The TGF-ß/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta.

Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-ß1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-ß1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-ß1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-ß1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-ß1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta.

Continuous monitoring of fetal gross movement and maternal glucose level using newly developed methods.

BACKGROUND: There is no consensus on the relationship between maternal glucose levels and fetal movements. OBJECTIVE: This study aimed to investigate the correlation between gross fetal movements and maternal glucose levels in the hours around food intake. STUDY DESIGN: This was an observational study with 2 newly developed technologies, which were a glucose monitoring system and a fetal movement acceleration measurement recorder. A total of 15 women with singleton pregnancies were provided with the glucose monitoring system that automatically recorded their glucose levels every 15 minutes. In addition, fetal movements were recorded using the fetal movement acceleration measurement recorder, for 4 hours starting from 1 hour before lunch, once a week beginning at 28 weeks of gestation. For the four 1-hour periods, the ratios of the number of 10-second epochs with fetal movement divided by the total number of epochs (defined as the fetal movement parameter) were compared at the earlier (28-33 weeks of gestation), later (34-39 weeks of gestation), and overall (28-39 weeks of gestation) gestational weeks using analysis of variance analyses. A linear regression analysis was developed between the glucose level and the movement parameter for the earlier, later, and overall gestational weeks. All data were divided into 4 categories: (1) both the glucose level and the fetal movement parameter increased from the previous 15 minutes; (2) the glucose level increased, but the fetal movement parameter did not increase; (3) the glucose level did not increase, but the fetal movement parameter increased; and (4) both glucose level and fetal movement parameter did not increase. The numbers for each category were compared for the earlier, later, and overall gestational weeks using χ2 analyses. RESULTS: There was no significant change in the fetal movement parameter among the four 1-hour periods at the earlier (P=.509), later (P=.884), and overall (P=.816) gestational weeks. There was a positive correlation between the glucose level and the movement parameter at 28 to 33 weeks of gestation (P=.001), but not at 33 to 39 (P=.129) and 28 to 39 (P=.115) weeks of gestation. Compared with fetuses whose mothers did not have increased glucose levels, fetuses whose mothers had increased glucose levels moved more at 28 to 33 weeks of gestation (P=.031), but not at 34 to 39 (P=.398) and 28 to 39 (P=.238) weeks of gestation. CONCLUSION: Having a meal did not change gross fetal movement counting; however, there are positive correlations between maternal glucose level and gross fetal movement at 28 to 33 weeks of gestation, but not at 34 to 39 weeks of gestation, for both glucose values and value changes under natural conditions of the mother and fetus.

Effect of ritodrine hydrochloride infusion on fetal movement with the use of a fetal movement acceleration measurement recorder (FMAM recorder).

AIM: To investigate the effect of ritodrine hydrochloride infusion on fetal movement. METHOD: We gathered 20 pregnant women who received ritodrine hydrochloride infusion as the treated group, and 147 pregnant women who did not as the control group. All women recorded gross fetal movement with the fetal movement acceleration measurement recorder after 28 gestational weeks. The record was divided into epochs of 10 s, and the ratio of movement-positive epochs to all epochs was calculated as the fetal movement index. Furthermore, the mean duration and the mean number per hour of no-fetal movement period, where the fetus did not move for 5 min or more, were calculated as the indexes of no-fetal movement. All indexes were compared between the two groups at 28-31 and 32-35 gestational weeks. RESULTS: The fetal movement indexes (%) were 17.29 ± 7.46 (mean ± SD) in the control group and 13.65 ± 7.13 in the treated group at 28-31 weeks (p = 0.139). At 32-35 weeks, they were 14.55 ± 6.43 and 18.50 ± 5.33, respectively (p = 0.03). Similarly, the no-fetal movement indexes (min, times/h) were 15.03 ± 10.99 and 1.61 ± 0.88, and 18.70 ± 15.80 and 1.75 ± 0.96 (p = 0.824, and 0.673) at 28-31 weeks. At 32-35 weeks, they were 18.13 ± 10.88 and 1.95 ± 0.97, and 9.20 ± 5.51 and 1.14 ± 0.71, respectively (p = 0.003, and 0.003). CONCLUSION: Ritodrine hydrochloride infusion increased the fetal movement and decreased the no-fetal movement period at 32-35 weeks.

