faculty perceive themselves as capable of teaching comprehensive abortion care. This study aims to evaluate the perceived self-efficacy to teach comprehensive abortion care among nursing and midwifery faculty in higher learning institutions in Rwanda. MATERIALS AND METHODS: The University of Rwanda College of Medicine and Health Sciences Institutional Review Board approved this study (UR-CMHS-IRB No 335/CMHSIRB/2022). In quantitative, a self-administered questionnaire was administered to 98 study participants. Data were entered into Statistical Package for the Social Sciences (SPSS) version 26 and analyzed using Chi-square test with a p-value of 0.05 set as the significance level. In the qualitative part, an interview guide was developed based on quantitative data to understand comprehensive abortion care teaching fully. Data were collected from four focus group discussions with eight participants in each group, entered in Dedoose, and analyzed thematically. RESULTS: Among the 98 study participants who were invited to participate in this study, only 85 filled out the questionnaires. This translates into 86.7% of the response rate. More than half 58.8% had adequate self-efficacy in teaching comprehensive abortion care. A Chi-square test has revealed that being a male, being a midwife, and having more years of working experience in nursing education were significantly associated with self-efficacy in teaching comprehensive abortion care (p value <0.05). In the qualitative phase, 32 study participants participated in four focus group discussions and four themes were identified: a) variability in confidence levels to teach comprehensive abortion care; b) readiness about teaching comprehensive abortion care; c) facilitators of teaching comprehensive abortion care; and d) contextual challenges to teach comprehensive abortion care. CONCLUSIONS: The findings revealed that faculty's self-efficacy in teaching comprehensive abortion care was not adequate. Personal and religious beliefs and institutional barriers were also reported to hinder self-efficacy in teaching comprehensive abortion care. Therefore, intensive comprehensive abortion care training for nursing and midwifery faculty in higher learning institutions should be provided, including values clarification and attitude transformation training for attitudes and beliefs. It is also critical for higher learning institutions to develop strategies for overcoming the challenges faculty face when teaching comprehensive abortion care.

Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

BACKGROUND: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were responsive to pegvaliase and chose to remain on pegvaliase throughout their pregnancy. METHODS: Fourteen pregnancies (one triplet pregnancy) and their offspring were identified at eight PKU treatment centers and medical records from pregnancy and birth were submitted for this study. Institutional Review Board approval was obtained. Responses to a dataset were provided to a single center and analyzed. RESULTS: Six females and eight males were born without congenital anomalies and all offspring had normal growth parameters. While mothers had preexisting comorbidities, no additional comorbidities were reported in the offspring. Four of eleven infants (excluding triplet pregnancies) were delivered preterm (36%), a higher rate than the general population (12%). A single first trimester (eight weeks) miscarriage in a 40y was not counted in this cohort of 14 live born infants. CONCLUSION: This retrospective study suggests that pegvaliase is effective at maintaining safe maternal blood Phe levels during pregnancy without deleterious effects on mother or child. A tendency toward premature birth (4/11; 36%) is higher than expected.

Navigating a maze: Midwives' identity response to the enactment of an abortion law in Chile.

BACKGROUND: Chilean midwives have been identified as essential for successfully implementing an abortion law, a practice which could potentially be understood as contradicting their central mission. Nevertheless, to date, there has been no investigation into how Chilean midwives have incorporated induced abortion care provision into their professional identity. OBJECTIVE: To elucidate how Chilean midwives understand and provide abortion care and how they have (re)defined their professional identity to include induced abortion care. This article reports the findings of the second part of this aim. METHODS: This study was underpinned by a constructivist grounded theory methodology informed by a reproductive justice and feminist perspective. Midwives from Chile who have cared for women undergoing abortion were invited to participate in the study. After purposive and theoretical sampling, fifteen midwives were recruited. FINDINGS: Midwives' identity is woman-centred, with high value placed on their role protecting life. These two aspects of midwives' identity are in contradiction when providing abortion care. Midwives' identity results from and informs midwives' practice. Midwifery regulation influences both practice and identity. The model 'Navigating a maze' explains the interaction of these three elements. CONCLUSION: Midwives' identity response to the enactment of the Chilean abortion law is an example of how professional identity must navigate regulation and practice to make sense of its purpose. In light of this study's findings, the current tension experienced in midwives' identity should be carefully attended to prevent adverse outcomes for midwives and the Chilean population.

