Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan.

AIM: This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan. METHODS: A web-based nationwide questionnaire survey regarding progestogen use for prevention of PTB was conducted among childbirth healthcare facilities from 2019 to 2021. RESULTS: Valid responses were obtained from 528 facilities (25.2% of those surveyed), including 155 tertiary perinatal facilities (making up 92.3% of all tertiary perinatal care facilities). In the survey period, progestogen treatment was implemented in 207 facilities (39.2%) for PTB prevention. Regarding types of progestogens, 17α-hydroxyprogesterone caproate was used in 170 facilities (82.1%), with a low dose (125 mg/week) administered in 62.9% of the facilities to comply with the regulations of the national health insurance system, although 250 mg/week is considered the best dose. Vaginal progesterone was used in 36 facilities (17.4%), although the cost of vaginal progesterone was not covered by health insurance. Of the facilities not administering progestogen treatment, approximately 40% expressed that vaginal progesterone would be their first choice for PTB prevention in daily practice if it would be covered by health insurance in the future. CONCLUSIONS: Due to the current regulations of the Japanese health insurance system, 17α-hydroxyprogesterone caproate, rather than vaginal progesterone, was mainly used for PTB prevention. Despite global evidence supporting vaginal progesterone as the approach with the highest efficacy, only a limited number of facilities have utilized it due to the current drug use regulations in Japan.

An up to 43-year longitudinal study of fixed prosthetic restorations retained with 4-META/MMA-TBB resin cement or zinc phosphate cement.

STATEMENT OF PROBLEM: Adhesive resin cement has been the preferred choice for the placement of prosthetic restorations, but evidence-based studies supporting this selection are sparse. PURPOSE: The purpose of this study was to test the hypothesis that restoration placement with the adhesive 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate-tributylborane (4-META/MMA-TBB) resin cement is associated with better longevity of teeth than zinc phosphate cement up to 43 years. MATERIALS AND METHODS: Study participants were individuals who had been visiting the clinic regularly for more than 20 years from their first visit between November 1970 and April 1985. The vital teeth with prosthetic restorations (N=454), including cast inlays, onlays, crowns, and fixed partial dentures, of 53 patients were assessed from dental charts and radiographs. Most of the bonding surfaces were precious metal alloy, excluding 4 restorations cemented with zinc phosphate and 6 ceramic crowns cemented with 4-META/MMA-TBB resin cement. The Kaplan-Meier method and log-rank test (α=.05) were used to compare longevity between the 2 materials. Chi-squared tests (α=.001) were also used to examine the occurrence rates of events such as secondary caries, endodontic treatment, and the dislodgement of restorations affecting the longevity of the 2 cements. RESULTS: Clinical review examination demonstrated that 55.4% of teeth retained with 4-META/MMA-TBB resin cement had been in service for 30 years compared with 43.5% of those retained with zinc phosphate cement, with a significant difference (P=.006). 4-META/MMA-TBB resin cement also demonstrated lower event occurrence rates than zinc phosphate cement for 3 assessed types of events (P<.001). CONCLUSIONS: Within the limitations of this study, 4-META/MMA-TBB resin adhesive cement demonstrated a higher survival rate than conventional zinc phosphate cement in service for 30 years with a lower occurrence of critical events.

Probiotics including Clostridium butyricum, Enterococcus faecium, and Bacillus subtilis may prevent recurrent spontaneous preterm delivery.

AIM: A large cohort study of Japanese women reported that the rate of recurrent spontaneous preterm delivery (sPTD) in the next pregnancy was 22.3%; therefore, it is important to prevent recurrent sPTD. The present study investigated the rate of recurrent sPTD in pregnant women treated with probiotics. METHODS: This was a retrospective study. Fifty-one pregnant women with a history of sPTD and who had been taking probiotics before 14 weeks of gestation were selected. The rate of sPTD in the next pregnancy among 255 pregnant women with a history of sPTD who had not taken probiotics was compared with that in the probiotics group. RESULTS: The rate of recurrent sPTD was 9.8% (5/51), which was lower than previously reported values. Furthermore, the rate of recurrent sPTD was significantly lower in the probiotics group (9.8%) than in the nonprobiotics group (31.0% [79/255]; p = 0.002). CONCLUSIONS: Probiotics may reduce the rate of recurrent sPTD.

Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia.

Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin-proteasome and autophagy-lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction.

Risk factors for spontaneous miscarriage above 12 weeks or premature delivery in patients undergoing cervical polypectomy during pregnancy.

BACKGROUND: It currently remains unknown whether the resection of cervical polyps during pregnancy leads to miscarriage and/or preterm birth. This study evaluated the risk of spontaneous PTB below 34 or 37 weeks and miscarriage above 12 weeks in patients undergoing cervical polypectomy during pregnancy. METHODS: This was a retrospective monocentric cohort study of patients undergoing cervical polypectomy for clinical indication. Seventy-three pregnant women who underwent polypectomy were selected, and risk factors associated with miscarriage above 12 weeks or premature delivery below 34 or 37 weeks were investigated. A multivariable regression looking for predictors of spontaneous miscarriage > 12 weeks and PTB < 34 or 37 weeks were performed. RESULTS: Sixteen patients (21.9%, 16/73) had spontaneous delivery at < 34 weeks or miscarriage above 12 weeks. A univariate analysis showed that bleeding before polypectomy [odds ratio (OR) 7.7, 95% confidence interval (CI) 1.6-37.3, p = 0.004], polyp width ≥ 12 mm (OR 4.0, 95% CI 1.2-13.1, p = 0.005), the proportion of decidual polyps (OR 8.1, 95% CI 1.00-65.9, p = 0.024), and polypectomy at ≤10 weeks (OR 5.2, 95% CI 1.3-20.3, p = 0.01) were significantly higher in delivery at < 34 weeks than at ≥34 weeks. A logistic regression analysis identified polyp width ≥ 12 mm (OR 11.8, 95% CI 2.8-77.5, p = 0.001), genital bleeding before polypectomy (OR 6.5, 95% CI 1.2-55.7, p = 0.025), and polypectomy at ≤10 weeks (OR 5.9, 95% CI 1.2-45.0, p = 0.028) as independent risk factors for predicting delivery at < 34 weeks. Polyp width ≥ 12 mm and bleeding before polypectomy are risk factors for PTB < 37 wks. CONCLUSIONS: Our cohort of patients undergoing polypectomy in pregnancy have high risks of miscarriage or spontaneous premature delivery. It is unclear whether these risks are given by the underlying disease, by surgical treatment or both. This study establishes clinically relevant predictors of PTB are polyp size> 12 mm, bleeding and first trimester polypectomy. PTB risks should be exposed to patients and extensively discussed with balancing against the benefits of intervention in pregnancy.

Method to evaluate intravenous maintenance tocolysis for preterm labor.

AIM: Despite the lack of evidence-based medicine, continuous intravenous maintenance tocolysis is the main treatment for preterm labor (PTL) in Japan because it is considered to prolong the gestational period. This treatment needs to be evaluated in more detail, and we herein propose one method to assess maintenance tocolysis using the timing of delivery by PTL patients. METHODS: PTL patients (n = 307) were divided into three groups according to delivery weeks of gestation. Group A (severe PTL) delivered at <34 weeks, group B (mild PTL) at 34-37 weeks and group C (cases suspected overtreatment) at ≥38 weeks. The percentages of patients in each group was calculated and clinical characteristics were compared between groups. RESULTS: The percentages of patients (%) in groups A, B and C were 33.9, 43.6 and 22.5, respectively. Gestational weeks on admission, maternal white blood cell count and C-reactive protein, PTL index, fetal fibronectin levels in vaginal secretions, amniotic fluid interleukin-8 levels, staying at neonatal intensive care unit were significantly different between these three groups by analysis of variance. Furthermore, amniotic fluid interleukin-8 levels were significantly higher in group B (3.5 [0.1-46.5] ng/mL) than in group C (1.7 [0.1-16.1], P < 0.05). CONCLUSIONS: PTL patients were classified according to the prognosis. The ratio of patients in each group represented the severity of PTL and the risk of overtreatment. When this ratio is investigated on a nationwide scale, the use of intravenous maintenance tocolysis or definition of PTL may need to be reconsidered.

