Tenofovir alafenamide in blocking mother-to-child transmission of hepatitis B virus: a multi-center, prospective study.

BACKGROUND: Data of tenofovir alafenamide (TAF) in preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) are limited. This study aimed to evaluate the effectiveness and safety of TAF for preventing MTCT. METHODS: Pregnant women with chronic HBV infection, positive for HBeAg and high-level HBV DNA, received oral TAF from gestational weeks 24-28 until postpartum week 4. All infants received HBV immunoprophylaxis. All mothers and infants were followed up until postpartum seven month. The primary outcome was the rate of MTCT at seven month. RESULTS: Eighty-nine mothers delivered and 91 infants were born. All were followed up to postpartum seven month. TAF was initiated at a mean gestational age of 25.0 (±1.0) weeks with the mean treatment duration of 14.3 (±1.2) weeks before delivery; 92.1% (82/89) mothers discontinued TAF, the median [IQR] time was 5.9 [4.7] weeks postpartum. The HBsAg positive rate was 0% at seven months in 91 infants, no growth retardation and congenital defects. All mothers were tolerated during TAF treatment. At delivery, 82.02% (73/89) mothers achieved HBV DNA < 200,000 IU/ml, 21.35% (19/89) achieved HBV DNA < 500 IU/ml. No significant changes on the mean (±SD) serum phosphate between baseline (1.20 ± 0.10 mmol/L) and at delivery (1.21 ± 0.13 mmol/L, p > .05). Serum creatinine at delivery (52.23 ± 8.50 µmol/L) was higher than baseline (45.97 ± 5.60 µmol/L, p < .05), but within normal range. Nine of 82 mothers stopped TAF treatment after delivery had mild ALT elevation. CONCLUSION: TAF therapy initiated during the second trimester was effective in preventing MTCT with no safety concerns for mothers and infants (ClinicalTrials.gov number, NCT04065230).

Association between Folic Acid Supplementation and Hypertensive Disorder Complicating Pregnancy in Jiangsu Province: A Cross-Sectional Study.

Objectives: To investigate the association of folic acid (FA) supplementation with hypertensive disorder complicating pregnancy (HDCP) and preeclampsia in Jiangsu Province, China. Materials and Methods: In this cross-sectional study, a total of 10,662 women with infants born between January 2017 and December 2018 were enrolled in Jiangsu Province, China. Maternal women with and without FA supplement intake were compared in this study. FA supplementation included 0.4 mg FA (0.4 FA), multivitamins with 0.4 mg FA (multivitamin (MV)+0.4 FA), and multivitamins with 0.8 mg FA (MV + 0.8 FA). Associations between FA intake, FA supplement dose or duration, (MV + FA) dosage per weight, and HDCP were analysed using ANOVA, the chi-square test, and logistic regression analysis. Results: Over the study follow-up period, the incidences of HDCP and preeclampsia were 3.5%, 1.4%, and 2.2%, 0.6% in the non-FA supplementation and FA supplementation groups, but only 1.5% and 0.1% in the MV + 0.8 FA group in early pregnancy. Compared with the non-FA group, HDCP and preeclampsia had the lowest risk in the MV + 0.8 FA group among the seven FA supplementation groups (HDCP: RR = 0.42, 95% CI = 0.27-0.68, P=0.001; preeclampsia: RR = 0.09, 95% CI = 0.03-0.33, P=0.001) in early pregnancy. Compared with the 0.4 FA alone group, the risk of HDCP and preeclampsia in women taking MV + 0.8 FA was significantly reduced (RR = 0.60, 95% CI = 0.41-0.87, P=0.008; preeclampsia: RR = 0.18, 95% CI = 0.06-0.60, P=0.005) in early pregnancy. (MV + FA)/BMI supplementation was associated with the risk of HDCP in early pregnancy (P trend = 0.002). Conclusions: MV supplement with 0.8 mg FA during early pregnancy may be effective in reducing HDCP and preeclampsia risk. The study provided the viewpoint that (MV + FA)/BMI could be used as a reference for FA intake in pregnant women of different weights.

Conservative management versus cesarean hysterectomy in patients with placenta increta or percreta.