A case-control retrospective study for the effect of Shoutai Wan on IVF-ET pregnancy outcome.

It has a long history of preventing and treating disease using traditional Chinese medicine (TCM). In recent years, it has been widely used in adjuvant therapies of in vitro fertilization - embryo transfer (IVF-ET) in China. To observe the effect and safety of Shoutai Wan on pregnancy outcomes after IVF-ET. A total of 352 patients who underwent IVF-ET from July 1, 2020 to June 30, 2021. The participants who only received routine luteal support during clinical pregnancy of FET were defined as the control group, and others who received TCM decoction Shoutai Wan for prevention of miscarriage and routine luteal support were defined as the Chinese medicine protection Shoutai Wan group (St group). This project has been approved by the Ethics Committee of Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine (Approval NO: 2023-0305). The results of this retrospective cohort study revealed that Shoutaiwan combined with luteal support treatment can significantly decreased the miscarriage rate in pregnancy undergoing IVF-FET compared to the group accepted only luteal support treatment (P = .001). Meanwhile, St during pregnancy did not affect fetal birth weight (P = .354), and there was no adverse event in the St group reported, which confirmed the safety of TCM for fetus protection during pregnancy. This study not only provides evidences for the clinical administration of Shoutai Wan in IVF-ET, but also provides a novel direction for basic research into the subsequent innovative application of TCM.

Jianpi Antai formula prevents miscarriage by repressing M1 polarization of decidual macrophages through ubiquitination of NLRP3 mediated by MARCH7.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Antai Formula (JAF) is an ancient formula from He's gynecology, which has been used clinically for more than 30 years and has significant therapeutic effects on spontaneous abortion (SA). Both macrophage polarization and NLRP3 inflammasome correlate with the occurrence of SA in women with recurrent or threatened miscarriage. Whether JAF prevent SA via mediating activation of decidual macrophage (dMφ) and ubiquitination-associated degradation of NLRP3 remains uncertain. AIM OF THE STUDY: This study aimed to clarify the effects of JAF on pregnancy outcomes and dMφ polarization at the maternal-fetal interface in an SA mouse model, and use in vivo and invitro methods to explore whether JAF can inhibit M1 polarization of dMφ by up-regulating MARCH7-mediated NLRP3 ubiquitination, thereby preventing SA. MATERIALS AND METHODS: The CBA/J × DBA/2 mating method was used to establish an SA model and the dMφs of SA mice were isolated and cultured. Th1-, Th2-, Th17- and Treg-related cytokine levels were evaluated using ELISA. qRT-PCR was used to detect the levels of M1/M2 macrophage-related cytokine mRNA in the decidua, and western blotting was used to detect the expression of NLRP3 inflammasome-related proteins in the decidua and placenta. The expression of M1/M2 markers of dMφ was detected using flow cytometry, ASC speck formation was observed using immunofluorescence, and the ubiquitination level of MARCH7-NLRP3 was detected using co-immunoprecipitation. RESULTS: JAF increased the survival rate of fetuses and the levels of estradiol and progesterone in SA model mice. It also reduced the serum Th1 and Th17-associated cytokine levels and decidual M1 macrophage-associated cytokine levels, while elevating the M2 macrophages in SA mice. NLRP3, caspase-1, ASC, and IL-1ß protein expression in the decidua and placenta were also reduced. si-MARCH7 transfection reversed the effect of JAF on inhibiting the formation of the NLRP3 inflammasome and the activation of macrophages in dMφs of SA mice. CONCLUSION: JAF could effectively prevent and treat SA by repressing M1 polarization of dMφs through NLRP3 ubiquitination and pyroptosis inhibition, which were mediated by MARCH7.

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes.

BACKGROUND: Vitamin B12 deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B12 supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes. OBJECTIVES: To evaluate the benefits and harms of oral vitamin B12 supplementation during pregnancy on maternal and child health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation during pregnancy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes. MAIN RESULTS: The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B12 deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B12 supplementation varied from 5 µg/day to 250 µg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B12 status: vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B12 supplements during pregnancy may have higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I2 = 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B12 supplementation during pregnancy on neural tube defects. Infant vitamin B12 status: children born to women who received vitamin B12 supplementation had higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B12 supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence). AUTHORS' CONCLUSIONS: Oral vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency and may improve maternal vitamin B12 concentrations during pregnancy or postpartum compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain. The effects of vitamin B12 supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B12 supplementation during pregnancy may improve maternal and infant vitamin B12 status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.