Placental autophagy failure: A risk factor for preeclampsia.

Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments. Autophagy is primarily involved in maintaining cellular homeostasis, and in immune regulation, longevity, cytokines secretion and a variety of other biological functions. Here, we review the role of autophagy in normal embryogenesis and placentation. Once placental autophagy is impaired by metabolic stress such as hypoxia, endoplasmic reticulum stress or starvation, placental development could be disrupted, resulting in functional maladaptations at the maternal-fetal interface. These malfunctions may result in fetal growth restriction or preeclampsia.

Disruption of Placental Homeostasis Leads to Preeclampsia.

Placental homeostasis is directly linked to fetal well-being and normal fetal growth. Placentas are sensitive to various environmental stressors, including hypoxia, endoplasmic reticulum stress, and oxidative stress. Once placental homeostasis is disrupted, the placenta may rebel against the mother and fetus. Autophagy is an evolutionally conservative mechanism for the maintenance of cellular and organic homeostasis. Evidence suggests that autophagy plays a crucial role throughout pregnancy, including fertilization, placentation, and delivery in human and mouse models. This study reviews the available literature discussing the role of autophagy in preeclampsia.

Congenital tuberculosis in an extremely preterm infant and prevention of nosocomial infection.

Congenital tuberculosis is a rare disease, especially in non-endemic countries. We present a preterm infant who developed congenital tuberculosis in a neonatal intensive care unit (NICU). The male patient, weighing 1140 g was born by cesarean section at 26 weeks gestation. The baby's respiratory condition suddenly deteriorated at 18 days old, and he was diagnosed with congenital tuberculosis after Gram stain revealed "ghost bacilli" in his tracheal aspirate. The mother, who was born in an endemic country, had fever with unknown cause during labor and was diagnosed with miliary tuberculosis after the infant was diagnosed. Both were successfully treated for tuberculosis with a four-drug regimen. The genotyping profiles of Mycobacterium tuberculosis were identical in both mother and baby based on variable number of tandem repeat (VNTR) analysis. The lineage was considered to be East-African Indian. To prevent nosocomial infection in the NICU, 23 potentially exposed infants received isoniazid for 2 months. Two infants showed a transient liver enzyme elevation that seemed to be due to isoniazid. For 10 months after the incident, there were no infants and medical staff who developed tuberculosis. Although the incidence of tuberculosis has steadily decreased in Japan, the percentage of foreign-born individuals has increased yearly, especially those of reproductive age. The evaluation of active tuberculosis should be considered in pregnant women with unexplained fever, history of tuberculosis, or emigration from high-burden areas.

Fermented foods and preterm birth risk from a prospective large cohort study: the Japan Environment and Children's study.

BACKGROUND: The dietary pattern of pregnant women is known to be associated with preterm birth (PTB). We investigated whether PTB was associated with intake of fermented food by using data from the Japan Environment and Children's Study. METHODS: From a data set of 103,099 pregnancies, 77,667 cases at low risk for PTB were analyzed. The primary outcome measurements were based on PTB. Fermented food (miso soup, yogurt, cheese, and fermented soybeans) consumption was assessed by using a semi-quantitative food frequency questionnaire. RESULTS: Intake of miso soup, yogurt, and fermented soybeans before pregnancy significantly reduced the risk of early PTB (< 34 weeks). The adjusted odds ratio (OR) for early PTB in women who had miso soup 1-2 days/week, 3-4 days/week, or ≥ 5 days/week were 0.58, 0.69, and 0.62, respectively, compared with those who had miso soup < 1 day/week (95% confidence interval (CI) 0.40-0.85, 0.49-0.98, and 0.44-0.87). The adjusted OR for early PTB in women who ate yogurt ≥ 3 times/week was 0.62 (95% CI, 0.44-0.87) compared to those who ate yogurt < 1 time/week. The adjusted OR for early PTB in women who ate fermented soybeans ≥ 3 times/week was 0.60 (95% CI, 0.43-0.84) compared to those who ate < 1 time/week. However, the incidence of overall PTB and late PTB (34-36 weeks) was not associated with fermented food intake. CONCLUSION: PTB low-risk women with a high consumption of miso soup, yogurt, and fermented soybeans before pregnancy have a reduced risk of early PTB.

