Association between adenomyosis and placenta accreta and mediation effect of assisted reproductive technology on the association: A nationwide observational study.

OBJECTIVES: To investigate the association between adenomyosis and placenta accreta spectrum (PAS) and to evaluate the effect of assisted reproductive technology (ART) in mediating this association. METHODS: We retrieved data for singleton women from the Japanese nationwide perinatal registry between 2013 and 2019, excluding women with a history of adenomyomectomy. To investigate the association between adenomyosis and PAS among women, we used a multivariable logistic regression model with multiple imputation for missing data. We evaluated mediation effect of ART including in vitro fertilization and intracytoplasmic sperm injection on the association between adenomyosis and PAS using causal mediation analysis based on the counterfactual approach. RESULTS: Of 1 500 173 pregnant women, 1539 (0.10%) had adenomyosis. The number receiving ART was 489/1539 (31.8%) and 117 482/1 498 634 (7.8%) in women with and without adenomyosis, respectively. The proportion of women who developed PAS was 21/1539 (1.4%) in women with adenomyosis and 7530/1 498 634 (0.5%) in women without adenomyosis. Adenomyosis was significantly associated with PAS (odds ratio [OR] 1.95; 95% confidence interval [CI] 1.26-3.00; P = 0.002). Mediation analysis showed that OR of the total effect of adenomyosis on PAS was 1.98 (95% CI 1.13-3.04), OR of natural indirect effect (effect explained by ART) was 1.15 (95% CI 1.01-1.41), and OR of natural direct effect (effect unexplained by ART) was 1.72 (95% CI 0.86-2.82). The proportion mediated (natural indirect effect/total effect) was 26.5%. Adenomyosis was also significantly associated with PAS without previa (OR 1.96; 95% CI 1.23-3.13, P = 0.005). CONCLUSION: Adenomyosis was significantly associated with PAS. ART mediated 26.5% of the association between adenomyosis and PAS.

Clinical relevance of reversible cerebral vasoconstriction syndrome in pregnant women with posterior reversible encephalopathy syndrome: review of case reports in Japan.

We systematically reviewed case reports of posterior reversible encephalopathy syndrome (PRES), and investigated the characteristics of PRES in pregnant Japanese women and the clinical relevance of reversible cerebral vasoconstriction syndrome (RCVS) in pregnant women with PRES. Articles were collected using the PubMed/Medline and Ichushi-Web databases. This review was ultimately conducted on 121 articles (162 patients). The clinical characteristics of PRES, individual sites of PRES lesions, edema types, and clinical characteristics of RCVS in PRES cases were examined. The most common individual site of PRES lesion was the occipital lobe (83.3%), followed by the basal ganglia, parietal lobe, frontal lobe, brain stem, cerebellum, temporal lobe, thalamus, and splenium corpus callosum (47.5, 42.6, 24.7, 16.1, 9.3, 5.6, 4.3, and 0.0%, respectively). Edema types in 79 cases with PRES were mainly the vasogenic edema type (91.1%), with very few cases of the cytotoxic edema type (3.8%) and mixed type (5.1%). Among 25 PRES cases with RCVS, RCVS was not strongly suspected in 17 (68.0%) before magnetic resonance angiography. RCVS was observed at the same time as PRES in 13 cases (approximately 50%), and between days 1 and 14 after the onset of PRES in the other 12. These results suggest that the basal ganglia is a frequent site of PRES lesions in pregnant women. RCVS may occur at or after the onset of PRES, even if there are no symptoms to suggest RCVS.

BeWo exomeres are enriched for bioactive extracellular placenta-specific C19MC miRNAs.

