Uterine contraction may not be an independent risk factor for spontaneous preterm birth before 35 weeks in women with cervical shortening.

OBJECTIVE: To compare the risk of spontaneous preterm birth (SPTB) before 35 weeks in symptomatic and asymptomatic women with cervical shortening at 16-34 weeks under mid-trimester universal screening of cervical length (CL). METHOD: Multicenter retrospective cohort study involving six secondary/tertiary perinatal centers was planned in 2016. Primary outcomes were SPTB before 35 weeks. In all, 407 women were analyzed using multivariable logistic regression analysis for predicting SPTB before 35 weeks while adjusting for presence/absence of uterine contraction, gestational weeks, vaginal bleeding, and CL classification (1-9, 10-14, 15-19, and 20-24 mm) at admission, the execution of cervical cerclage, and the presence/absence of past history of preterm delivery. RESULTS: SPTB before 35 weeks of pregnancy occurred in 14.5%. Presence of uterine contraction was not an independent risk factor for SPTB before 35 weeks (adjusted odds ratio [aOR] 1.22, 95% confidence interval [CI] 0.67-2.20). CL of 1-9 mm, CL of 10-14 mm, and vaginal bleeding at admission were independent risk factors for SPTB before 35 weeks (aOR 5.35, 95% CI 2.11-13.6; aOR 2.79, 95% CI 1.12-6.98; and aOR 2.37, 95% CI 1.12-5.10, respectively). CONCLUSION: In women with a cervical shortening at 16-34 weeks, presence of uterine contractions at admission may not be an independent risk factor for the occurrence of SPTB before 35 weeks.

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.

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.

New geological and palaeontological age constraint for the gorilla-human lineage split.

The palaeobiological record of 12 million to 7 million years ago (Ma) is crucial to the elucidation of African ape and human origins, but few fossil assemblages of this period have been reported from sub-Saharan Africa. Since the 1970s, the Chorora Formation, Ethiopia, has been widely considered to contain ~10.5 million year (Myr) old mammalian fossils. More recently, Chororapithecus abyssinicus, a probable primitive member of the gorilla clade, was discovered from the formation. Here we report new field observations and geochemical, magnetostratigraphic and radioisotopic results that securely place the Chorora Formation sediments to between ~9 and ~7 Ma. The C. abyssinicus fossils are ~8.0 Myr old, forming a revised age constraint of the human-gorilla split. Other Chorora fossils range in age from ~8.5 to 7 Ma and comprise the first sub-Saharan mammalian assemblage that spans this period. These fossils suggest indigenous African evolution of multiple mammalian lineages/groups between 10 and 7 Ma, including a possible ancestral-descendent relationship between the ~9.8 Myr old Nakalipithecus nakayamai and C. abyssinicus. The new chronology and fossils suggest that faunal provinciality between eastern Africa and Eurasia had intensified by ~9 Ma, with decreased faunal interchange thereafter. The Chorora evidence supports the hypothesis of in situ African evolution of the Gorilla-Pan-human clade, and is concordant with the deeper divergence estimates of humans and great apes based on lower mutation rates of ~0.5 × 10(-9) per site per year (refs 13 - 15).

[Emergency medicine for pregnant women].

Emergency medicine for pregnant women should be treated basically as same as non-pregnant women but there are many characteristic change to be considered. Some of the pregnancy-related diseases may bring them critical condition. Massive postpartum hemorrhage is one of the most important and life-threatening events for them and so are stroke and thromboembolism. Multidisciplinary practice is indispensable for taking good care of the pregnant women in emergent situation. Every person who may take part in emergency medicine should understand the protocol and wide area medical care cooperation should be maintained.

Safety and efficacy of preoperative autologous blood donation for high-risk pregnant women: experience of a large university hospital in Japan.

AIM: Preoperative autologous blood donation (PAD) has the advantages over allogeneic blood transfusion of theoretically no risk of viral infection and alloimmunization. However, there are some concerns regarding PAD in pregnant women, as they sometimes become anemic and adverse effects such as low blood pressure could be harmful to fetuses. In our hospital, the PAD program was implemented in 2006 and has been used in pregnant women at high risk of massive hemorrhage. In this study, the safety of PAD in pregnant women and its efficacy for avoiding allogeneic blood transfusion were investigated. METHODS: The hospital records of pregnant women who delivered at our hospital from January 2009 to June 2012 were reviewed and those who were enrolled in the PAD program for predicted massive hemorrhage were analyzed. RESULTS: Among the total of 3095 deliveries, 69 cases enrolled in the PAD program were analyzed. Blood donation was performed 189 times for the 69 cases. The median donated blood volume was 1200 mL (range, 400-2000). The mean blood loss during delivery was 1976 ± 1654 mL. Autologous blood was transfused in 64 cases. Allogeneic blood transfusion was required in five cases of massive blood loss exceeding 5000 mL. In the other 64 cases, no additional allogeneic blood transfusion was required. No adverse events were observed in either the pregnant women or fetuses. CONCLUSION: For pregnant women at a high risk of massive hemorrhage, our PAD program was safe and effective for avoiding allogeneic blood transfusion.

