Fetal heart rate evolution and brain imaging findings in preterm infants with severe cerebral palsy.

BACKGROUND: Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care. OBJECTIVE: This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy. STUDY DESIGN: This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group. RESULTS: Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury. CONCLUSION: Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants.

Prevention of fetal brain injury in category II tracings.

INTRODUCTION: With category II fetal heart rate tracings, the preferred timing of interventions to prevent fetal hypoxic brain damage while limiting operative interventions remains unclear. We aimed to estimate fetal extracellular base deficit (BDecf ) during labor with category II tracings to quantify the timing of potential interventions to prevent severe fetal metabolic acidemia. MATERIAL AND METHODS: A longitudinal study was conducted using the database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy, including infants with severe cerebral palsy born at ≥34 weeks' gestation between 2009 and 2014. Cases included those presumed to have an intrapartum onset of hypoxic-ischemic insult based on the fetal heart rate pattern evolution from reassuring to an abnormal pattern during delivery, in association with category II tracings marked by recurrent decelerations and an umbilical arterial BDecf ≥ 12 mEq/L. BDecf changes during labor were estimated based on stages of labor and the frequency/severity of fetal heart rate decelerations using the algorithm of Ross and Gala. The times from the onset of recurrent decelerations to BDecf 8 and 12 mEq/L (Decels-to-BD8, Decels-to-BD12) and to delivery were determined. Cases were divided into two groups (rapid and slow progression) based upon the rate of progression of acidosis from onset of decelerations to BDecf 12 mEq/L, determined by a finite-mixture model. RESULTS: The median Decels-to-BD8 (28 vs. 144 min, p < 0.01) and Decels-to-BD12 (46 vs. 177 min, p < 0.01) times were significantly shorter in the rapid vs slow progression. In rapid progression cases, physicians' decisions to deliver the fetus occurred at ~BDecf 8 mEq/L, whereas the "decisions" did not occur until BDecf reached 12 mEq/L in slow progression cases. CONCLUSIONS: Fetal BDecf reached 12 mEq/L within 1 h of recurrent fetal heart rate decelerations in the rapid progression group and within 3 h in the slow progression group. These findings suggest that cases with category II tracings marked by recurrent decelerations (i.e., slow progression) may benefit from operative intervention if persisting for longer than 2 h. In contrast, cases with sudden bradycardia (i.e., rapid progression) represent a challenge to prevent severe acidosis and hypoxic brain injury due to the limited time opportunity for emergent delivery.

Correlation between fetal heart rate evolution patterns and magnetic resonance imaging findings in severe cerebral palsy: A longitudinal study.

OBJECTIVE: To investigate the association between hypoxic-ischaemic insult timing and brain injury type in infants with severe cerebral palsy (CP). DESIGN: Longitudinal study. SETTING: Database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy. SAMPLE: Infants with severe CP born at ≥34 weeks of gestation. METHODS: The intrapartum fetal heart rate (FHR) strips were categorised as continuous bradycardia; persistently non-reassuring (NR-NR); reassuring-prolonged deceleration (R-PD); Hon's pattern (R-Hon); persistently reassuring (R-R); and unclassified. The brain magnetic resonance imaging (MRI) scans were categorised based on the predominant site involved: basal ganglia-thalamus (BGT); white matter (WM); watershed (WS); stroke; normal; and unclassified. MAIN OUTCOME MEASURES: Manifestations of the brain MRI types and the association between FHR evolution pattern and MRI type were analysed. RESULTS: Among 672 eligible infants, 76% had BGT-dominant injury, 5.4% WM, 1.2% WS, 1.6% stroke, 1.9% normal, and 14% unclassified. Placental abruption and small-for-gestational age were associated with an increased (adjusted odds ratio [aOR] 8.02) and decreased (aOR 0.38) risk of BGT injury, respectively. The majority of infants had BGT injury in most FHR groups (bradycardia, 97%; NR-NR, 75%; R-PD, 90%; R-Hon, 76%; and R-R, 45%). The risk profiles in case of BGT in the NR-NR group were similar to those in the R-PD and R-Hon groups. CONCLUSION: BGT-dominant brain damage accounted for three-fourths of the cases of CP in term or near-term infants, even in prenatal onset cases. Hypoxic-ischaemic insult has a major impact on CP development during the antenatal period. TWEETABLE ABSTRACT: Basal ganglia-thalamus injury constitutes 76% of severe cerebral palsy cases, predominant even in antenatal-onset cases.

