A study on the efficacy and safety of long-term adjusted low-dose gonadotropin-releasing hormone agonist therapy for uterine fibroids and adenomyosis.

AIM: To investigate the efficacy and safety of long-term adjusted low-dose gonadotropin-releasing hormone agonist therapy (GnRH agonist drawback therapy) with nafarelin acetate in patients with uterine fibroids and/or adenomyosis with menstrual symptoms. METHODS: This single-center, retrospective, observational study initially included 118 patients with uterine fibroids and/or adenomyosis with menstrual symptoms who had received GnRH agonist (nafarelin acetate) drawback therapy for at least 7 months between 2010 and 2020. Blood hemoglobin level, maximum fibroid diameter, area of the corpus uteri, blood estradiol level, daily dosage of nafarelin acetate, and bone density in the lumbar spine and femoral neck were assessed before and after the treatment initiation. RESULTS: The median treatment period was 28 months. Menstruation had ceased in all patients. The median hemoglobin level significantly increased from 8.6 to 13.2 g/dL before treatment and at 12 months after the treatment initiation in patients with fibroids and from 8.8 to 13.3 g/dL in patients with adenomyosis, respectively. Although the treatment did not exert a significant shrinking effect on the fibroids and adenomyosis, an increase in their size was not observed in any patient. The initial dose of nafarelin acetate was 400 µg/day and was lowered to 130 µg/day at 12 months. Only 29 patients (25%) had an estradiol level <30 pg/mL. The average rate of bone density change over 6 months was -1.23% in the lumbar spine and -1.12% in the femoral neck in patients with fibroids and -1.06% in the lumbar spine and -0.14% in the femoral neck in patients with adenomyosis, which were lower than the previously reported rates. CONCLUSIONS: GnRH agonist drawback therapy was found to be useful for the long-term conservative treatment of uterine fibroids and adenomyosis. The treatment was safely and inexpensively performed with few adverse events.

Changes in In-Hospital Survival and Long-Term Neurodevelopmental Outcomes of Extremely Preterm Infants: A Retrospective Study of a Japanese Tertiary Center.

OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Vulnerability of primitive human placental trophoblast to Zika virus.

Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas.

Human embryonic stem cells (ESCs) readily commit to the trophoblast lineage after exposure to bone morphogenetic protein-4 (BMP-4) and two small compounds, an activin A signaling inhibitor and a FGF2 signaling inhibitor (BMP4/A83-01/PD173074; BAP treatment). During differentiation, areas emerge within the colonies with the biochemical and morphological features of syncytiotrophoblast (STB). Relatively pure fractions of mononucleated cytotrophoblast (CTB) and larger syncytial sheets displaying the expected markers of STB can be obtained by differential filtration of dispersed colonies through nylon strainers. RNA-seq analysis of these fractions has allowed them to be compared with cytotrophoblasts isolated from term placentas before and after such cells had formed syncytia. Although it is clear from extensive gene marker analysis that both ESC- and placenta-derived syncytial cells are trophoblast, each with the potential to transport a wide range of solutes and synthesize placental hormones, their transcriptome profiles are sufficiently dissimilar to suggest that the two cell types have distinct pedigrees and represent functionally different kinds of STB. We propose that the STB generated from human ESCs represents the primitive syncytium encountered in early pregnancy soon after the human trophoblast invades into the uterine wall.

Effects of Lipopolysaccharide on Human First Trimester Villous Cytotrophoblast Cell Function In Vitro.