The role of alloantibodies against human platelet antigen-15 in multiply platelet transfused patients.

BACKGROUND: Several studies have documented the role of antibodies against human platelet (PLT) antigen (HPA)-15 in alloimmune-mediated thrombocytopenia including neonatal alloimmune thrombocytopenia, PLT transfusion refractoriness (PTR), and posttransfusion purpura in Caucasian persons. However, the relevance of anti-HPA-15 in PTR among the Japanese population is still unclear. STUDY DESIGN AND METHODS: The sera of 305 multiply PLT transfused (MPT) patients, previously investigated for the presence of human leukocyte antigen (HLA) and HPA antibodies by mixed passive hemagglutination, were reexamined for the presence of HPA-15 alloantibodies, using the monoclonal antibody-specific immobilization of PLT antigens (MAIPA) technique. RESULTS: Among the 305 MPT samples, antibodies against HPA-15 alloantigen was detected in seven (2.3%), two (0.66%) being anti-HPA-15a and five (1.64%) being anti-HPA-15b. Additionally, one case of CD109 panreactive antibody was found (0.33%). Among them, one aplastic anemia patient with blood group O developed multispecific anti-HLA and anti-HPA-15b alloantibody after MPTs. However, transfusion with HLA-matched PLTs of blood group AB did not result in adequate PLT count increment. Analysis of the possible influence of immune anti-A and anti-B by the MAIPA assay resulted negative, indicating that anti-HPA-15b is responsible for the refractory state in this patient. CONCLUSION: In this study, we found alloimmunization against HPA-15a and -15b in Japanese populations and demonstrated the relevance of these antibodies in a patient with PTR.

Cardiac magnetic resonance imaging in a patient with amniotic fluid embolism associated with severe cardiopulmonary complications.

Amniotic fluid embolism (AFE) is a rare but devastating complication of pregnancy. Acute circulatory failure and obstetric disseminated intravascular coagulopathy are often associated with AFE and lead to poor prognosis of this syndrome. Although many reports of AFE and its cardiopulmonary complications exist, their etiology remains unknown. Classically, it was believed that the fatal cardiopulmonary complication in AFE is due to acute and severe pulmonary hypertension caused by critical obstruction of the pulmonary vessels by embolized amniotic fluid. However, recent hypotheses are suggesting that anaphylactic reaction or a cytokine effect induced by amniotic fluid is the main pathophysiological mechanism. We report a case in which cardiac magnetic resonance imaging was performed at the chronic stage of AFE. Late gadolinium enhancement (LGE) was detected at the mid-wall of the left ventricle with no evidence of pulmonary hypertension. This finding suggests that the pathophysiological mechanism of severe cardiac complications in AFE may include direct left ventricular myocardial injury through an immune reaction or cytokine release, rather than pulmonary embolism.

Introduction of a new index of cervical consistency with transvaginal B-mode ultrasonography.

Changes in the length and consistency of the uterine cervix during pregnancy are known to precede pre-term labor. However, cervical consistency has not been studied in depth because its objective evaluation requires special equipment. Our aim was to define a new index to evaluate cervical consistency simply and easily using B-mode ultrasonography. The cervical length-consistency index (CLCI) is defined as the ratio of the length of the cervix stretched during compression to that before compression. CLCI increases as pregnancy progresses. The CLCI values that corresponded to digital examination results of firm, medium and soft were 112.0 ± 10.0, 124.1 ± 22.4 and 153.2 ± 35.7, respectively, thus confirming the existence of a significant relationship between the index and consistency. The CLCI may be useful in predicting pre-term labor and should therefore be investigated further in larger cohorts.

Diagnosis of anal sphincter defects by three-dimensional transperineal ultrasound in women with anal incontinence.