Fetal heart rate evolution patterns in cerebral palsy associated with umbilical cord complications: a nationwide study.

BACKGROUND: The aim of the present study was to clarify fetal heart rate (FHR) evolution patterns in infants with cerebral palsy (CP) according to different types of umbilical cord complications. METHODS: This case-control study included children born: with a birth weight ≥2000 g, at gestational age ≥33 weeks, with disability due to CP, and between 2009 and 2014. Obstetric characteristics and FHR patterns were compared among patients with CP associated with (126 cases) and without (594 controls) umbilical cord complications. RESULTS: There were 32 umbilical cord prolapse cases and 94 cases with coexistent antenatal umbilical cord complications. Compared with the control group, the persistent non-reassuring pattern was more frequent in cases with coexistent antenatal umbilical cord complications (p = 0.012). A reassuring FHR pattern was observed on admission, but resulted in prolonged deceleration, especially during the first stage of labor, and was significantly identified in 69% of cases with umbilical cord prolapse and 35% of cases with antenatal cord complications, compared to 17% of control cases (p < 0.001). CONCLUSION: Hypercoiled cord and abnormal placental umbilical cord insertion, may be associated with CP due to acute hypoxic-ischemic injury as well as sub-acute or chronic adverse events during pregnancy, while umbilical cord prolapse may be characterized by acute hypoxic-ischemic injury during delivery.

Risk factors for cerebral palsy in neonates due to placental abruption.

AIM: This study aimed to identify risk factors for the onset of cerebral palsy (CP) in neonates due to placental abruption and investigate their characteristics. METHODS: A retrospective case-control study was conducted using a nationwide registry from Japan. The study population included pregnant women (n = 122) who delivered an infant with CP between 2009 and 2015, where placental abruption was identified as the single cause of CP. The control group consisted of pregnant women with placental abruption, who delivered an infant without CP and were managed from 2013 to 2014. They were randomly identified from the prenatal database of the Japan Society of Obstetrics and Gynecology (JSOG-DB; n = 1214). Risk factors were investigated using multivariate analysis. RESULTS: Alcohol consumption (3.38, 2.01-5.68) (odds ratio, 95% confidence interval), smoking during pregnancy (3.50, 1.32-9.25), number of deliveries (1.28, 1.05-1.56), polyhydramnios (5.60, 1.37-22.6), oral administration of ritodrine hydrochloride (2.09, 1.22-3.57) and hypertensive disorders in pregnancy (2.25, 1.27-4.07) were significant risk factors. In contrast, intravenous administration of oxytocin (odds ratio, 95% confidence interval: 0.22, 0.09-0.58) and magnesium sulfate (0.122, 0.02-0.89) attenuated risk. CONCLUSION: Alcohol consumption, smoking during pregnancy, number of deliveries, polyhydramnios, oral administration of ritodrine hydrochloride and hypertensive disorders in pregnancy were identified as risk factors for CP following placental abruption. Regarding alcohol consumption and smoking during pregnancy, the results suggest the importance of educational activities targeting pregnant women to increase their awareness of placental abruption.

Fetal heart rate pattern in term or near-term cerebral palsy: a nationwide cohort study.

BACKGROUND: It is crucial to interpret fetal heart rate patterns with a focus on the pattern evolution during labor to estimate the relationship between cerebral palsy and delivery. However, nationwide data are not available. OBJECTIVE: The aim of our study was to demonstrate the features of fetal heart rate pattern evolution and estimate the timing of fetal brain injury during labor in cerebral palsy cases. STUDY DESIGN: In this longitudinal study, 1069 consecutive intrapartum fetal heart rate strips from infants with severe cerebral palsy at or beyond 34 weeks of gestation, were analyzed. They were categorized as follows: (1) continuous bradycardia (Bradycardia), (2) persistently nonreassuring, (3) reassuring-prolonged deceleration, (4) Hon's pattern, and (5) persistently reassuring. The clinical factors underlying cerebral palsy in each group were assessed. RESULTS: Hypoxic brain injury during labor (those in the reassuring-prolonged deceleration and Hon's pattern groups) accounted for 31.5% of severe cerebral palsy cases and at least 30% of those developed during the antenatal period. Of the 1069 cases, 7.86% were classified as continuous bradycardia (n=84), 21.7% as persistently nonreassuring (n=232), 15.6% as reassuring-prolonged deceleration (n=167), 15.9% as Hon's pattern (n=170), 19.8% as persistently reassuring (n=212), and 19.1% were unclassified (n=204). The overall interobserver agreement was moderate (kappa 0.59). Placental abruption was the most common cause (31.9%) of cerebral palsy, accounting for almost 90% of cases in the continuous bradycardia group (64 of 73). Among the cases in the Hon's pattern group (n=67), umbilical cord abnormalities were the most common clinical factor for cerebral palsy development (29.9%), followed by placental abruption (20.9%), and inappropriate operative vaginal delivery (13.4%). CONCLUSION: Intrapartum hypoxic brain injury accounted for approximately 30% of severe cerebral palsy cases, whereas a substantial proportion of the cases were suspected to have either a prenatal or postnatal onset. Up to 16% of cerebral palsy cases may be preventable by placing a greater focus on the earlier changes seen in the Hon's fetal heart rate progression.