Counting gross fetal movement using a fetal movement acceleration measurement recorder in two fetuses with gastroschisis.

We used the fetal movement acceleration measurement recorder to count gross fetal movement in two fetuses with gastroschisis. In conclusion, both fetuses moved as much as normal fetuses, which suggested that normal fetal movement could indicate reassuring status also in fetuses with malformation when they have normal neurological developments.

Correlation between newborn size and gross fetal movement as counted by a fetal movement acceleration measurement recorder.

The development of the fetal movement acceleration measurement (FMAM) recorder has enabled the accurate counting of gross fetal movements. The aim of the study was to investigate whether gross fetal movement is related to a newborn's size. A total of 90 pregnant women who delivered singleton infant at term were recruited. Gross fetal movements were counted using an FMAM recorder during maternal sleep. The ratio of movement positive 10-s epochs to all epochs during one night was calculated as an index of fetal movement. Independent explanatory variables for the fetal movement index were selected from eight possibilities, that is, maternal age, gestational week, and the six physical measures of the newborn (height, weight, head circumference, chest circumference, Kaup index, and the ratio of head to chest circumference) with the stepwise regression procedure. The selected physical variables and the fetal movement index were analyzed using multiple regression analysis. A total of 2812.95 h from 423 night records were available. Gestational weeks and weight of the newborn were selected as the significant independent variables. Multiple regression analysis revealed that newborn weight had a positive correlation with the fetal movement index (p < 0.0001). The multiple regression equation was "The fetal movement index (%) = 34.9989-0.9088 × gestational weeks + 0.0033 × newborn weight (g)." A person's physical ability and lifetime activity level may originate from fetal health. This study may provide a new way of looking at the Developmental Origins of Health and Disease theory.

Counting fetal movements of small-for-gestational infants using a fetal movement acceleration measurement recorder.

Background: Our purpose was to clarify whether small-for-gestational (SGA) infants is associated with a decrease in fetal movements (FMs) even in the absence of hypoxia. We used a fetal movement acceleration measurement (FMAM) recorder, which enabled counting gross FMs for hours at a time.Methods: (1) Parameters of FMs for 13 women who delivered SGA infants were plotted over normal reference value curves made from 64 normal pregnant women in another study. (2) Linear regression analysis was conducted for the women with SGA infants and the normal pregnant women.Results: Thirty-eight data recordings were available in the SGA group. (1) For the ratio of movement positive 10-s epoch, 14 recordings (36.8%) were below 10% of the normal values. For an average number of movements, 13 (34.2%) were below 10%. Regarding average number, average duration, and longest duration of non-movement period, 12 (31.6%), 13 (34.2%), and 15 records (39.4%) were above 90% of the normal values, respectively. (2) SGA was a factor that decreased the positive epoch ratio and the average movements number, and increased the average number and duration, and the longest duration of non-movement period.Conclusions: SGA is associated with decreased movements even in the absence of hypoxia.

Correlation between umbilical cord length and gross fetal movement as counted by a fetal movement acceleration measurement recorder.

INTRODUCTION: The fetal movement acceleration measurement (FMAM) recorder has made it possible to count gross fetal movements over many hours. Our purpose was to examine the relationship between umbilical cord length and fetal movements as counted by the FMAM recorder. METHODS: Sixty-two pregnant women recorded fetal movements weekly from 28 weeks to term. The ratio of 10-s periods in which movement occurred to total time was calculated as a movement index. Umbilical cord length was measured at delivery. (1) Multiple linear regression analyses were conducted with six explanatory variables (primipara / multipara, anterior / posterior located placenta, placental weight, the mean movement index of 28-31, 32-35, and 36-39 week) and a response valuable (umbilical cord length). (2) All women were divided into groups of shorter, middle, and longer cord length, specifically less than 50 cm, between 50 and 60 cm, and more than 60 cm. The movement index was compared among the three groups at 28-31, 32-35, and 36-39 weeks. RESULTS: A total of 2355.6 h from 368 night records were available. (1) There were no relationships between the cord length and the movement index of 28-31, 32-35, and 36-39 weeks (p = 0.090, 0.235, 0.129, respectively). (2) There were no differences in the movement index among the three groups at 28-31 and 32-35 gestational weeks (p = 0.096, and 0.465, respectively); however, the longer cord group had a greater movement index than the other two groups at 36-39 weeks (p = 0.0008). DISCUSSION: This study suggested that fetal movement near term is an important factor in determining whether cord length becomes relatively longer in normal pregnancies.

