A novel variant in IFT122 associated with a severe phenotype of cranioectodermal dysplasia.

A 27-year-old multiparous woman conceived her fetus naturally. Early second-trimester ultrasound showed short extremities with systemic subcutaneous edema. The pregnancy was artificially terminated at 19 weeks of gestation because of the abnormalities based on the parents' wishes. The parents desired whole-exome sequencing to detect a causative gene using the umbilical cord and the parents' saliva. Compound heterozygous variants (NC_000003.11(NM_052989.3):c.230 T > G/NC_000003.11(NM_052985.4):c.1178A > T) were identified. We described a fetus with a novel compound heterozygous variant in IFT122. The phenotype of this case was severer than of other types of cranioectodermal dysplasia.

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.

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.

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.

Prognosis and Prognostic Factors of Patients with Emergent Cerclage: A Japanese Single-Center Study.

OBJECTIVES: The aims of this study were to clarify the following: (1) how often does prolonged pregnancy ≥34 weeks occur in patients with emergent cerclage without progesterone and (2) the risk factors preventing such pregnancy continuation. MATERIALS AND METHODS: This retrospective observational study was performed using medical records of patients for whom emergent cerclage had been performed between April 2006 and December 2018 in our institute. RESULTS: Emergent cerclage was performed in 123 patients (median age: 34, interquartile range: 31-36). Primiparous patients numbered 44 (36%). A history of spontaneous preterm birth (SPTB) was present in 30 (24%). The median presurgical cervical length (CL) was 16 (8-21) mm at surgery. Of the 123, 20 (16%) were delivered at 33 + 6 weeks or less (<34 weeks). We conducted logistic regression analysis of the risk factors of SPTBs <34 weeks after cerclage. Three risk factors were identified that increased the risk of SPTB <34 weeks: presurgical CL 0 mm (odds ratio (OR): 5.30; 95% confidence interval (CI): 1.58-17.7), a history of SPTB (OR: 4.65; 95% CI: 1.38-15.7), and the presence of sludge (OR: 4.14; 95% CI: 1.20-14.3). CONCLUSION: Three risk factors predicted SPTB <34 weeks after emergency cerclage without progesterone administration: unmeasurable CL (CL 0 mm), a history of SPTB, and the presence of sludge on ultrasound. SPTB <34 weeks occurred after emergency cerclage in 16% of patients, being comparable with the recent data with progesterone.

Difficulty of predicting early-onset super-imposed preeclampsia in pregnant women with hemodialysis due to diabetic nephropathy by serum levels of sFlt-1, PlGF, and sEng.

There are few case reports in which circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured before the onset of super-imposed preeclampsia in women with hemodialysis. A 40-year-old Japanese nulliparous women with hemodialysis due to diabetic nephropathy became pregnant by frozen embryo transfer. Intensive hemodialysis was started at 5 weeks of gestation. Her blood pressure (BP) in the first trimester was around 130/80 mmHg. At 20+3 weeks, she was admitted for close monitoring; her BP was 137/75 mmHg. Her BP increased to 157/88 mmHg at 31+2 weeks, and nifedipine at 20 mg/day was started at 31+6 weeks. However, the serial longitudinal measurements of sFlt-1, PlGF, and sEng did not predict the onset of super-imposed preeclampsia. Cesarean section was performed at 33+6 weeks due to uncontrollable hypertension. A healthy female infant weighing 2138 g was delivered. As for the changes of biomarkers between just before and just after hemodialysis, sFlt-1 was significantly higher just after compared with just before hemodialysis (5774 ± 1875 pg/mL vs. 2960 ± 905 pg/mL, respectively, p < 0.001). PlGF was also significantly higher just after compared with just before hemodialysis (2227 ± 1038 pg/mL vs. 1377 ± 614 pg/mL, respectively, p < 0.001). However, the sFlt-1/PlGF ratio and sEng levels were not significantly different between just before and just after hemodialysis (p = 0.115, p = 0.672, respectively). In conclusion, prediction of early-onset super-imposed preeclampsia using angiogenic and anti-angiogenic markers in pregnant women with hemodialysis might be difficult.

Markedly higher sFlt-1/PlGF ratio in a woman with acute fatty liver of pregnancy compared with HELLP syndrome.