Diagnostic value of combination serum assay of lactate dehydrogenase, D-dimer, and C-reactive protein for uterine leiomyosarcoma.

AIM: Leiomyosarcoma is the most common type of uterine sarcoma. In some leiomyosarcoma cases, preoperative diagnosis might be difficult, and they might be treated as benign lesions. We evaluated diagnostic values of preoperative serum lactate dehydrogenase (LDH), D-dimer and C-reactive protein for differentiating leiomyosarcoma. METHODS: From 2008 to 2013, leiomyosarcoma cases in three university hospitals were enrolled. Preoperative serum LDH, D-dimer and C-reactive protein were analyzed if tested. These markers of pathologically diagnosed leiomyoma cases presumed benign (group B) and presumed malignant (group PM) were compared with those of leiomyosarcoma cases (group S). RESULTS: Groups S, PM and B had 36, 28 and 69 cases, respectively. Positive rates of LDH were 66.7%, 14.3% and 0% in groups S, PM and B, respectively. Positive rates of D-dimer and C-reactive protein were 83.3% and 64.5%, 17.9% and 10.7% and 5% and 2.9% in groups S, PM and B, respectively. Positive rates of all three markers were high in the order of leiomyosarcoma, atypical leiomyoma and typical leiomyoma. In group PM, 12 (63.2%) cases were negative for all three markers, whereas 1 (3.3%) case was negative in group S. No case was positive for all markers in group PM, whereas 41.2% leiomyosarcoma cases were positive for all markers. When all parameters were positive, specificity and positive predictive value were 100% in differentiating leiomyosarcoma from group PM. CONCLUSION: Combination of LDH, D-dimer and C-reactive protein could be useful for distinguishing leiomyosarcoma from especially degenerated or atypical leiomyoma.

Randomized trial of the efficacy of intravaginal ulinastatin administration for the prevention of preterm birth in women with a singleton pregnancy and both cervical shortening and inflammation of lower genital tract.

AIM: To assess the preventive effect on preterm birth of intravaginal ulinastatin (urinary trypsin inhibitor; UTI) administration during the mid-trimester in women with singleton pregnancy and both cervical shortening and lower genital infections. METHODS: Pregnant women with a short cervical length < 25 mm between 16 and 26 weeks of gestation and who had been diagnosed with a lower genital infection were randomly assigned for intravaginal UTI administration or placebo. All of the women were screened for infection or inflammation of the lower genital tract, and women with negative results were excluded. RESULTS: Of the 92 patients with a short cervical length who were assessed for eligibility for this study, 86 singleton patients were enrolled. All patients were randomized to one of two treatment groups: patients administered UTI (n = 35) and placebo (n = 35). There were no differences between the two groups in the incidence of preterm delivery before 28, 30, 32, 34 and 37 weeks of gestation and in perinatal outcomes. CONCLUSION: For women diagnosed with a short cervical length < 25 mm) between 16 and 26 weeks of gestation and lower genital infection, who were at risk of preterm birth, administration of transvaginal UTI with vaginal irrigation showed no apparent benefit. Future research on the efficacy of UTI should evaluate modified modes of UTI application.

Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2017 edition.

Six years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the third revised edition was published in 2017. The 2017 Guidelines includes 10 additional clinical questions (CQ), which brings the total to 95 CQ (12 on infectious disease, 28 on oncology and benign tumors, 27 on endocrinology and infertility and 28 on healthcare for women). Currently a consensus has been reached on the Guidelines and therefore the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding recommendation level (A, B, C) is indicated.