Extracellular vesicles (EVs), including exosomes, are carriers of extracellular microRNAs (miRNAs). Exomeres, non-vesicular extracellular nanoparticles (NVEPs), are novel extracellular cargo carriers. However, little is known of the characteristics of placental trophoblast-derived exomeres. In this study, we characterized trophoblast-derived exomeres and investigated the cell-cell communication of placenta-specific miRNAs carried by those exomeres using an in vitro model system (BeWo trophoblasts and Jurkat T cells). BeWo exomeres (∼ 40 nm diameter) had pilling-like nanoparticle structures, which were distinct from cup-shaped exosomes (∼ 90-110 nm diameter). BeWo cells secreted more exomeres than exosomes. Exomeres were positive for AGO2 but negative for exosome markers (CD63, CD9, CD81, FLOT1, and TSG101). The levels of placenta-specific miRNAs in exomeres were significantly higher than in exosomes. In a cell-cell communication analysis using a placenta-specific miRNA, BeWo exomeres delivered significantly more miR-517a-3p to recipient Jurkat cells compared with exosomes. Moreover, exomere-miR-517a-3p significantly reduced the expression of PRKG1 in miR-517a-3p-inhibitor (-) Jurkat cells compared with miR-517a-3p-inhibitor (+) cells, suggesting that miR-517a-3p inhibition reversed the exomere-miR-517a-3p-mediated repression of PRKG1 expression in recipient cells. Therefore, BeWo trophoblast exomeres are enriched with bioactive extracellular placenta-specific miRNAs, which were formerly considered to be carried by exosomes. Our findings provide insight into trophoblast-derived NVEPs.

Cytoplasmic and nuclear DROSHA in human villous trophoblasts.

In villous trophoblasts, DROSHA is a key ribonuclease III enzyme that processes pri-microRNAs (pri-miRNAs) into pre-miRNAs at the placenta-specific, chromosome 19 miRNA cluster (C19MC) locus. However, little is known of its other functions. We performed formaldehyde crosslinking, immunoprecipitation, and sequencing (fCLIP-seq) analysis of terminal chorionic villi to identify DROSHA-binding RNAs in villous trophoblasts. In villous trophoblasts, DROSHA predominantly generated placenta-specific C19MC pre-miRNAs, including antiviral C19MC pre-miRNAs. The fCLIP-seq analysis also identified non-miRNA transcripts with hairpin structures potentially capable of binding to DROSHA (e.g., SNORD100 and VTRNA1-1). Moreover, in vivo immunohistochemical analysis revealed DROSHA in the cytoplasm of villous trophoblasts. DROSHA was abundant in the cytoplasm of villous trophoblasts, particularly in the apical region of syncytiotrophoblast, in the full-term placenta. Furthermore, in BeWo trophoblasts infected with Sindbis virus (SINV), DROSHA translocated to the cytoplasm and recognized the genomic RNA of SINV. Therefore, in trophoblasts, DROSHA not only regulates RNA metabolism, including the biogenesis of placenta-specific miRNAs, but also recognizes viral RNAs. After SINV infection, BeWo DROSHA-binding VTRNA1-1 was significantly upregulated, and cellular VTRNA1-1 was significantly downregulated, suggesting that DROSHA soaks up VTRNA1-1 in response to viral infection. These results suggest that the DROSHA-mediated recognition of RNAs defends against viral infection in villous trophoblasts. Our data provide insight into the antiviral functions of DROSHA in villous trophoblasts of the human placenta.

Automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation predicts preterm preeclampsia: a retrospective cohort study.

Our aims were to obtain the gestational-age-specific median of common logarithmic placental growth factor (PlGF) values in the first trimester in women with a singleton pregnancy in order to generate the gestational-age-specific multiple of the median (MoM) of log10PlGF at 9-13 weeks of gestation, to evaluate screening parameters of MoM of log10PlGF at 9-13 weeks of gestation to predict preterm preeclampsia (PE), and to construct an appropriate prediction model for preterm PE using minimum risk factors in multivariable logistic regression analyses in a retrospective sub-cohort study. Preterm PE occurred in 2.9% (20/700), and PE in 5.1% (36/700). Serum PlGF levels were measured using Elecsys PlGF®. MoMs of log10PlGF at 9-13 weeks of gestation in Japanese women with a singleton pregnancy followed a normal distribution. We determined the appropriate cut-off value of MoM of log10PlGF to predict preterm PE at around a10% false-positive rate (0.854). The MoM of log10PlGF < 0.854 yielded sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (95% confidence interval [CI]), and negative likelihood ratio (95% CI) of 55.0%, 91.9%, 17.5%, 98.5%, 6.79 (4.22-10.91), and 0.49 (0.30-0.80), respectively. The combination of MoM of log10PlGF and presence of either chronic hypertension or history of PE/gestational hypertension (GH) yielded sensitivity and specificity of 80.0 and 85.7%, respectively, to predict preterm PE. In conclusion, the automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation may be useful to predict preterm PE.

Uterine cervical conisation and chorioamnionitis: A nationwide observational study.