OBJECTIVE: To compare conservative management and cesarean hysterectomy in patients with placenta increta or percreta. MATERIALS AND METHODS: In this multicenter retrospective study, we recorded data on 2219 patients with placenta increta or percreta from 20 tertiary care centers in China from 1 January 2011 to 31 December 2015. Propensity score analysis was used to control for baseline characteristics. We divided patients into conservative management (C) and hysterectomy (H) groups. The primary outcome was operative/postoperative maternal morbidity; secondary outcomes were maternal-neonatal outcomes. RESULTS: In total, 17.9% (398/2219) of patients had placenta increta and percreta; 82.1% (1821/2219) of the patients were in group C. After propensity score matching, 140 pairs of patients from the two groups underwent one-to-one matching. Group C showed less average blood loss within 24 h of surgery (1518 ± 1275 vs. 4309 ± 2550 ml in group H, p<.001). There were more patients with blood loss >1000 ml in group H than in group C (93.6% [131/140] vs. 61.4% [86/140], p<.001). More patients received blood transfusions in group H than in group C (p=.014). There was no significant difference between the groups in terms of bladder injury, postoperative anemia, fever, and disseminated intravascular coagulation. Neonatal outcomes in the two groups were similar. CONCLUSION: Either conservative management or hysterectomy should be considered after thorough evaluation and detailed discussion of risks and benefits. A balance between bleeding control and fertility can be achieved.

(Epi)genetic variants of the sarcomere-desmosome are associated with premature utero-contraction in spontaneous preterm labor.

Spontaneous preterm birth is a syndrome with clinical and genetic heterogeneity. Few studies have focused on the genetic and epigenetic defects and pathogenic mechanisms associated with premature uterine contraction in spontaneous preterm birth. The objective of this study was to investigate the (epi)genetic variations associated with premature uterine contraction of spontaneous preterm birth. A systems biology approach with an integrated multiomic study was employed. Biobanked pregnancy tissues selected from a pregnancy cohort were subjected to genomic, transcriptomic, methylomic, and proteomic studies, with a focus on genetic loci/genes related to uterine muscle contraction, specifically, genes associated with sarcomeres and desmosomes. Thirteen single nucleotide variations and pathogenic variants were identified in the sarcomere gene, TTN, which encodes the protein Titin, from 146 women with spontaneous preterm labor. Differential expression profiles of five long non-coding RNAs were identified from loci that overlap with four sarcomeric genes. Longitudinally, the long non-coding RNA of gene TPM3 that encodes the protein tropomysin 3 was found to significantly regulate the mRNA of TPM3 in the placenta, compared to maternal blood. The majority of genome methylation profiles related to premature uterine contraction were also identified in the CpG promoters of sarcomeric genes/loci. Differential expression profiles of mRNAs associated with premature uterine contraction showed 22 genes associated with sarcomeres and three with desmosomes. The results demonstrated that premature uterine contraction was associated mainly with pathogenic variants of the TTN gene and with transcriptomic variations of sarcomeric premature uterine contraction genes. This association is likely regulated by epigenetic factors, including methylation and long non-coding RNAs.

[Mutational analysis of 117 patients with non-syndromic hearing loss].

OBJECTIVE: To determine the frequencies of deafness gene mutations among patients with non-syndromic hearing loss (NSHL) from northern Jiangsu province. METHODS: A total of 117 patients with NSHL were enrolled. The coding region of GJB2 gene, IVS7-2A>G and 2168A>G mutations of SLC26A4 gene, and 1555A>G and 1494C>T mutations of mitochondrial DNA 12S rRNA were subjected to Sanger sequencing. Patients in whom no mutation was detected were further tested by targeted gene capture and high-throughput sequencing. RESULTS: Among the 117 patients, 86 (73.50%) were found to carry mutations. GJB2 gene mutations were found in 61 patients (52.14%), including 22 (18.80%) with homozygous mutations and 39 (33.33%) with heterozygous mutations. SLC26A4 gene mutations were found in 19 patients (16.24%), including 4 (3.42%) with homozygous mutations and 15 with heterozygous mutations (14.53%). Mitochondrial 12S rRNA gene mutation was found in 6 patients (5.13%). Targeted gene capture and high-throughput sequencing of 8 patients identified 4 further cases, including 1 with RDX gene 129_130del and 76_79del compound heterozygous mutations, 1 with OTOF gene 1274G>C homozygous mutation, 1 with SLC26A4 gene 919-2A>G and IVS16-6G>A compound heterozygous mutation, and 1 with SLC26A4 gene 919-2A>G and A1673T compound heterozygous mutation. CONCLUSION: The frequency of mutation among patients with NSHL from north Jiangsu was 73.50%, and GJB2 gene was most commonly mutated.

Maternal and neonatal outcomes of placenta increta and percreta from a multicenter study in China.