Reference values for a fetal movement acceleration measurement recorder to count fetal movements.

BackgroundA newly developed fetal movement acceleration measurement recorder has made it possible to count gross movements for hours. The purpose of this study was to determine the normal reference values for such movements.MethodsOne hundred and six pregnant women recorded fetal movements by themselves when they slept at home weekly from 28 weeks to term. The normal reference values were determined based on the data that could be recorded for more than 4 h per night.ResultsA total of 2,458 h of data from 385 recordings from 64 women was available. The median ratio of 10-s periods in which fetal movements occurred to the total time interval was 17% at 28 gestational weeks, decreasing to ∼6% at term. The number of fetal movements was 74 times/h, decreasing to 29 times at term. The number, the mean, and the longest durations of periods with no fetal movement, meaning no fetal movements were found for more than 5 min, were 1.56 times/h, 7.95 and 14.25 min, respectively, at 28 weeks, and increasing to 2.54 times, and 9.63 and 19.67 min, respectively, at term.ConclusionsThis study provides normal reference values for gross fetal movement count using the fetal movement acceleration measurement recorder.

Counting fetal hiccups using a fetal movement acceleration measurement recorder.

OBJECTIVE: To clarify the degree of fetal hiccup occurrence by using a fetal movement acceleration measurement recorder. METHODS: A total of 23 pregnant women recorded fetal movements weekly or biweekly between 28 and 39 gestational weeks at home with the recorder. Fetal hiccups were defined as regular sharp oscillations - which occurred at 2-4 second intervals, more than 15 times per minute - on the maternal abdomen. The duration and frequency of the hiccup bouts were counted. The data were classified into an early (28-33 weeks) gestational group and a late (34-39 weeks) group, and compared between the two. RESULTS: A total of 164 records were obtained, and the total time analyzed amounted to 1035 hours. The mean incidence of a fetal hiccup bout at an early group was 0.19 times per hour, and it decreased to 0.15 at a late group (p = 0.02). The durations of fetal hiccup bouts were 8.17 and 7.88 minutes at an early and a late group, respectively, with no significant difference (p = 0.64). CONCLUSIONS: The duration of a fetal hiccup bout did not change after 28 gestational weeks; however, incidence slightly decreased from an early to a late group.

Changes in uterine flexion caused by cesarean section: correlation between post-flexion and deficient cesarean section scars.

PURPOSE: To investigate changes in uterine flexion after cesarean delivery in comparison with vaginal delivery, and their relationship with the presence of deficient cesarean section scars. METHODS: In 147 women who had a vaginal delivery and 101 women who had a cesarean delivery, transvaginal ultrasonographic photographs of the uterus were obtained at the first trimester of pregnancy and at 1 month postpartum, and they were reviewed to determine changes in uterine flexion. The presence of a deficient cesarean section scar was also reviewed in women with a cesarean section. RESULTS: Changes in uterine flexion were observed more frequently among the woman with a cesarean delivery than in those with a vaginal delivery. The incidence of post-flexed uterus during puerperium tended to increase depending on the number of cesarean sections the woman had undergone. In the women with a cesarean section, changes in uterine flexion were more frequently observed in the women with a deficient cesarean section scar than in those without one. CONCLUSION: Changes in uterine flexion after birth occurred more frequently in the women who had a cesarean delivery than in those who had a vaginal delivery, especially in the presence of a deficient cesarean section scar.

Automated Software Analysis of Fetal Movement Recorded during a Pregnant Woman's Sleep at Home.