It has been shown that adverse obstetrical outcomes such as pre-eclampsia and intrauterine growth retardation correlate with maternal infection. In this study, we investigated mechanisms involved in infection-associated abnormalities in cytotrophoblast function. Primary human first trimester cytotrophoblast cells were isolated and treated with lipopolysaccharide (LPS). Levels of the cytokines and chemokines were measured and cytotrophoblast invasion was investigated. In addition, first trimester decidual macrophages were isolated and treated with the conditioned medium from LPS-treated cytotrophoblast cells, and macrophage migration was assessed. Coculturing decidual macrophages with cytotrophoblast cells was conducted to investigate macrophage costimulatory molecule and receptor expression and intracellular cytokine production. We found that LPS exposure increased cytotrophoblast production of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and chemokines IL-8, macrophage inflammatory protein (MIP)-1alpha, and CXCL12 in a dose-dependent manner. In addition, LPS decreased cytotrophoblast invasion, and its effect was Toll-like receptor 4 (TLR4)-dependent and partly TNF-alpha-dependent. Conditioned medium from LPS-stimulated cytotrophoblast cells increased decidual macrophage migration and this effect was partly TLR4-dependent. Furthermore, coculturing decidual macrophages with LPS-exposed cytotrophoblast cells up-regulated macrophage CD80 and CD86 expression and intracellular TNF-alpha and IL-12p40 production, while down-regulating macrophage CD206 and CD209 expression and intracellular IL-10 secretion. LPS-stimulated macrophages also inhibited cytotrophoblast invasion. In conclusion, our results indicate that LPS increases the production of a subset of proinflammatory cytokines and chemokines by human first trimester cytotrophoblast cells, decreases cytotrophoblast invasion, and alters the cross talk between cytotrophoblast cells and decidual macrophages.

A pregnant woman with long-standing, retained intraabdominal glass shards who gave birth to a live infant with no complications: a case report.

BACKGROUND: Most cases of traumatic injury during pregnancy involve blunt trauma, with penetrating trauma being uncommonly rare. In glass shard injuries, fragments often penetrate deeply, and multiple injuries may occur simultaneously; attention must be paid to the possibility of organ injury from the residual fragments. However, no case of this occurring during pregnancy has been reported yet. CASE PRESENTATION: We present the case of a 34-year-old pregnant Cameroonian woman who retained intraabdominal glass shards following a penetrating injury at 13 weeks gestation and not diagnosed until 22 weeks gestation. Notably, this patient continued the pregnancy without complications and gave birth via cesarean section at 36 weeks gestation. CONCLUSION: In pregnant women sustaining a penetrating glass trauma during pregnancy, careful attention should be paid to the fragments; in that case, computed tomography is a useful modality for accurately visualizing any remaining fragments in the body. Essentially, the foreign bodies in glass shard injuries during pregnancy should be removed immediately, but conservative management for term delivery is an important choice for patients at risk for preterm delivery.

Prolonged oligohydramnios and the adverse composite outcome of death or severe neurodevelopmental impairment at 3 years of age in infants born at 22-29 gestational weeks.

OBJECTIVE: To investigate the association between prolonged oligohydramnios and a composite outcome of death or severe neurodevelopmental impairment (NDI) at 3 years of age. METHODS: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age without major congenital anomalies. The patients were classified into three groups depending on the existence and duration of oligohydramnios: no/non-prolonged oligohydramnios (no or 0-7 days of oligohydramnios), prolonged oligohydramnios (8-14 days), and very prolonged oligohydramnios (> 14 days). The primary outcome was a composite of death or severe NDI, which was defined as severe cerebral palsy, developmental delay, severe visual impairment, or deafness at age 3. RESULTS: Out of the 843 patients, 784 (93 %), 30 (3.6 %), and 29 (3.4 %) were classified into the no/non-prolonged, prolonged, and very prolonged oligohydramnios groups, respectively. After excluding patients lost to follow-up, the adverse composite outcome at 3 years of age was observed in 194/662 (29 %), 7/26 (27 %), and 8/23 (35 %) in the corresponding groups. The composite outcome showed no significant trend with the duration of oligohydramnios (P = 0.70). In a logistic regression model controlling the known predictors of gestational age, birth weight, small-for-gestational-age, male sex, multiple pregnancy, hypertensive disorders of pregnancy, antenatal corticosteroids, and the number of family-social risk factors, the duration of oligohydramnios was not independently associated with the composite outcome; odds ratio 1.3 (95 % confidence interval, 0.78-2.0). CONCLUSION: Prolonged oligohydramnios was not associated with the composite outcome of death or severe NDI at 3 years of age.

Ultrasonographic vascularity assessment for predicting future severe hemorrhage in retained products of conception after second-trimester abortion.