OBJECTIVE: To investigate whether conisation increases chorioamnionitis (CAM) and assess whether this risk differs between preterm and term periods. Furthermore, we estimated mediation effects of CAM between conisation and preterm birth (PTB). DESIGN: A nationwide observational study. SETTING: Japan. POPULATION: Singleton pregnant women derived from the perinatal registry database of the Japan Society of Obstetrics and Gynaecology between 2013 and 2019. METHODS: The association between a history of conisation and clinical CAM was examined using a multivariable logistic regression model with multiple imputation. We conducted mediation analysis to estimate effects of CAM on PTB following conisation. MAIN OUTCOME MEASURES: Clinical CAM. RESULTS: Of 1 500 206 singleton pregnant women, 6961 (0.46%) underwent conisation and 1 493 245 (99.5%) did not. Clinical CAM occurred in 150 (2.2%) and 11 484 (0.8%) women with and without conisation, respectively. Conisation was associated with clinical CAM (odds ratio [OR] 3.09; 95% confidence interval (CI) 2.63-3.64; p < 0.001) (risk difference 1.57%; 95% CI 1.20-1.94). The association was detected among 171 440 women with PTB (OR 3.09; 95% CI 2.57-3.71), whereas it was not significant among 1 328 284 with term birth (OR 0.88; 95% CI 0.58-1.34). OR of total effect of conisation on PTB was 2.71, OR of natural indirect effect (effect explained by clinical CAM) was 1.04, and OR of natural direct effect (effect unexplained by clinical CAM) was 2.61. The proportion mediated was 5.9%. CONCLUSIONS: Conisation increased CAM occurrence. Obstetricians should be careful regarding CAM in women with conisation, especially in preterm period. Bacterial infections may be an important cause of PTB after conisation.

Maternal outcomes of placental abruption with intrauterine fetal death and delivery routes: A nationwide observational study.

INTRODUCTION: Placental abruption is a serious complication, especially when accompanied by intrauterine fetal death. The optimal delivery route for placental abruption with intrauterine fetal death for reducing maternal complications is still unclear. In this study we aimed to compare the maternal outcomes between cesarean delivery and vaginal delivery in women with placental abruption with intrauterine fetal death. MATERIAL AND METHODS: Using the Japan Society of Obstetrics and Gynecology nationwide perinatal registry database, we identified pregnant women with placental abruption with intrauterine fetal death between 2013 and 2019. The following women were excluded: those with multiple pregnancies, placenta previa, placenta accreta spectrum, amniotic fluid embolism, or whose delivery route was missing data. The association between delivery routes (cesarean delivery and vaginal delivery) and the maternal outcome was examined using a linear regression model with inverse probability weighting. The primary outcome was the amount of bleeding during delivery. Missing data were imputed using multiple imputation. RESULTS: The number of women with placental abruption with intrauterine fetal death was 1218/1601932 (0.076%). Of 1134 women analyzed, 608 (53.6%) underwent cesarean delivery. Bleeding during delivery (median [interquartile range]) was 1650.00 (950.00-2450.00) (mL) and 1171.00 (500.00-2196.50) (mL) in cesarean and vaginal delivery, respectively. Bleeding during delivery (mL) was significantly greater in cesarean delivery than in vaginal delivery (regression coefficient, 1086.39; 95% confidence interval, 130.96-2041.81; p = 0.026). Maternal death and uterine rupture occurred in four (0.4%) and five (0.4%) women, respectively. The four maternal deaths were noted in the vaginal delivery group. CONCLUSIONS: Bleeding during delivery was significantly greater in cesarean delivery than that in vaginal delivery in women with placental abruption with intrauterine fetal death. However, severe complications, including maternal death and uterine rupture, occurred in vaginal delivery-related cases. The management of women with placental abruption with intrauterine fetal death should be cautious regardless of the delivery route.

Placental Insertion into the Cervix with Cervical Shortening as a Clinical Sign to Suspect Cervico-Isthmic Pregnancy: A Case Report and Literature Review.