A Yolk Sac Larger Than 5 mm Suggests an Abnormal Fetal Karyotype, Whereas an Absent Embryo Indicates a Normal Fetal Karyotype.

OBJECTIVES: It is very hard to estimate an abnormal or normal fetal karyotype in miscarriage before surgery. We investigated whether the abnormal fetal karyotype in early miscarriage could be estimated by comprehensive ultrasonographic findings by a multivariate analysis. METHODS: One hundred fifty-one patients with early miscarriage (<12 weeks' gestation) were selected in our hospital. The clinical characteristics were compared between pregnant women carrying a fetus with an abnormal karyotype and those with a normal one, and the size and configuration of the gestational sac, yolk sac, and embryo at diagnosis of early miscarriage were also evaluated. RESULTS: The rate of abnormal fetal karyotypes was 66.2 % (100 of 151). A maternal age older than 35 years (odds ratio, 3.2; 95% confidence interval, 1.4-7.4; P = .005), yolk sac larger than 5 mm (odds ratio, 6.2; 95% confidence interval, 2.2-22.7, P < .001), and absent embryo (odds ratio, 0.40; 95% confidence interval, 0.16-0.95; P = .038) were independent markers for predicting an abnormal fetal karyotype by multiple logistic regression analysis. CONCLUSIONS: At the point of early miscarriage diagnosis, a yolk sac larger than 5 mm suggests an abnormal fetal karyotype, whereas an absent embryo indicates a normal fetal karyotype.

In which preterm labor-patients is intravenous maintenance tocolysis effective?

AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear.

Effectiveness of Helicobacter pylori eradication in pregnant women with idiopathic thrombocytopenic purpura.

Platelet counts increase after eradication of Helicobacter pylori (Hp) infection in non-pregnant patients with Hp-associated idiopathic thrombocytopenic purpura (ITP); however, improvement in pregnant patients has not yet been reported. We treated four pregnant women for Hp-positive ITP after Hp eradication. In three of four cases, platelet counts increased to levels exceeding 10 × 109 /L two weeks after eradication, and these levels were maintained until delivery. Vaginal deliveries were uncomplicated, and no excessive blood loss occurred in any of the cases. There were no remarkable side effects of Hp eradication in pregnant women or fetuses. In pregnant women with Hp-associated ITP, Hp eradication might be worthwhile prior to considering steroid administration.

Calcium concentration in hypoxic-ischemic encephalopathy during hypothermia.

BACKGROUND: The aim of this study was to investigate the relationship between prognosis and the changes in serum-ionized calcium concentration in neonates with hypoxic-ischemic encephalopathy (HIE) before and during brain hypothermia (BHT). METHODS: Serum samples were obtained from 16 HIE neonates who underwent BHT. All patients underwent developmental testing at 18 months of age. RESULTS: Mean serum-ionized calcium concentration in the poor outcome group (developmental quotient [DQ], <80; nine infants) was significantly lower than in the good outcome group (DQ >80; seven infants), both immediately before and after 6 h of BHT. Mean serum-ionized calcium concentration significantly decreased in both groups for 6 h, and the lowest adjusted serum-ionized calcium during 6 h of BHT was <1.05 mmol/L, known as the cut-off value for poor outcome, in 57.1% of the good outcome group. CONCLUSION: The influx of calcium into cells continues regardless of neurological prognosis during the early phase of BHT, but BHT might protect some high-risk patients against neurological damage at low adjusted serum-ionized calcium concentration.