Objectives: To investigate the spontaneous outcomes of vascularized retained products of conception (RPOC) detected by ultrasonography after second-trimester abortion, and to identify the predictive factors for the development of severe postpartum hemorrhage (SPPH).Study design: This is a retrospective cohort study on all cases after second-trimester abortion managed at our institute between January 2014 and December 2016. We assessed the associations between the occurrence of SPPH requiring invasive treatment and clinical factors including ultrasonographic findings (size and the vascularity status of RPOC classified as follows: type 1: vascularity confined to endometrium, type 2: vascularity reaching <1/2 myometrium, and type 3: vascularity reaching ≥1/2 myometrium) in vascularized RPOC cases.Results: Among 103 cases after second-trimester abortion, 19 patients (18.4%) were diagnosed as RPOC, and five patients eventually failed expectant management due to SPPH. Of them, 66.7% (4/6) of patients with type 3 developed SPPH as compared with 7.7% (1/13) of patients with type 1/type 2 (p < .05). The maximum vascularized mass diameter was significantly greater among the five patients who experienced SPPH than among the 14 patients who demonstrated spontaneous remission (43.0 ± 12.0 mm versus 20.7 ± 8.3 mm, p < .01). Patients with type 3 RPOC and a maximum vascularized mass diameter ≥30 mm, compared with other patients, demonstrated sensitivity, specificity, and risk ratio related to SPPH of 80, 92.9%, and 11.2, respectively.Conclusions: Our findings suggest that the ultrasonographic assessment of RPOC focused on the depth of vascularity in combination with the measurement of its size appears to be essential in determining women with RPOC who are at high risk for SPPH.

Placental expression of lysophosphatidic acid receptors in normal pregnancy and preeclampsia.

PROBLEM: Recent advances in lipid research have revealed that impairments in lipid mediator signaling can be involved in the pathoetiology of a variety of diseases. We previously reported aberrant expression of autotaxin, a key enzyme for lysophosphatidic acid (LPA) production, in placentas from women with preeclampsia. The present study aimed to further explore the involvement of LPA signaling in the pathoetiology of preeclampsia. METHOD OF STUDY: Term placentas were obtained from deliveries after uncomplicated pregnancy (n = 18) and those complicated by preeclampsia (n = 24). First-trimester placental tissues were collected after elective terminations of pregnancy (n = 20). Placental expression of the six identified LPARs (LPAR1-6) was analyzed at protein and mRNA levels. RESULTS: In normal pregnancy, the mRNA expression levels of all LPARs except LPAR4 were significantly higher in term. Levels of mRNA encoding LPAR2-5 were significantly increased in preeclampsia placentas compared with those in the normal term placentas. Using Western immunoblotting, only LPAR3 was noted to be increased at the protein level in placentas from preeclamptic pregnancies. This was validated by immunohistochemistry. CONCLUSION: In summary, the placental expression of LPARs, particularly LPAR3, is enhanced in preeclampsia, suggesting that disturbances in placental LPA signaling may be involved in the pathogenesis of preeclampsia.

FRL-1, a member of the EGF-CFC family, is essential for neural differentiation in Xenopus early development.

Recent studies indicate an essential role for the EGF-CFC family in vertebrate development, particularly in the regulation of nodal signaling. Biochemical evidence suggests that EGF-CFC genes can also activate certain cellular responses independently of nodal signaling. Here, we show that FRL-1, a Xenopus EGF-CFC gene, suppresses BMP signaling to regulate an early step in neural induction. Overexpression of FRL-1 in animal caps induced the early neural markers zic3, soxD and Xngnr-1, but not the pan-mesodermal marker Xbra or the dorsal mesodermal marker chordin. Furthermore, overexpression of FRL-1 suppressed the expression of the BMP-responsive genes, Xvent-1 and Xmsx-1, which are expressed in animal caps and induced by overexpressed BMP-4. Conversely, loss of function analysis using morpholino-antisense oligonucleotides against FRL-1 (FRL-1MO) showed that FRL-1 is required for neural development. FRL-1MO-injected embryos lacked neural structures but contained mesodermal tissue. It was suggested previously that expression of early neural genes that mark the start of neuralization is activated in the presumptive neuroectoderm of gastrulae. FRL-1MO also inhibited the expression of these genes in dorsal ectoderm, but did not affect the expression of chordin, which acts as a neural inducer from dorsal mesoderm. FRL-1MO also inhibited the expression of neural markers that were induced by chordin in animal caps, suggesting that FRL-1 enables the response to neural inducing signals in ectoderm. Furthermore, we showed that the activation of mitogen-activated protein kinase by FRL-1 is required for neural induction and BMP inhibition. Together, these results suggest that FRL-1 is essential in the establishment of the neural induction response.