Study on the clinical value of Vitamin D in recurrent spontaneous abortion: Revisiting the Importance of Vitamin D.

OBJECTIVE: This study explores the possible pathogenesis of recurrent spontaneous abortion (RSA) caused by vitamin D (VD), provides evidence-based bases for prevention and treatment of RSA, improves female reproductive health. METHODS: This study randomly selected 305 patients without spontaneous abortion (SA0), 216 patients with a spontaneous abortion (SA1) and 200 patients with RSA from 1421 women of childbearing age who visited the RSA specialty clinic of Hangzhou First People's Hospital from January 2021 to June 2023 to conduct a prospective clinical study. Then, we collected the data of clinical diagnosis and treatment, conducted intervention and follow-up, and finally executed statistical analysis. RESULTS: (1) RSA patients were significantly older than the other two groups. (2) The rates of VD deficiency in SA1 and RSA patients were significantly higher than those in SA0. (3) When BMI < 20  or > 24 kg/m2 , there were abnormal increase in VD and increased number of spontaneous abortions. (4) The bilateral S/D of the VD-sufficient, VD-insufficient and VD-deficient groups gradually increased with statistical significance (p ≤ .018). (5) Among the 65 cases undergoing embryo chromosome examinations, chromosomal abnormalities accounted for 55.38% and 69.05% in RSA patients. (6) Among 186 patients with abnormal ACA, there was a certain negative correlation between ACA and VD, which was stronger among RSA patients. Moreover, ACA significantly decreased (p < .001) after effectively supplementing VD, and the miscarriage rate of re-pregnancy also decreased. CONCLUSION: The rate of VD deficiency is higher in RSA patients. VD deficiency may be related to the age of women of childbearing age and too low or high BMI, and may cause abnormal plasma antiphospholipid antibodies, increased uterine artery resistance and abnormal chromosomal division during fertilization, leading to spontaneous abortion and even RSA. The improvement of VD deficiency may reduce the risk of RSA occurrence.

Bushen Antai recipe alleviates embryo absorption by enhancing immune tolerance and angiogenesis at the maternal-fetal interface via mobilizing MDSCs in abortion-prone mice.

BACKGROUND: Recurrent pregnancy loss (RPL) is a tricky puzzle that disturbs female reproduction worldwide. According to previous research, Bushen Antai recipe (BAR), a classic Chinese herbal formula widely used in clinic for miscarriage, exhibited multifaceted benefits in improving embryo implantation and attenuating early pregnancy loss. Myeloid-derived suppressor cells (MDSCs), a set of immunoregulatory cells critical in inflammation balance, get growing attention for their indispensable role in successful pregnancy. PURPOSE: To investigate the therapeutic efficacy of BAR in abortion-prone mice and explore the potential mechanisms of BAR regarding MDSCs. METHODS: RPL mice (CBA/J females paired with DBA/2 males, BALB/c males were used as the control) were administered with BAR1 (5.7 g/kg), BAR2 (11.4 g/kg), progesterone (P4), or distilled water from embryo day (D) 0.5 until D10.5. The rate of embryo absorption on D10.5 and the health status of progeny were measured. The systemic inflammatory states and the placenta-uterus milieu were assessed by serum cytokine levels, placenta-uterus architecture, and related protein expression at the maternal-fetal interface. Flow cytometry analysis was carried out to measure the frequency of MDSCs. Furthermore, we established the MDSCs-depletion mouse model by using C57BL/6 females mated with BALB/c males via intraperitoneal injection of anti-Gr-1 antibody on D6.5, while irrelative LTF antibody was used as the control. Similarly, BAR1, BAR2, P4, or distilled water was separately applied. Embryo absorption rate, systemic inflammatory states, placenta-uterus milieu, and MDSCs frequency were evaluated as mentioned above. RESULTS: Significantly, embryo absorption rate was increased with disrupted placenta-uterus milieu and exorbitant proinflammatory cytokines in RPL mice, meanwhile, MDSCs number in the placenta-uterus unit were apparently reduced (⁎⁎⁎p < 0.001). BAR treatment markedly alleviated the poor conditions above and increased MDSCs number (####p < 0.0001). Flow cytometry analysis validated the efficacy of anti-Gr-1 antibody and the raised embryo absorption rate confirmed the essentiality of MDSCs in normal pregnancy (⁎⁎p < 0.01). Besides, the placenta-uterus milieu was destroyed, accompanied by the impaired expression of immune tolerance and angiogenesis related factors in the MDSCs-depletion mice. Even though, BAR treatment reversed the embryo resorption phenotype and optimized the serum cytokine milieu, mobilizing MDSCs and rejuvenating active intercellular communication. Thereby, BAR facilitated the expression of MDSCs-related functional molecules, promoting immune tolerance and vascular remodeling at the placenta-uterus unit. CONCLUSION: We unfurled the remarkable therapeutic ability of BAR in abortion-prone mice, and this was achieved by mobilizing MDSCs, thus favoring immune tolerance and angiogenesis at the maternal-fetal interface.