OBJECTIVE: The objective of this study is to identify the maternal and neonatal outcomes in women with placenta increta or placenta percreta in China. MATERIALS AND METHODS: We retrospectively analyzed 2219 cases from 20 tertiary care centers in China between January 2011 and December 2015. All cases were diagnosed of placenta increta or placenta percreta, based on either intraoperative findings or histopathological findings. RESULTS: The incidence of placenta increta and placenta percreta progressively increased from 0.18% in 2011 to 0.78% in 2015. Compared with the placenta increta, placenta percreta was strongly related to serious adverse outcomes: postpartum hemorrhage (65.9% versus 38.6%, p = .003), blood transfusion (86.2% versus 46.5%, p < .001), hysterectomy (43.3% versus 11.2%, p < .001), preterm birth (65.7% versus 49.9%, p < .001), and the need for neonatal intensive care unit (NICU) admission (54.5% versus 36.7%, p < .001). CONCLUSION: The incidence of placenta increta and placenta percreta is likely to increase in China. The depth of placenta implantation is associated with the severity of outcomes. Placenta percreta tends to have worse maternal and neonatal outcomes.

Long Non-Coding RNAs Serve as Diagnostic Biomarkers of Preeclampsia and Modulate Migration and Invasiveness of Trophoblast Cells.

BACKGROUND Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of tumor progression. However, the effects of lncRNAs in preeclampsia are not entirely clear. The aim of this study was to demonstrate the potential of lncRNAs to serve as biomarkers in preeclampsia. MATERIAL AND METHODS The RNA expression levels of lncRNAs (NR_027457, BC030099, AF037219, NR_024178, AF085938, G43016, G36948, NR_029420, NR_024015, AK002210, NR_026643, and AL049277) in the serum of patients with preeclampsia and in the serum of normal controls were measured by qRT-PCR. The area under the curve (AUC), the optimal cut-off values, the specificity, and the sensitivity of NR_027457, AF085938, G36948, and AK002210 were analyzed by receiver operating characteristic (ROC) curve analysis. We designed RNA interference species to suppress NR_027457 and G36948 and identified the roles of NR_027457 and G36948 in the functions of a trophoblast cell line (HTR-8/SVneo). RESULTS The qRT-PCR results indicated that NR_027457 and AF085938 were significantly up-regulated, whereas G36948 and AK002210 were significantly down-regulated in preeclampsia. We found that NR_027457, AF085938, G36948, and AK002210 had potential diagnostic value for the detection of preeclampsia. Furthermore, the levels of NR_027457, AF085938, G36948, and AK002210 in the serum of patients were significantly different before vs. after surgery. The silencing of NR_027457 inhibited the proliferation, migration, and invasion abilities of HTR-8/SVneo cells, while the silencing of G36948 promoted the proliferation, migration, and invasion abilities of HTR-8/SVneo cells. CONCLUSIONS NR_027457, AF085938, G36948, and AK002210 can serve as potential diagnostic biomarkers in preeclampsia, and NR_027457 and G36948 might be involved in the pathogenesis of preeclampsia.

Post-marketing safety surveillance and reevaluation of Motherwort injection: A clinical study of 10 094 cases.

OBJECTIVE: To investigate the safety profiles of Motherwort injection (MI). METHODS: A multi-center, prospective and drug- derived hospital intensive monitoring method was conducted to assess the safety of MI in real world applications. This study was based on a very large population after the injection was approved and marketed in China. All patients using the injection in participating hospitals were monitored to determine the incidence, pattern, severity and outcome of associated adverse events. RESULTS: The post-marketing surveillance was performed in 10 094 female patients from April to December, 2015. The incidence of adverse drug reactions (ADRs) was 0.79¡ë(8/10 094). Among the 8 patients, the reported adverse events mainly included systemic abnormalities, such as fever, chills and eyelid edema; skin and appendages disorders, such as pruritus and rash; gastrointestinal disorders, such as nausea, abdominal distension and pain; heart rate and rhythm disorders, such as palpitation and increased heart rate. All of these ADRs were mild in severity. CONCLUSION: In this study the ADRs incidence rate of MI is very low, which supports that it is generally safe for use in obstetric and gynecological diseases. However, the total number of 8 ADRs recorded over a relatively short time span seems limited, and the low number of reports could not represent an absolute guarantee of safety.

Ubiquitin-Proteasome-Collagen (CUP) Pathway in Preterm Premature Rupture of Fetal Membranes.