The clinical signs of cervico-isthmic pregnancy during pregnancy remain unknown. We herein report a case of cervico-isthmic pregnancy showing placental insertion into the cervix with cervical shortening, with a final diagnosis of placenta increta at the uterine body and cervix. A 33-year-old multiparous woman with a history of cesarean section was referred to our hospital at 7 weeks of gestation with suspected cesarean scar pregnancy. Cervical shortening with a cervical length of 14 mm was noted at 13 weeks of gestation. The placenta is gradually inserted into the cervix. An ultrasonographic examination and magnetic resonance imaging strongly suggested placenta accreta. We planned elective cesarean hysterectomy at 34 weeks of gestation. The pathological diagnosis was cervico-isthmic pregnancy with placenta increta at the uterine body and cervix. In conclusion, placental insertion into the cervix with cervical shortening in the early pregnancy period may be a clinical sign to suspect cervico-isthmic pregnancy.

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.

Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

Non-Coding RNAs and Prediction of Preeclampsia in the First Trimester of Pregnancy.

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The only fundamental treatment for PE is the termination of pregnancy. Therefore, not only severe maternal complications but also perinatal complications due to immaturity of the infant associated with early delivery are serious issues. The treatment and prevention of preterm onset preeclampsia (POPE) are challenging. In 2017, the ASPRE trial showed that a low oral dose of aspirin administered to POPE high-risk women in early pregnancy reduced POPE by 62%. A prediction algorithm at 11-13 weeks of gestation identifies POPE with 75% sensitivity when the false positive rate is set at 10%. New biomarkers to increase the accuracy of the prediction model for POPE high-risk women in early pregnancy are needed. In this review, we focused on non-coding RNAs (ncRNAs) as potential biomarkers for the prediction of POPE. Highly expressed ncRNAs in the placenta in early pregnancy may play crucial roles in placentation. Furthermore, placenta-specific ncRNAs have been detected in maternal blood. In this review, we summarized ncRNAs that were highly expressed in the primary human placenta in early pregnancy. We also presented highly expressed ncRNAs in the placenta that were associated with or predictive of the development of PE in an expression analysis of maternal blood during the first trimester of pregnancy. These previous studies showed that the chromosome 19 microRNA (miRNA) -derived miRNAs (e.g., miR-517-5p, miR-518b, and miR-520h), the hypoxia-inducible miRNA (miR-210), and long non-coding RNA H19, were not only highly expressed in the early placenta but were also significantly up-regulated in the blood at early gestation in pregnant women who later developed PE. These maternal circulating ncRNAs in early pregnancy are expected to be possible biomarkers for POPE.

Bleeding-related outcomes of low-risk total placenta previa are equivalent to those of partial/marginal placenta previa.

OBJECTIVE: To clarify whether "low-risk total PP" patients bleed more than partial/marginal PP patients. MATERIALS AND METHODS: The retrospective cohort study was performed involving patients with PP between April 2006 and December 2018. The placental position was determined by ultrasound. From medical charts, the backgrounds as well as obstetric and neonatal outcomes of PP patients were retrieved. RESULTS: This study included 349 patients with PP, which was classified into three types according to the distance between the placenta and internal ostium: total (n = 174), partial (n = 52), and marginal (n = 123) PP. In total PP patients, three factors (prior CS, anterior placenta, and placental lacunae on ultrasound) significantly increased blood loss at CS, the need for hysterectomy, homologous transfusion (≥10 U), and ICU admission. No significant difference was observed in bleeding-related poor outcomes (rate of blood loss ≥2000 mL, amount of homologous transfusion, need for hysterectomy, and ICU admission) between total PP patients without all three factors: "low-risk total PP patients" and partial/marginal PP patients (19.8 vs. 17.1%; p = 0.604, 3.7 vs. 1.1%; p = 0.330, 1.2 vs. 1.1%; p = 1.000, and 1.2 vs. 1.1%; p = 1.000, respectively). CONCLUSION: Prior CS, anterior placenta, and placental lacunae on ultrasound were risk factors for a bleeding-related poor outcome in total PP patients. Total PP patients without these three factors showed the same bleeding-related poor outcome as partial/marginal PP patients.

Elevated S100A9 in preeclampsia induces soluble endoglin and IL-1ß secretion and hypertension via the NLRP3 inflammasome.