Caffeine intake during pregnancy and adverse outcomes: An integrative review.

Caffeine intake during pregnancy is common. Caffeine crosses the placenta, raising concerns about its possible deleterious effects on the developing embryo/fetus. Studies on this subject show conflicting results, and still there is no consensus on the recommended dose of caffeine during pregnancy. We performed an integrative review with studies from six databases, using broad MESH terms to allow the identification of publications that addressed the outcomes of caffeine use during pregnancy, with no date limit for publications, in English and Portuguese language. The research returned 16,192 articles. After removing duplicates, screening by title, abstract and full-text, we evaluated 257 and included 59 articles. We found association between caffeine intake and pregnancy loss, low birth weight, cardiac and genital anomalies, higher body mass, and neurodevelopmental and neurobehavioral outcomes. The effects were often dose dependent. No association with prematurity has been demonstrated, but one study showed a small reduction in gestational age with increasing doses of caffeine intake. Defining a safe dose for caffeine intake during pregnancy is a challenging task due to the heterogeneity in study designs and results, as well as the difficulty of reliably assessing the amount of caffeine consumed. In some studies, exposures below the recommended level of caffeine intake during pregnancy (200 mg/day), as suggested by the guidelines, were associated with pregnancy loss, low birth weight, cardiac and genital anomalies, higher body mass, and neurodevelopmental and neurobehavioral outcomes. Well-designed studies with reliable quantification of caffeine intake are needed to assess the safety of low doses during pregnancy.

Contraception after abortion, miscarriage, ectopic and molar pregnancy.

Regardless of whether a pregnancy ends in abortion, miscarriage or ectopic pregnancy, fertility and sexual activity can resume quickly. For those who do not plan to become pregnant again immediately, effective contraception is therefore required. Although a contraceptive discussion and the offer to provide contraception is considered an integral part of abortion care, health care providers may not always offer this same standard of care to those whose pregnancy ends in miscarriage or ectopic due to sensitivities or assumptions around this and future fertility intentions. Yet, evidence-based recommendations support the safety of initiating contraception at these times. Provision of a chosen method of contraception may be convenient for women and valued by them. As part of holistic care, healthcare professionals who care for women around these reproductive events should therefore offer quality information on contraception and help them access their chosen method to better meet their ongoing reproductive health needs.

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage.

Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of FOLR2+ macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.

Association Between Serum Glycated Hemoglobin Levels at Early Gestation and the Risk of Subsequent Pregnancy Loss in Pregnant Women Without Diabetes Mellitus: Prospective Cohort Study.