Spontaneous preterm birth (sPTB) occurs before 37 gestational weeks, with preterm premature rupture of the membranes (PPROM) and spontaneous preterm labor (sPTL) as the predominant adverse outcomes. Previously, we identified altered expression of long non-coding RNAs (lncRNAs) and message RNAs (mRNAs) related to the ubiquitin proteasome system (UPS) in human placentas following pregnancy loss and PTB. We therefore hypothesized that similar mechanisms might underlie PPROM. In the current study, nine pairs of ubiquitin-proteasome-collagen (CUP) pathway-related mRNAs and associated lncRNAs were found to be differentially expressed in PPROM and sPTL. Pathway analysis showed that the functions of their protein products were inter-connected by ring finger protein. Twenty variants including five mutations were identified in CUP-related genes in sPTL samples. Copy number variations were found in COL19A1, COL28A1, COL5A1, and UBAP2 of sPTL samples. The results reinforced our previous findings and indicated the association of the CUP pathway with the development of sPTL and PPROM. This association was due not only to the genetic variation, but also to the epigenetic regulatory function of lncRNAs. Furthermore, the findings suggested that the loss of collagen content in PPROM could result from degradation and/or suppressed expression of collagens.

Dysregulation of LncRNAs in Placenta and Pathogenesis of Preeclampsia.

BACKGROUND: Preeclampsia, a gestational disease characterized by hypertension and proteinuria twenty weeks into pregnancy, is one of the leading causes of fetal and maternal mortality. Although multiple genetic and environmental factors are found to be related to the preeclampsia risk, the pathogenic pathways remain largely undefined. The placenta plays a critical role in the fetal development by carrying out the barrier, fetal-maternal exchange, and endocrine functions during pregnancy. Accumulated data indicated that the expression of multiple long noncoding RNA (LncRNA) is dysregulated in preeclamptic placentas. Moreover, manipulation of LncRNA expression led to functional alterations in trophoblast cell cultures, including changes in proliferation, differentiation, apoptosis, and migration. OBJECTIVE: This article reviews published data on this subject and provides detailed information on the regulation and function of LncRNAs IGF2/H19, MEG3, SPRY4-IT1, HOTAIR, MALAT1, and FLT1P1 and CEACAMP8 in placental trophoblasts. The potential mechanisms underlying the action of these LncRNAs are also discussed to facilitate a better understanding on the potential role of these LncRNAs for the pathogenesis of preeclampsia. CONCLUSION: It is elaborated that some lncRNAs probably contribute to the pathogenesis of preeclampsia through methylation, Notch-EGFL7 signaling pathway and Wnt/ß-catenin pathway.

Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies.

BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy, and has important health implications for mother and child. Changes in the fetoplacental vessels may predict those in the vasculature of the developing fetus, as these have been implicated in the pathogenesis of human GDM. This study aimed to determine the differences in the localization and expression level of VEGFA and VEGFR2 between placentas of women with GDM and placentas of normal pregnancies, which is the first step in elucidating the possible roles of VEGFA and VEGFR2 in the altered uteroplacental function resulting from maternal hyperglycaemia and ultimately in the manifestation of GDM. METHODS: The expressions of VEGFA and VEGFR2 mRNA and protein in 20 samples from each group were analyzed by real-time PCR, immunohistochemistry and Western blot. The placental blood barrier and angiogenesis were observed by the transmission electron microscopy (TEM) in10 GDM samples and ten controls. RESULTS: The expression levels of VEGFA and VEGFR2 mRNA and protein were significantly decreased in the GDM group (P < 0.05 or 0.01). Immunohistochemical analysis showed the reduced expression of VEGFA and VEGFR2 protein in GDM-affected placental tissues, and the degenerative alterations of the terminal villi vascular. CONCLUSION: The expressions of VEGFA and VEGFR-2 mRNAs and protein were reduced in GDM-affected placental tissues, suggesting that maternal GDM affects the pathophysiological function of placentas.

Ultrastructure of Placenta of Gravidas with Gestational Diabetes Mellitus.