Fetal movement is an important biological index of fetal well-being. Since 2008, we have been developing an original capacitive acceleration sensor and device that a pregnant woman can easily use to record fetal movement by herself at home during sleep. In this study, we report a newly developed automated software system for analyzing recorded fetal movement. This study will introduce the system and compare its results to those of a manual analysis of the same fetal movement signals (Experiment I). We will also demonstrate an appropriate way to use the system (Experiment II). In Experiment I, fetal movement data reported previously for six pregnant women at 28-38 gestational weeks were used. We evaluated the agreement of the manual and automated analyses for the same 10-sec epochs using prevalence-adjusted bias-adjusted kappa (PABAK) including quantitative indicators for prevalence and bias. The mean PABAK value was 0.83, which can be considered almost perfect. In Experiment II, twelve pregnant women at 24-36 gestational weeks recorded fetal movement at night once every four weeks. Overall, mean fetal movement counts per hour during maternal sleep significantly decreased along with gestational weeks, though individual differences in fetal development were noted. This newly developed automated analysis system can provide important data throughout late pregnancy.

Decreased fetal movements at home were recorded by a newly developed fetal movement recorder in a case of a non-reassuring fetal status.

A fetal movement acceleration measurement (FMAM) recorder was developed for home monitoring of fetal movements. We provided a 32-year-old pregnant woman with the FMAM recorder to home monitor fetal movements, thereby self-recording decreased fetal movements at 30 weeks' gestation. On routine checkup, a non-stress test revealed scant fetal heart rate accelerations. At 31 weeks' gestation, the woman underwent an emergent caesarean delivery because of a non-reassuring fetal heart rate pattern, and delivered a female neonate weighing 1312 g, whose umbilical cord was slightly narrowed at the umbilicus. Our experience with the present case suggests the usefulness of the FMAM recorder.

Fetal movement counting at home with a fetal movement acceleration measurement recorder: a preliminary report.

OBJECTIVE: Fetal Movement Acceleration Measurement (FMAM) recorder was developed to facilitate gross fetal movement counting. The aim was to assess its reliability. METHODS: Using the recorder, six pregnant women recorded fetal movements by themselves when they slept at their home weekly from 30 weeks to term. The recorder has 2 acceleration sensors; 1 for fetal movement (FM sensor) and another for maternal movement (MM sensor). Before sleeping, each subject attached the FM sensor to her abdomen, and the MM sensor to her thigh. All the recorded data were divided into 10-sec epochs, and presence of fetal movements was judged for all epochs (total epoch). The epoch was judged as positive for movement (positive epoch) when the FM sensor detected abdominal wall oscillations and the MM sensor did not detect maternal movements. The percentage of positive epoch number to total epoch and the maximum consecutive negative epoch number was calculated. RESULTS: The mean percentage was approximately 20-25% at 30-34 weeks and 10-15% at 35-38 weeks. The negative epoch number linearly increased after approximately 33-34 weeks of gestation. CONCLUSIONS: The FMAM recorder was reliable for long-duration recording of gross fetal movements at home.

A new method for long-term home monitoring of fetal movement by pregnant women themselves.

Fetal movement is one index of fetal well-being. We designed and built a new recorder based on fetal movement acceleration measurement (FMAM). The FMAM recorder has a newly developed, capacitive acceleration sensor that can detect the oscillations of the maternal abdominal wall caused by fetal movements. In this study, the recorder was examined for its suitability for long-term home monitoring of fetal movement by pregnant women themselves. Experiment I: Fourteen pregnant women underwent 45 examinations in the laboratory at gestational 20-39 weeks. We simultaneously recorded fetal movement as detected by the recorder, ultrasonography, and maternal perception, and then calculated agreement among the three methods. We evaluated agreement using prevalence-adjusted bias-adjusted kappa (PABAK). Agreement for gross fetal movement as detected by FMAM and ultrasonography was substantial or almost perfect, while agreement between maternal perception and ultrasonography was moderate or substantial. Experiment II: Six pregnant women undertook 53 experiments at home by themselves. Fetal movement during maternal nocturnal sleep was successfully recorded 50 out of 53 times at home. In conclusion, there was high agreement for gross fetal movement between FMAM and ultrasonography. The recorder is promising for objective, accurate, and long-term home monitoring of gross fetal movement by pregnant women themselves.