BACKGROUND: As a severe morbidity during pregnancy, the etiology of spontaneous pregnancy loss (SPL) remains largely unknown. Serum glycated hemoglobin (HbA1c) level is an established predictor of SPL risk among women with diabetes, but little is known about whether such an association exists among pregnant women without diabetes when glycemic levels are within the normal range. OBJECTIVE: This study aimed to quantify the association between maternal HbA1c levels in early pregnancy and subsequent SPL risk in a cohort of pregnant women without diabetes. METHODS: This prospective cohort study involved 10,773 pregnant women without diabetes enrolled at their first antenatal care visit at a hospital's early pregnancy clinic from March 2016 to December 2018 in Shanghai, China. HbA1c and fasting blood glucose (FBG) levels were examined at enrollment. Participants with diabetes before or pregnancy or those diagnosed with gestational diabetes were excluded. Diagnosis of SPL, defined as fetal death occurring before 28 gestational weeks, was derived from medical records and confirmed via telephone interviews. We used generalized linear models to quantify the associations of continuous and dichotomized maternal HbA1c levels with SPL risk and reported crude and adjusted risk ratios (RRs) and 95% CIs. A restricted cubic spline (RCS) regression model was used to assess the potential nonlinear dose-response relationship. Adjusted covariates included maternal age, education level, preconception BMI, gestational weeks, gravidity, history of adverse pregnancy outcomes, family history of diabetes, folic acid supplementation, and smoking and drinking during the periconception period. RESULTS: In total, 273 (2.5%) SPL cases occurred. Every 0.5% increase in HbA1c levels was linearly associated with a 23% increase in SPL risk (adjusted RR [aRR] 1.23; 95% CI 1.01-1.50). The RCS model revealed that this association was linear (P=.77 for the nonlinearity test). Analyses based on dichotomized HbA1c levels showed a significantly increased risk of SPL when HbA1c levels were ≥5.9% (aRR 1.67; 95% CI 0.67-3.67), and the significance threshold was ≥5.6% (aRR 1.60; 95% CI 1.01-2.54). Sensitivity analyses showed similar results when including the participants with missing SPL records or HbA1c data. Linear associations of HbA1c levels remained significant even in the subgroups without overweight, alcohol consumption, and a family history of diabetes and adverse pregnancy outcomes. Every 1 mmol/L increment in maternal FBG levels was associated with a >2-fold higher risk of SPL (aRR 2.12; 95% CI 1.61-2.80; P<.001). CONCLUSIONS: Higher HbA1c levels in early pregnant women without diabetes are associated with an increased SPL risk in a dose-response manner. Pregnant women with an HbA1c level above 5.6% at early gestation need attention for its potentially increased risk for SPL. Our findings support the need to monitor HbA1c levels to identify individuals at high risk of subsequent SPL in the general population of pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737644; https://clinicaltrials.gov/study/NCT02737644.

Determinants of neural tube defects among women who gave birth in hospitals in Eastern Ethiopia: evidence from a matched case control study.

INTRODUCTION: Neural tube defects (NTDs) are severe birth defects caused by nutritional, genetic or environmental factors. Because NTDs continue to have a significant health and economic impact on children and community at large, it is crucial to investigate potential risk factors in order to develop novel approaches to NTDs prevention. Determinants for the development of NTDs differ by country, region as well as within the country. The objective of this study was to identify the determinants of NTDs among newborns delivered in three hospitals found in eastern Ethiopia. METHODS: A hospital-based matched case-control study was conducted among 138 cases and 138 control women who delivered in three teaching hospitals in Eastern Ethiopia in 2021. Data were collected using a structured and pre-tested interviewer-administered questionnaire. Cases were mothers who delivered a neonate with any type of NTDs regardless of gestational age or fetal viability, whereas controls were mothers who delivered an apparently healthy newborn. Chi-square was used to assess the significant difference between the two groups. Conditional logistic regression model was used to generate adjusted odds ratio with its corresponding 95% confidence intervals and compare the two groups. RESULTS: Anencephaly (51.4%) and spinal bifida (34.1%) were the most frequently observed NTDs. None of study participants took preconception folic acid supplementation. Being a non-formal mothers (AOR = 0.34, 95% CI: 0.12-0.92, P = 0.034), rural residence, (AOR = 3.4, 95% CI: 1.18-9.78, P = 0.023), history of spontaneous abortion (AOR = 2.95, 95% CI: 1.15-7.55, P = 0.023), having severe anemia (AOR = 3.4, 95% CI: 1.17-9.87, P = 0.024), history of fever or cold (AOR = 2.75; 95% CI: 1.05-7.15, P = 0.038), and an exposure to various agro-chemicals (AOR = 3.39, 95% CI: 1.11-10.3, P = 0.032) were independent determinants of NTDs. CONCLUSION AND RECOMMENDATION: In this study, NTDs were associated to several determinant factors in the area, including residential area, history of spontaneous abortion, severe anemia, fever/cold, antibiotic use before or during early pregnancy, and exposure to agrochemicals. Addressing the identified determinants is critical in averting the incidence of NTDs in the study area. Moreover, more research is needed to investigate women's dietary practices as well as the practice of preconception folic acid supplementation for pregnant women in Ethiopia's current health care system.