Objectives. Gestational diabetes mellitus (GDM) leads to an abnormal placental environment which may cause some structural alterations of placenta and affect placental development and function. In this study, the ultrastructural appearances of term placentas from women with GDM and normal pregnancy were meticulously compared. Materials and Methods. The placenta tissues of term birth from 10 women with GDM and 10 women with normal pregnancy were applied with the signed informed consent. The morphology of fetomaternal interface of placenta was examined using light microscopy (LM) and transmission electron microscopy (TEM). Results. On LM, the following morphological changes in villous tissues were found in the GDM placentas when compared with the control placentas: edematous stroma, apparent increase in the number of syncytial knots, and perivillous fibrin deposition. On TEM, the distinct ultrastructural alterations indicating the degeneration of terminal villi were found in the GDM placentas as follows: thickening of the basal membrane (BM) of vasculosyncytial membrane (VSM) and the VSM itself, significantly fewer or even absent syncytiotrophoblastic microvilli, swollen or completely destroyed mitochondria and endoplasmic reticulum, and syncytiotrophoblasts with multiple vacuoles. Conclusion. Ultrastructural differences exist between GDM and control placentas. The differences of placenta ultrastructure are likely responsible for the impairment of placental barrier and function in GDM.

Viral Infection-Induced Differential Expression of LncRNAs Associated with Collagen in Mouse Placentas and Amniotic Sacs.

PROBLEM: We have previously determined that long non-coding RNAs (lncRNAs) are differentially expressed in preterm premature rupture of membranes (PPROM) and hypothesized that the collagenolysis ubiquitin-proteasome system may be activated by infection and inflammation. However, direct evidence of the involvement of lncRNAs in transcriptional and posttranscriptional regulation of the infection-triggered alteration of collagen is lacking. METHOD OF STUDY: A previously developed mouse model with MHV68 viral infection was assessed to determine whether viral infection may induce differential expression of lncRNAs in mouse placentas and amniotic sacs. RESULTS: Differential expression of lncRNAs that are associated with collagen was found in HMV68 viral-infected, compared to non-infected, mouse placentas and amniotic sacs. Differential expression of messenger RNAs (mRNAs) of collagen was also documented. CONCLUSIONS: Our data demonstrate, for the first time, that viral infection may induce the differential expression of lncRNAs that are associated with collagen. Based on this finding, we propose that lncRNA may have involved in regulating of infection-induced collagen transcription.

Epigenetic regulation of lncRNA connects ubiquitin-proteasome system with infection-inflammation in preterm births and preterm premature rupture of membranes.

BACKGROUND: Preterm premature rupture of membranes (PPROM) is responsible for one third of all preterm births (PTBs). We have recently demonstrated that long noncoding RNAs (lncRNAs) are differentially expressed in human placentas derived from PPROM, PTB, premature rupture of the membranes (PROM), and full-term birth (FTB), and determined the major biological pathways involved in PPROM. METHODS: Here, we further investigated the relationship of lncRNAs, which are differentially expressed in spontaneous PTB (sPTB) and PPROM placentas and are found to overlap a coding locus, with the differential expression of transcribed mRNAs at the same locus. Ten lncRNAs (five up-regulated and five down-regulated) and the lncRNA-associated 10 mRNAs (six up- and four down-regulated), which were identified by microarray in comparing PPROM vs. sPTB, were then validated by real-time quantitative PCR. RESULTS: A total of 62 (38 up- and 24 down-regulated) and 1,923 (790 up- and 1,133 down-regulated) lncRNAs were identified from placentas of premature labor (sPTB + PPROM), as compared to those from full-term labor (FTB + PROM) and from premature rupture of membranes (PPROM + PROM), as compared to those from non-rupture of membranes (sPTB + FTB), respectively. We found that a correlation existed between differentially expressed lncRNAs and their associated mRNAs, which could be grouped into four categories based on the gene strand (sense or antisense) of lncRNA and its paired transcript. These findings suggest that lncRNA regulates mRNA transcription through differential mechanisms. Differential expression of the transcripts PPP2R5C, STAM, TACC2, EML4, PAM, PDE4B, STAM, PPP2R5C, PDE4B, and EGFR indicated a co-expression among these mRNAs, which are involved in the ubiquitine-proteasome system (UPS), in addition to signaling transduction and beta adrenergic signaling, suggesting that imbalanced regulation of UPS may present an additional mechanism underlying the premature rupture of membrane in PPROM. CONCLUSION: Differentially expressed lncRNAs that were identified from the human placentas of sPTB and PPROM may regulate their associated mRNAs through differential mechanisms and connect the ubiquitin-proteasome system with infection-inflammation pathways. Although the detailed mechanisms by which lncRNAs regulate their associated mRNAs in sPTB and PPROM are yet to be clarified, our findings open a new approach to explore the pathogenesis of sPTB and PPROM.

LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.

Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.