Significance of gestational weight gain in spontaneous onset of labor at term.

AIM: To investigate the significance of gestational weight gain (GWG) in association with the spontaneous onset of labor at term. METHODS: A retrospective cohort study on 985 pregnant women (629 nullipara and 356 pluripara) who delivered singleton babies at term was conducted. We reviewed the maternal demographics (age, parity, prepregnancy body mass index [BMI]) and the perinatal outcomes (gestational age [GA] and the type [spontaneous or induced] of labor onset, and GWG). The subjects were categorized by prepregnancy BMI and GWG. The rates of spontaneous onset of labor were compared between the nullipara and pluripara groups. Kaplan-Meier survival analysis was applied to evaluate the time to spontaneous labor according to prepregnancy BMI and GWG. A Cox proportional hazards model was used to determine the independent predictive factor for spontaneous onset of labor. RESULTS: In both the nullipara and pluripara group, women with prepregnancy obesity were less likely to enter spontaneous labor. In nullipara, women with excessive weight gain were less likely to enter spontaneous labor. In pluripara, women with poor gain were more likely to enter spontaneous labor. In the multivariate model, GWG was independently associated with the spontaneous onset of labor in both nullipara (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.98, P = 0.03) and pluripara (HR 0.82, 95% CI 0.64-0.93, P = 0.005). CONCLUSION: Greater maternal weight gain was significantly associated with longer gestation and a decreased likelihood of spontaneous onset of labor at term.

Influence of maternal obesity on fetal growth at different periods of pregnancies with normal glucose tolerance.

AIM: We aimed to examine the influence of maternal obesity on fetal growth in utero at different periods of pregnancies with normal glucose tolerance. METHODS: A retrospective cohort study on 356 pregnant women with normal glucose tolerance was conducted. The women were categorized by pre-pregnancy body mass index (BMI) as obese (OB; BMI ≥ 25.0 kg/m2 ) or non-obese (n-OB). Z-scores of the fetal abdominal circumference (AC) and the rate of fetal macrosomia (AC ≥ 90th percentile) at 19, 30, and 36 gestational weeks (GW) were compared between the two groups. Maternal demographics (age, parity, height, pre-pregnancy BMI, history of prior large-for-gestational-age delivery) were compared between the pregnancies with and without fetal macrosomia at each gestational age. Multiple logistic regression analysis was performed to determine the independent risk factors for fetal macrosomia. RESULTS: Birthweights of the neonates were significantly higher in the OB group. Z-scores of the fetal AC were significantly higher in the OB group at 30 and 36 GW, while no significant difference was found at 19 GW. The rates of fetal macrosomia in the OB group were also higher at 30 and 36 GW, while maternal obesity was not associated with fetal macrosomia at 19 GW. Pre-pregnancy BMI was detected as the independent predictor of fetal macrosomia at 30 GW (odds ratio, 1.19 [95% CI]) and 36 GW (odds ratio, 1.13 [95% CI]). CONCLUSION: Maternal pre-pregnancy obesity has a promoting effect on fetal growth from the third trimester through birth.

Increased maternal insulin resistance promotes placental growth and decreases placental efficiency in pregnancies with obesity and gestational diabetes mellitus.

AIM: Homeostasis model assessment for insulin resistance (HOMA-IR) was measured during pregnancy to analyze placental weight and efficiency in relation to maternal insulin resistance. METHODS: A retrospective study of 510 pregnant women (130 with gestational diabetes mellitus [GDM], 380 with normal glucose tolerance) was conducted. We reviewed the patients' demographic data (age, parity, pre-pregnancy body mass index [BMI]) and perinatal outcomes (birth weight, placental weight, BMI at delivery, maternal weight gain, HOMA-IR). The birth weight to placental weight (B/P) ratio was calculated for placental efficiency. The subjects were categorized by BMI at delivery, and maternal, neonatal and placental characteristics were compared between the groups to investigate the determinants of placental weight and B/P ratios. RESULTS: Obesity was significantly associated with heavier placental weight and lower B/P ratios. The presence of GDM did not affect placental weight, whereas the B/P ratios in women with GDM were significantly lower than in women with normal glucose tolerance. HOMA-IR was positively correlated with placental weight (ρ = 0.217, P < 0.001) and negatively with B/P ratio (ρ = -0.181, P < 0.001). CONCLUSIONS: Increased maternal insulin resistance promoted placental growth and inhibited placental efficiency. Maternal insulin resistance may be one of the pathophysiological conditions responsible for altered placental size and function in pregnancies with obesity and GDM.