Effect of extra-low dose levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism undergoing in vitro fertilization and embryo transfer.

OBJECTIVE: This study was undertaken to test the therapeutic effect of extra-low dose of levothyroxine (LT4; 25 mcg/day) to preconception and pregnant women with subclinical hypothyroidism (SCH). MATERIALS AND METHODS: This is a retrospective study, SCH women who succeeded in their first in vitro fertilization (IVF) cycle between January 1, 2018, to December 31, 2020 were included. SCH is defined as normal serum free thyroxine (T4) level and an elevated serum thyroid stimulating hormone (TSH) level >4 mIU/L. Extra-low dose of levothyroxine (LT4; 25 mcg/day) was prescribed to the SCH women from the establish of diagnosis of SCH to the end of pregnancy. The pregnancy outcomes (miscarriage, live birth, preterm birth, and small for gestational age baby) were compared to the euthyroid pregnant women. RESULTS: Totally, 589 women were screened, and 317 cases received their first time IVF treatment. 167 women were clinically pregnant after IVF treatment, 155 of them were euthyroid and 12 of these women were diagnosed to have SCH. The average age of the participants was 35 years old. There were no significant differences in age, body mass index (BMI), anti-müllerian hormone (AMH), types of embryo transfer, number of embryos to transfer, or embryo stage during transfer between two groups. The live birth rate, miscarriage rate, and preterm birth rate in women with SCH supplemented with extra-low dose of LT4 were non-inferior to euthyroid patients (miscarriage rate: P = 0.7112; live birth rate: P = 0.7028; preterm delivery: P = 0.2419; small for gestational age: P = 0.2419). CONCLUSION: Our result demonstrated that supplementation with extra-low dose of levothyroxine at 25 mcg/day to SCH women can produce the comparable obstetrical and neonatal outcome as that in euthyroid pregnant women. Accordingly, we suggest extra-low-dose of levothyroxine may be considered as a safe and effective alternative for those SCH pregnant women who were not tolerated to the standard dose of levothyroxine.

Pregnancy Benefit of Acupuncture on in vitro Fertilization: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, more and more infertility couples are opting for combined acupuncture to improve success rate of in vitro fertilization (IVF). However, evidence from acupuncture for improving IVF pregnancy outcomes remains a matter of debate. OBJECTIVE: To quantitatively summarized the evidence of the efficacy of acupuncture among women undergoing IVF by means of systematic review and meta-analysis. METHODS: Four English (PubMed, Web of Science, EMBASE, and Cochrane Register of Controlled Clinical Trials) and Four Chinese databases (Wanfang Databases, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and SinoMed) were searched from database inception until July 2, 2023. Randomized controlled trials (RCTs) that evaluated the acupuncture's effects for women undergoing IVF were included. The subgroup analysis was conducted with respect to the age of participants, different acupuncture types, type of control, acupuncture timing, geographical origin of the study, whether or not repeated IVF failure, and acupuncture sessions. Sensitivity analyses were predefifined to explore the robustness of results. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR), and the secondary outcomes were ongoing pregnancy rate and miscarriage rate. Random effects model with I2 statistics were used to quantify heterogeneity. Publication bias was estimated by funnel plots and Egger's tests. RESULTS: A total of 58 eligible RCTs representing 10,968 women undergoing IVF for pregnant success were identifified. Pooled CPR and LBR showed a signifificant difference between acupuncture and control groups [69 comparisons, relative risk (RR) 1.19, 95% confifidence intervals (CI) 1.12 to 1.25, I2=0], extremely low evidence; 23 comparisons, RR 1.11, 95%CI 1.02 to 1.21, I2=14.6, low evidence, respectively). Only transcutaneous electrical acupoint stimulation showed a positive effect on both CPR (16 comparisons, RR 1.17, 95%CI 1.06 to 1.29; I2=0, moderate evidence) and LBR (9 comparisons, RR 1.20, 95%CI 1.04 to 1.37; I2=8.5, extremely low evidence). Heterogeneity across studies was found and no studies were graded as high-quality evidence. CONCLUSION: Results showed that the convincing evidence levels on the associations between acupuncture and IVF pregnant outcomes were relatively low, and the varied methodological design and heterogeneity might inflfluence the fifindings. (Registration No. PROSPERO CRD42021232430).