PURPOSE: To assess the utility of transperineal three-dimensional (3D) ultrasound for diagnosing anal sphincter defects and evaluating the function of the anal canal in women with anal incontinence. METHODS: The study subjects were 13 women with anal incontinence. Symptoms of fecal incontinence were assessed by Wexner score. The anal canal of each woman was examined ultrasonically with both a convex transperineal 3D scanner and a radial transanal scanner to compare the accuracy of the two approaches for diagnosis of anal sphincter defects. The anorectal angle and the length of the anal canal were also measured by utilizing the functionality of the transperineal 3D ultrasound. RESULTS: The mean age was 58.9 ± 14.9 years (±SD), and the mean Wexner score was 8.4 ± 5.6. In terms of ultrasound diagnosis of anal sphincter defects, the two methods showed consistent results in each woman. The length of the portion where both the internal and external anal sphincters were intact was significantly correlated with the Wexner score, whereas the total length of the anal canal was not. CONCLUSIONS: Less invasive transperineal 3D ultrasound provides accurate evaluation of the internal and external anal sphincters in women with anal incontinence, and the method is potentially useful for detection of anal sphincter abnormalities.

A possible coagulation-independent mechanism for pregnancy loss involving ß(2) glycoprotein 1-dependent antiphospholipid antibodies and CD1d.

PROBLEM ß(2) glycoprotein1 (ß(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-ß(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound ß(2) GP1. Anti-ß(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-ß2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-ß2GP1 mAbs. CONCLUSIONS ß(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.

Prediction model for the incidence of emergent cesarean section during induction of labor specialized in nulliparous low-risk women.

AIM: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS). MATERIAL AND METHODS: By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed. RESULTS: The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) ∗ 100, odds = e(X) and X = 8.18 + 1.23 ∗ BW (kg)- 7.74 ∗ MH (m)- 0.253 ∗ BS. CONCLUSION: This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome.

A case of vasa previa diagnosed prenatally, and review of the literature.

The perinatal mortality rate of vasa previa is high if it is not prenatally diagnosed. In this report, a case of vasa previa diagnosed prenatally is presented. Antepartum hemorrhage at 24 weeks of gestation prompted a close investigation of the uterine cervix, internal os, and placenta. We detected a low-lying bilobed placenta with umbilical cord insertion in the lower uterine segment. Furthermore, one of the connecting vessels of the bilobed placenta passed directly above the internal os. Vasa previa was suspected and confirmed with color Doppler and MRI. The fetus was delivered uneventfully by planned Cesarean section at 38 weeks of gestation. It should be considered that placenta previa (including low-lying placenta), bilobed placenta, and umbilical cord insertion in the lower uterine segment are associated with high risk of vasa previa. Ultrasound screening for cord insertion and placenta around the internal os enables efficient and certain detection of vasa previa.

Expression of autotaxin, an ectoenzyme that produces lysophosphatidic acid, in human placenta.

PROBLEM: Lysophosphatidic acid (LPA) is a bioactive lipid mediator and thought to play an important role in pregnancy. Plasma LPA is produced by autotaxin (ATX), and ATX activity in plasma increases during pregnancy paralleled with gestational weeks and decreases to near the non-pregnant level soon after delivery. However, the source of increased ATX during pregnancy is still uncertain. We hypothesized that the source of increased ATX might be placenta. METHOD OF STUDY: We investigated the protein and mRNA expression of ATX in human placenta using immunohistochemistry and RT-PCR, respectively. RESULTS: At all 3 gestational trimesters, immunohistochemical staining for placenta tissues revealed the most marked positive staining of ATX protein in trophoblasts. Real-time PCR revealed that mRNA amounts of ATX in placenta tissues paralleled with gestational weeks, i.e. ATX level in plasma. CONCLUSION: These findings suggest that trophoblasts might produce ATX and its bioactive resultant substance, LPA, paralleled with gestational weeks.

Effect of progesterone on HLA-E gene expression in JEG-3 choriocarcinoma cell line.

PROBLEM: Among class Ib human leukocyte antigen (HLA) molecules, HLA-E is known to be a major ligand of CD94/NKG2 receptor on natural killer (NK) cells, and to play a pivotal role in recognition of extravillous trophoblasts (EVTs) by maternal immune cells. However, it is scarcely known how HLA-E expression is regulated in EVTs. METHOD OF STUDY: In this study, we investigated whether progesterone, an essential hormone in maintaining pregnancy, regulated HLA-E expression in EVT-like cell line, JEG-3. HLA-E mRNA amount in cultured JEG-3 cells was assessed by real-time PCR and cell-surface HLA-E protein was analyzed by flowcytometry. RESULTS: Real-time PCR showed 3.5-fold increase 1 hour after the addition of 1000 ng/ml progesterone. This response was diminished by the addition of RU486, an antagonist for progesterone receptor. Flowcytometry indicated that 1000 ng/ml progesterone slightly enhanced HLA-E expression on the surface of JEG-3. CONCLUSION: These results suggest that progesterone up-regulates HLA-E expression in JEG-3 cells through the pathway mediated by progesterone receptor. Our findings might give a new insight into immunomodulatory function of progesterone at fetomaternal interface.