Non-essential and branched-chain amino acids differentially regulate insulin-like growth factor binding protein-1 production and phosphorylation in HepG2 cells.

Deprivation of branched-chain amino acids (BCAAs) induces insulin-like growth factor binding protein-1 (IGFBP-1) production in HepG2 cells, while the role of non-essential amino acids (NEAAs) remains unknown. We investigated changes in IGFBP-1 production and phosphorylation induced by NEAAs and also examined its significance on IGF-I activity in HepG2 cells. We demonstrated that decreased BCAAs and increased NEAAs stimulated phosphorylated IGFBP-1 secretion. We also revealed that decreased BCAA-to-NEAA ratios enhanced phosphorylated IGFBP-1 secretion, while changes in the total amount of amino acids (AAs) had no effect. Phosphorylation of IGF-I receptor ß-subunits mediated by exogenous IGF-I in HepG2 cells was inhibited by decreased BCAAs, increased NEAAs, and decreased BCAA-to-NEAA ratios, while the total amount of AAs had no effect. In addition to BCAAs, NEAAs are also responsible for the regulation of IGFBP-1 secretion and phosphorylation in HepG2 cells. Moreover, the balance of BCAAs and NEAAs regulated IGFBP-1 secretion and phosphorylation.

Histologic grade and peritoneal cytology as prognostic factors in type 1 endometrial cancer.

BACKGROUND: Prognostic clinicopathological factors for type 1 endometrial cancer are unknown and the purpose of the current study was to determine the independent prognostic variables for type 1 endometrial cancer. METHODS: We performed a retrospective study of 168 patients with type 1 endometrial cancer primarily treated with comprehensive staging surgery. The median follow-up time was 68 (12-100) months. Independent risk factors for disease-free survival (DFS) and overall survival (OS) were determined using multivariate Cox regression models. Sub-group analysis of stage I was also performed. We also assessed the patterns of failure among patients with recurrences and investigated the associations with the prognostic variables determined by multivariate analysis. RESULTS: Twenty patients (11.9%) had recurrence and 13 patients (7.7%) died of the disease overall. Multivariate analysis revealed that grade 2 (G2) histology (p = 0.008) and positive peritoneal cytology (p = 0.001) predicted the recurrent event in type 1 endometrial cancer. G2 histology (p = 0.007) and positive peritoneal cytology (p = 0.003) were also found to be independent risk factors for tumor-related deaths. Among stage I patients, G2 histology and positive peritoneal cytology were also independent prognostic variables for DFS and OS. Patients with G2 histology and/or positive peritoneal cytology were more likely to have recurrence at distant sites. CONCLUSIONS: G2 histology and positive peritoneal cytology were independent prognostic factors for DFS and OS in type 1 endometrial cancer.

Women with Subclinical Hypothyroidism Are at Low Risk of Poor Pregnancy Outcome in Japan.

Maternal subclinical hypothyroidism may be associated with adverse pregnancy outcomes, although not consistently across regions. Here, we sought to determine the effect of elevated thyroid-stimulating hormone (TSH) on pregnancy outcomes in Japanese women without known medical complications. TSH was determined by dried blood spots at 8-20 weeks of gestation, and 3.0-10.0 µU/mL of TSH was considered as elevated TSH (eTSH). A retrospective study involving 167 cases of eTSH was conducted. Five hundred and seventy eight of controls with normal TSH and without thyroid antibodies were selected. We compared a composite adverse maternal outcome comprised of spontaneous abortion, premature delivery, gestational diabetes mellitus (GDM), placental abruption, and pregnancy-induced hypertension, as well as composite adverse neonatal outcome including stillbirths, heavy for date, light for date, and a low Apgar score (< 7) at 5 minutes between two groups. The incidence of GDM was significantly higher in eTSH (p < 0.01); however, composite adverse maternal and neonatal outcome did not differ between groups (p = 0.19 and p = 0.50, respectively). Although 27 out of 167 cases in eTSH have antibodies, composite adverse outcome did not differ between eTSH with antibodies and controls (p = 0.64 and p = 0.50, respectively). Additionally, composite adverse maternal and neonatal outcome did not differ between the group larger than the median of TSH in eTSH (n = 81) and controls (p = 0.43 and p = 0.98, respectively). Thus, elevated TSH is not associated with overall adverse pregnancy outcomes in women without known medical complications.