The forgotten girls: the state of evidence for health interventions for pregnant adolescents and their newborns in low-income and middle-income countries.

Every year, an estimated 21 million girls aged 15-19 years become pregnant in low-income and middle-income countries (LMICs). Policy responses have focused on reducing the adolescent birth rate whereas efforts to support pregnant adolescents have developed more slowly. We did a systematic review of interventions addressing any health-related outcome for pregnant adolescents and their newborn babies in LMICs and mapped its results to a framework describing high-quality health systems for pregnant adolescents. Although we identified some promising interventions, such as micronutrient supplementation, conditional cash transfers, and well facilitated group care, most studies were at high risk of bias and there were substantial gaps in evidence. These included major gaps in delivery, abortion, and postnatal care, and mental health, violence, and substance misuse-related outcomes. We recommend that the fields of adolescent, maternal, and sexual and reproductive health collaborate to develop more adolescent-inclusive maternal health care and research, and specific interventions for pregnant adolescents. We outline steps to develop high-quality, evidence-based care for the millions of pregnant adolescents and their newborns who currently do not receive this.

The regulation of tolerogenic dendritic cells by a Chinese herb formula improves abortion prone in mice.

BACKGROUND: Abortion prone (AP) is a common clinical event. The underlying mechanism remains unclear. Traditional Chinese formulas are known to be efficient in the management of abortion. The purpose of this study is to observe the effects of Anzitiaochongtang (AZT), a traditional formulation of Chinese medicine, on improving AP in mice by regulating immune tolerance. METHODS: An established abortion model (CBA/J×DBA/2) was employed. AZT was prepared and administered to mice in a manner consistent with clinical practice. Tolerogenic dendritic cells (tDC) and type 1 regulatory T cells (Tr1 cell) in mice were analyzed by immunological approaches to be used as representative immune tolerant parameters. RESULTS: An AP model was established with CBA/J × DBA/2 mice. The expression of IL-10 in tDC and Tr1 cell frequency in the mouse decidua tissues were lower in the AP group than that in the normal pregnancy (NP) group. Administration of AZT up regulated the expression of IL-10 in tDCs and Tr1 cell generation in the decidua tissues, and improved the pregnancy and tissue structure in AP mice. The main mechanism by which AZT improves pregnancy in AP mice is that AZT enhanced the expression of galectin-9 in the epithelial cells of decidua tissues. Galectin 9 activates TIM3 on DCs to promote the IL-10 expression. The DCs induced more Tr1 cells in the decidua tissues. CONCLUSIONS: Dysfunctional tDCs were detected in the AP decidua tissues. Administration of AZT improved pregnancy in AP mice by regulating tDC function and generation of Tr1 cells in the maternal-fetal interface.

BaP/BPDE suppressed endothelial cell angiogenesis to induce miscarriage by promoting MARCHF1/GPX4-mediated ferroptosis.

Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe2+ level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe2+ and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes.

Impact of Homocysteine as a Preconceptional Screening Factor for In Vitro Fertilization and Prevention of Miscarriage with Folic Acid Supplementation Following Frozen-Thawed Embryo Transfer: A Hospital-Based Retrospective Cohort Study.

Homocysteine is an amino acid naturally produced in the body and metabolized via the methionine cycle. High homocysteine levels can increase the risk of infertility and pregnancy complications, such as preeclampsia, preterm delivery, miscarriage, and low birth weight. Preconceptional homocysteine levels may be reduced by taking folic acid supplements to reduce the risk of such complications. This cross-sectional, hospital-based study was conducted to examine the role of homocysteine in 1060 infertile women with a history of IVF/intracytoplasmic sperm injection (ICSI) failure. We analyzed whether folic acid intervention altered homocysteine levels and influenced reproductive outcome. We found that a higher homocysteine level was statistically associated with a lower fertilization rate in patients with a history of IVF/ICSI failure. There was an inverse relationship between homocysteine levels and serum 25(OH)VD, and a trend towards lower anti mullerian hormone in the group with higher homocysteine levels. This is the first interventional study to identify that folic acid supplementation improved pregnancy outcomes following freeze embryo transfer (FET) in women with a history of FET failure by monitoring the reduction in homocysteine levels. Therefore, folic acid supplementation and homocysteine level monitoring may constitute a novel intervention for improving IVF/ICSI pregnancy outcomes.