OBJECTIVES: Maternal systemic and placental inflammatory responses participate in the pathogenesis of hypertensive disorders of pregnancy including preeclampsia, a pregnancy-specific syndrome, although the role of inflammation remains unclear. The NLRP3 inflammasome has been implicated in the control of sterile inflammation involved in preeclampsia. In the present study, we hypothesized that S100A9, as major alarmin, are associated with the pathogenesis of preeclampsia and induction of a preeclampsia-like phenotype in pregnant mice. METHODS: Plasma were taken from normal pregnant women and preeclampsia patients. Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical vein endothelial cells (HUVEC) were treated with S100A9 with or without inhibitors associated with NLRP3 inflammasome. Pregnant mice were administered S100A9. RESULTS: S100A9 was elevated in plasma and released from placentas of preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in IL-1ß secretion, by human placental tissues and trophoblasts. In addition, secretion of soluble endoglin, a main contributor to the pathogenesis of preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation in the human placenta and HUVECs. S100A9 administration significantly elevated maternal blood pressure and neutrophil accumulation within the placentas of pregnant mice, and both were significantly decreased in Nlrp3-knock out pregnant mice. CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger signal to activate the NLRP3 inflammasome in the placenta, associating with hypertension during pregnancy.

Effects of prophylactic vaginal progesterone administration on mild cervical shortening (TROPICAL study): a multicenter, double-blind, randomized trial.

Vaginal progesterone reduces the preterm birth frequency among high-risk women with a cervical length ≤25 mm at midtrimester. However, the strategy may promote no substantial reduction in overall preterm birth rates, because such high-risk women are only approximately 2% of all pregnant women, which restrict the number of participants. Our purpose was to determine whether prophylactic vaginal progesterone administration can preserve cervical length and reduce preterm birth rates among women with mild cervical shortening.This multicenter, parallel-arm, double-blind, randomized, placebo-controlled trial involved vaginal progesterone administration (200 mg daily from 16 to 33 weeks of gestation) among asymptomatic women with a singleton pregnancy and a sonographic cervical length of 25 to <30 mm between 16 and 23 weeks of gestation. The primary and secondary endpoints were cervical shortening rates at 34 weeks of gestation and preterm birth rates, respectively. The trial was registered at the University Hospital Medical Information Network (UMIN000013518) in Japan.Between April 2014 and March 2018, 119 women were randomly assigned to the progesterone group (n = 59) and the placebo group (n = 60). No significant differences in the frequency of women with a cervical length ≥20 mm at 34 weeks of gestation were observed between both groups. All preterm births occurred after 34 weeks of gestation, except for one patient in the placebo group. The progesterone group had a lower rate of preterm birth before 37 weeks than the placebo group (3.4% vs. 15.0%, respectively; p < .05).Despite having no effect on preserving cervical length, prophylactic vaginal progesterone administration reduced preterm birth frequency among women with mild cervical shortening. Our results are suggesting that women with mild cervical shortening are at risk for late preterm birth and the need for expanding progesterone treatment indications to include not only high-risk but also low-risk populations.

Hemostatic effect of combined procedures for placenta previa: cervix-holding, intrauterine balloon, and uterine compression suture.

OBJECTIVES: Various procedures have been introduced to achieve hemostasis for postpartum hemorrhage (PPH) in placenta previa (PP). This study attempted to clarify the effectiveness of the combined use of three hemostatic procedures: Matsubara-Takahashi cervix-holding (MT-holding), intrauterine balloon (IUB), and uterine compression suture (UCS). STUDY DESIGN: This was a historical cohort study on the hemostatic effect of combined procedures for patients with placenta previa (PP) undergoing cesarean section between April 2006 and December 2018. Until 2011 (2006-2011), we used MT-holding alone, whereas since 2012 we have also been using IUB and UCS: MT-holding alone was used in the former period whereas three procedures (MT-holding, IUB, UCS, and their combinations) have been used in the latter period. Perinatal outcomes were compared between 2006-2011 (before group) and 2012-2018 (after group). RESULTS: Of 416 patients with PP, excluding 273 patients with cesarean hysterectomy or no hemostatic procedure, the remaining 143 patients were analyzed. In the after group, intraoperative blood loss, the percentage of patients with postoperative blood loss ≥ 500 ml, and incidence of autologous blood transfusion were significantly lower than in the before group. Multivariate analysis showed that postoperative blood loss ≥ 500 ml decreased in the after group (adjusted OR: 0.3, 95%CI: 0.1-0.8, compared with the before group). CONCLUSION: PPH decreased after introducing the combination of hemostatic procedures in patients with PP. Further studies are needed to determine the best combination and optimal indication for combining hemostatic procedures for PP.

Long-term outcome of fetus with ameliorated cystic hygroma.