Improving the Accuracy of Diagnosing Placenta Previa on Transvaginal Ultrasound by Distinguishing between the Uterine Isthmus and Cervix: A Prospective Multicenter Observational Study.

OBJECTIVE: To clarify whether distinguishing between the uterine isthmus and cervix can improve the accuracy of diagnosing placenta previa at term. METHODS: A multicenter prospective observational study was conducted among pregnant women with suspected placenta previa at 20-24 weeks' gestation. Subjects were divided into the open isthmus group and closed isthmus group. The accuracy of diagnosing placenta previa at term was compared between the 2 groups. RESULTS: We screened 9,341 patients, and 53 (0.6%) met the inclusion criteria. Nineteen cases with an open isthmus and 34 with a closed isthmus were followed. The accuracy for diagnosing placenta previa or a low-lying placenta at term was 94.7% in the open isthmus group and 26.5% in the closed isthmus group (p < 0.001). Elective or emergency Cesarean section was required in 100% of cases in the open isthmus group and 20.6% in the closed isthmus group (p < 0.001). CONCLUSION: A high prediction rate of placenta previa was obtained by using transvaginal ultrasound at 20-24 weeks' gestation after the isthmus opened by carefully distinguishing between the cervix and isthmus.

Branched-chain amino acids regulate insulin-like growth factor-binding protein 1 (IGFBP1) production by decidua and influence trophoblast migration through IGFBP1.

STUDY QUESTION: Do branched-chain amino acids (BCAAs) influence the migration of human extravillous trophoblast (EVT) cells through changes in insulin-like growth factor-binding protein 1 (IGFBP1) production in decidual cells? STUDY FINDING: Decidua-derived IGFBP1 had a stimulating effect on migration of EVT. WHAT IS KNOWN ALREADY: IGFBP1 is abundantly secreted from human decidual cells and influences trophoblast migration in human placenta of early pregnancy. In hepatic cells, the expression of IGFBP1 is influenced by nutritional status and BCAAs regulate IGFBP1 production. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: This is a laboratory-based study using human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy (n = 50) and grown as primary cultures. Production of IGFBP1 from decidual cells was examined by enzyme-linked immunosorbent assay and immunoblotting after incubation with or without BCAAs. EVT migration was evaluated using the media conditioned by decidual cells. The effect of conditioned media on phosphorylation of focal adhesion kinase (FAK) in EVT was also analyzed by immunoblotting. The same experiments were repeated in the presence of RGD peptide, which inhibits IGFBP1 binding to α5ß1 integrin. An EVT migration assay and the immunoblotting of phosphorylated FAK were also conducted with exogenous IGFBP1. The effect of the conditioned media on cytotrophoblast cell number was also assessed using WST-1 in a cell proliferation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Deprivation of BCAAs on decidual cells significantly suppressed IGFBP1 secretion (P < 0.05, versus BCAA+). Exogenous IGFBP1-stimulated EVT migration (P < 0.05) and phosphorylation of FAK (P < 0.05), and the RGD peptide inhibited these effects. EVT migration and phosphorylation of FAK were stimulated by the conditioned media, presumably by IGFBP1 in the media. RGD treatment abrogated the stimulating effects of conditioned media. The conditioned media deprived of BCAAs had suppressive effects on EVT migration (P < 0.05, versus BCAA+) and phosphorylation of FAK (P < 0.05, versus BCAA+). The conditioned media did not affect number of cytotrophoblast cells. LIMITATIONS, REASONS FOR CAUTION: The conclusions are based on in vitro experiments with human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy, and we were unable to ascertain whether these mechanisms actually operate in vivo. We investigated the effect of decidua-derived IGFBP1 on EVT migration, however, we cannot completely rule out the possibility that endogenous IGF could also influence cell migration. WIDER IMPLICATIONS OF FINDINGS: Interruption of the BCAA supply to uterine decidual cells in early pregnancy may suppress EVT migration through reduced IGFBP1 secretion, which may be one of the pathophysiological conditions responsible for pre-eclampsia. LARGE SCALE DATA: None. STUDY FUNDING/ AND COMPETING INTERESTS: All funds were obtained through Kyorin University School of Medicine. The authors have no conflict of interest to declare.