AIM: To compare serum levels of angiogenesis-related factors between 14 women with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome and a woman with acute fatty liver of pregnancy (AFLP). METHODS: Serum samples were collected in 2004-2008 and 2013-2016. The levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured by an automated electrochemiluminescence immunoassay using Elecsys sFlt-1 and Elecsys PlGF. After logarithmic transformation, levels of sFlt-1, PlGF and the sFlt-1/PlGF ratio in a woman with AFLP were compared with those in women with HELLP syndrome, using the one-sample t-test. RESULTS: At 37 weeks of gestation, a patient was diagnosed with AFLP based on Swansea criteria (showing six features including elevated transaminases), and she also showed a duodenal ulcer with active bleeding, thrombocytopenia and hypertension. Her serum levels of sFlt-1 and sFlt-1/PlGF ratio were significantly higher than in those with HELLP syndrome (273 040 pg/mL vs 15 135 [mean], P < 0.001; 4236 vs 224, P < 0.001; respectively). However, her serum level of PlGF was not significantly different from those with HELLP syndrome. CONCLUSION: Serum levels of sFlt-1 and the sFlt-1/PlGF ratio, but not PlGF, in a woman with AFLP were markedly higher than those in women with HELLP syndrome. AFLP may be a different clinical entity from HELLP syndrome based on angiogenesis-related factors. Clinically, the sFlt-1/PlGF ratio may be used to rapidly distinguish AFLP from HELLP syndrome.

Serum soluble LIGHT in the early third trimester as a novel biomarker for predicting late-onset preeclampsia.

Our aim was to evaluate whether serum levels of soluble LIGHT (sLIGHT) at 27-31 weeks can predict the later occurrence of gestational hypertension (GH), late-onset preeclampsia (PE), and early-onset PE. Mean blood pressure (MBP), soluble fma-like tyrosine kinase 1/placental growth factor (sFlt-1/PlGF) ratio at 27-31 weeks, and sLIGHT at 27-31 weeks were independent risk factors for late-onset PE. The combination of the three risk factors improved sensitivity with a false-positive rate of 10% (MBP: 60%, log10(sFlt-1/PlGF): 45%, sLIGHT: 35%, combination: 75%). Serum sLIGHT in the early third trimester may be a novel biomarker for predicting late-onset PE.

Increased serum levels of sFlt-1/PlGF ratio in preeclamptic women with onset at <32 weeks compared with ≥32 weeks.

OBJECTIVE: Our first aim was to construct gestational-age-specific reference ranges of serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1/PlGF ratio at 19-38 weeks of gestation. Our second aim was to compare the serum levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in 81 women with PE which occurred at <32, 32-33, 34-35, and ≥36 weeks. METHOD: Serum levels of sFlt-1 and PlGF were measured by automated immunoassays (Elecsys sFlt-1 and Elecsys PlGF). We constructed the normal reference ranges of log10sFlt-1, log10PlGF, and the log10(sFlt-1/PlGF) between 19 and 38 weeks using 309 samples, which could be represented by a quadratic curve. The cut-off levels were defined as the 5th and 95th percentiles of their gestational-age-specific reference ranges. RESULTS: The frequencies of high sFlt-1, low PlGF, and a high sFlt-1/PlGF ratio in women with an onset at <32 weeks were all 100%, whereas there were no groups showing 100% abnormalities of sFlt-1, PlGF or the sFlt-1/PlGF ratio in women with an onset at 32-33, 34-35, and ≥36 weeks. The levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at <32 weeks were significantly different from those in women with an onset at ≥32-33 weeks, although the levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at 32-33, 34-35, and ≥36 weeks were almost the same. CONCLUSION: The appropriate threshold weeks for defining early-onset PE might be 32+0 weeks rather than 34+0 or 36+0 weeks.

Galectin-1 as a novel risk factor for both gestational hypertension and preeclampsia, specifially its expression at a low level in the second trimester and a high level after onset.

Our aim was to evaluate whether the serum level of galectin-1 (Gal-1) at 18-24 and 27-31 weeks of gestation is a risk factor for predicting the later occurrence of not only preeclampsia (PE) but also gestational hypertension (GH). We measured serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and Gal-1 using an enzyme-linked immunosorbent assay in 81 and 73 normal pregnant women, 22 and 16 women with a later onset of GH, and 37 and 29 women with a later onset of PE at 18-24 and 27-31 weeks, respectively. We also measured Gal-1 in 33 women with GH and 78 women with PE after the onset. The levels of Gal-1 after the onset of GH, late-onset PE (onset at ⩾34 weeks), and early-onset PE (onset at <34 weeks) were significantly higher than those in normal pregnant women at 27-31 weeks. However, the low levels of Gal-1 (<8.1 ng ml-1) at 18-24 weeks, but not at 27-31 weeks, predicted the later occurrence of not only early-onset PE and late-onset PE but also GH. The low level of Gal-1 at 18-24 weeks was an independent risk factor for the later occurrence of GH and PE, after adjusting for the effects of a high BP and increased sFlt-1/PlGF ratio at 18-24 weeks. In conclusion, the serum level of Gal-1 is a novel risk factor for both GH and PE, specifically its expression at a low level in the second trimester and a high level after onset.

AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration.

PROBLEM: Advanced glycation end products (AGEs) and high-mobility group box-1 (HMGB1) are considered contributing to placental inflammation. We examined the effect of AGEs and HMGB1 on cytokines from Sw.71 human trophoblast cell lines and the interactions between Sw.71 cells and THP-1-monocytes. METHODS OF STUDY: Sw.71 cells were cultured with/without AGEs or HMGB1. We examined the role of AGEs or HMGB1 on THP1 migration and effect of AGEs on IL-6 from Sw.71 cells using co-cultures or conditioned medium from THP-1 cells. RESULTS: AGEs and HMGB1 increased interleukin (IL)-6, IL-8, and chemokine C-C motif ligand 2 (CCL2) secretion from Sw.71 cells. The secretion of IL-6 was dependent on reactive oxygen species (ROS) and NF-κB. AGEs stimulated IL-6 secretion through receptor RAGE and TLR4, whereas HMGB1 stimulated it through TLR4. AGEs, but not HMGB1, increased monocyte migration via IL-8 and CCL2 from Sw.71 cells. THP-1 monocytes induced IL-6 secretion from Sw.71 cells, and AGEs further stimulated it. CONCLUSIONS: AGEs and HMGB1 may promote sterile placental inflammation cooperating with monocytes/macrophages.

Moderate Hypoxia Down-Regulates Interleukin-6 Secretion and TLR4 Expression in Human Sw.71 Placental Cells.

BACKGROUND/AIMS: The placenta is a vital organ for pregnancy. Many in vitro placental experiments are conducted under 21% O2; however, O2 tension could influence cellular functions, including cytokine secretion. We investigated the effects of oxygen tension between moderate hypoxia (5% O2) and normoxia (21% O2) by testing the hypothesis that moderate hypoxia regulates cellular phenotypes differently from normoxia in human trophoblast cells. METHODS AND RESULTS: Sw.71 trophoblast cells were incubated under normoxic or moderately hypoxic conditions. Cells were also treated with lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR4) ligand inducing inflammation. Interleukin-6 (IL-6) as an inflammatory cytokine was determined, and TLR4, hypoxia-induced factor-1α (HIF1α), and reactive oxygen species (ROS) production were detected. Moderate hypoxia increased HIF1α expression and cell proliferation and acted by two different mechanisms to decrease IL-6 secretion compared with normoxia: it limits the TLR4 expression and ROS production. Treatment with cobalt chloride as an HIF1 activator inhibited IL-6 secretion and TLR4 expression; this effect was reversed on treatment with PX-12 as an HIF1 suppressor. CONCLUSION: IL-6 secretion, TLR4 expression, and ROS production, classical markers of inflammation, are down-regulated by moderate hypoxia, and HIF1α and ROS have a potential to regulate these responses in human trophoblast cells.

Intravascular large B-cell lymphoma involving mainly the uterus: report of a case using liquid-based cytology of the endometrium.

BACKGROUND: Intravascular lymphoma is a rare subtype of extranodal lymphoma. Most instances of the disease are of B-cell lineage. Diagnosis is difficult because of its nonspecific clinical signs, and many cases are diagnosed at autopsy. Uterine involvement is rare, and it is commonly manifested as genital bleeding. In this case, the chief complaint was fever, which is also very rare. CASE REPORT: A 62-year-old woman presented with fever of unknown origin. Computed tomography revealed no localized lesion except for swelling of the right internal iliac nodes. A cytologic smear of the endometrium by liquid-based cytology demonstrated malignant cells. Based on the curettage material, the lesion was diagnosed as an undifferentiated malignant tumor. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic/paraaortic lymphadenectomy revealed widely scattered lymphoma cells of B-cell lineage mainly in the vascular lumina of the uterus, right ovary and lymph nodes. CONCLUSION: The final histologic type was established on the basis of the surgical material of hysterectomy. Diagnosis was difficult because of prominent cellular atypia and rare location of the tumor. Immunocytochemical examination of liquid-based samples can lead to a correct diagnosis of malignant lymphoma, even at the stage of endometrial cytologic examination.