Multiple pregnancy, short cervix, part-time worker, steroid use, low educational level and male fetus are risk factors for preterm birth in Japan: a multicenter, prospective study.

AIM: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy. METHODS: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8⁺° to 12⁺6 weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed. RESULTS: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation. CONCLUSION: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth.

Outcomes of surgery in lung cancer patients with schizophrenia.

PURPOSE: There are very few reports regarding the outcome of lung cancer surgery in patients with schizophrenia, and the clinical features of such patients are still unclear. METHODS: From 2004 to 2012, 11 lung cancer patients (six male, five female; mean age, 62.7 years) with schizophrenia underwent lung resections at our institutions. All patients had been institutionalized because they were unable to live independently at home. We retrospectively evaluated their postoperative clinical outcomes and long-term results. RESULTS: Ten of the 11 patients had comorbidities, such as diabetes mellitus and chronic obstructive pulmonary disease. Preoperatively, two patients had a history of treatment for other primary cancers in other organs, and one was on hemodialysis. A lobectomy was performed in nine patients, a segmentectomy in one, and a partial resection in one. There were no hospital deaths. The postoperative morbidity included two cases of pneumonia, one of atelectasis, and one of prolonged air leakage lasting more than 7 days. Wandering was postoperatively observed in two patients; one of these fell and fractured the left femur. At the time of our investigation, two patients were deceased, and the overall 5-year survival rate was 74.1 %. CONCLUSIONS: The postoperative morbidity and long-term results of schizophrenic patients with lung cancer were acceptable. Therefore, even in patients with schizophrenia, surgical treatment for lung cancer should be recommended when deemed to be necessary.

Management of a pregnant woman with a large cervical polyp and moderate genital bleeding in the first trimester.

Polypectomy during pregnancy is known to be a risk for spontaneous late miscarriage or preterm delivery. We managed a pregnant woman in her 30s with a large cervical polyp without polypectomy, and we administered probiotics including Clostridium butyricum and 17-alpha-hydroxyprogesterone caproate. As a result, she delivered a healthy baby at 38 weeks.

Immunological regulation and the role of autophagy in preeclampsia.

Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.

Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts.

Inhibition of autophagy contributes to the pathophysiology of preeclampsia. Although chloroquine (CHQ) is an autophagy inhibitor, it can reduce the occurrence of preeclampsia in women with systemic lupus erythematosus. To clarify this important clinical question, this study aimed to address the safety of CHQ in trophoblast cells from the viewpoint of homeostasis, in which the anti-oxidative stress (OS) response and autophagy are involved. We used Western blotting to evaluate the protein levels in the trophoblast cells. The expression levels of heme oxygenase-1 (HO-1), an anti-OS enzyme, mediate resistance to OS induced by hydrogen peroxide (H2O2) in trophoblast cell lines. Among the autophagy modulators, bafilomycin A1 (BAF), an autophagy inhibitor, but not autophagy activators, suppressed HO-1 expression in BeWo cells; CHQ did not suppress HO-1 expression in BeWo cells. To clarify the role of autophagy in HO-1 induction, we observed no difference in HO-1 induction by H2O2 between autophagy-normal and autophagy-deficient cells. As for the mechanism of HO-1 induction by OS, BAF suppressed HO-1 induction by downregulating the expression of neighbor of BRCA1 gene 1 (NBR1) in the selective p62-NBR1-nuclear factor erythroid 2-related factor 2 (Nrf2) autophagy pathway. CHQ did not inhibit HO-1 expression by sustaining NBR1 expression in human villous tissues compared to BAF treatment. In conclusion, CHQ is a safer medicine than BAF for sustaining NBR1, which resist against OS in trophoblasts by connecting selective autophagy and the anti-OS response.

The Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field.

Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field.