OBJECTIVE: Cystic hygroma often ameliorates or disappears with pregnancy progression. Fetuses/neonates with amelioration, when without chromosomal or major structural abnormality, generally show a favorable outcome at birth. The present study was aimed to clarify the short/long-term outcomes of fetuses/neonates with the amelioration of cystic hygroma during pregnancy. MATERIAL AND METHODS: This was a retrospective observational study. We focused on fetuses with cystic hygroma managed in our institute between January 2006 and June 2019. The infants were followed by pediatricians (neonatologist, pediatric cardiologist, and pediatric neurologist) and pediatric outcomes were retrieved from the medical records up to 3 years old. RESULTS: One hundred and seven fetuses with cystic hygroma were included. Of the 107, cystic hygromas ameliorated in 31 fetuses (31/107: 29%). Of the 31, there were 26 livebirths. Half (n = 13) of the 26 fetuses had a good outcome, whereas the remaining half (n = 13) had abnormalities. Various abnormalities were detected in their infancies. A nuchal thickness (diameter of hygroma) of ≥5 mm was significantly correlated with abnormalities (P = 0.047). CONCLUSION: Physicians should pay attention to fetuses/neonates with ameliorated cystic hygroma. Of those, special attention should be paid to fetuses/neonates with a nuchal thickness at diagnosis ≥5 mm.

A randomized phase 3 trial evaluating antithrombin gamma treatment in Japanese patients with early-onset severe preeclampsia (KOUNO-TORI study): Study protocol.

INTRODUCTION: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. Several studies have demonstrated the beneficial effects of antithrombin replacement in patients with preeclampsia. Here, we describe the study protocol of KOUNO-TORI (KW-3357 randOmized, mUlti-center, double-bliNd, placebO-controlled phase 3 sTudy in patients with early Onset pReeclampsIa) to evaluate recombinant human antithrombin gamma (rhAT-gamma) for the treatment of early-onset severe de novo preeclampsia. MATERIAL AND METHODS: Patients with early-onset severe de novo preeclampsia who are ≥24 to <32 weeks pregnant at the time of registration and have an antithrombin activity of ≤100% at screening are included. The target population is selected based on a reanalysis of the data of a previous plasma-derived antithrombin phase 3 study. Primary endpoint is the prolongation of pregnancy from the initiation of rhAT-gamma treatment to the pregnancy termination. Secondary endpoints include gestational age in terms of achievement of 32- and 34-weeks'gestation, and gestational age in terms of achievement of 28 weeks' gestation for patients enrolled at <28 weeks' gestation. Maternal, fetal, and neonatal outcomes will be assessed. DISCUSSION: As we have selected a specifically defined target population based on reanalysis of data of a previous plasma-derived antithrombin phase 3 study, the results of our study are expected to provide efficacy and safety data concerning rhAT-gamma treatment in Japanese patients. This study could help identify an effective novel treatment for such patients with early-onset severe preeclampsia for whom appropriate treatment is unavailable.

Expectant management of retained products of conception following abortion: A retrospective cohort study.

OBJECTIVE: To clarify the natural history of retained products of conception (RPOC) following abortion at less than 22 weeks of gestation, and those who show major bleeding during course observation. STUDY DESIGN: We retrospectively reviewed 640 patients who had spontaneous or artificial abortion at less than 22 weeks of gestation between January 2011 and August 2019 in our institute. Of those, patients with RPOC were included. The maternal background, RPOC characteristics, and subsequent complications including additional interventions were reviewed. RESULTS: Fifty-four patients with RPOC were included. The incidence of RPOC was 6.7 %. The median (interquartile range: IQR) RPOC length was 29 (20-38) mm. RPOC hypervascularity was observed in 26 (48 %) patients. The median (IQR) periods of RPOC flow disappearance and RPOC disappearance on ultrasound from abortive treatment were 50 (28-76) and 84 (50-111) days, respectively. Of the 54, 44 patients were selected for expectant management. Of the 44, 34 (77 %) patients were observed without intervention (recovery group); the other 10 (23 %) patients required additional interventions associated with subsequent bleeding (intervention group). Compared with the recovery group, heavy bleeding (> 500 mL) at abortion (6/10: 60 %) and RPOC hypervascularity (8/10: 80 %) were more frequently observed in the intervention group. CONCLUSION: Expectant management was successful in almost 80 % of patients with RPOC following abortion. The additional interventions were required in patients with heavy bleeding at abortion and RPOC hypervascularity.

Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study.

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys® sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.