First-trimester pre-eclampsia biomarker profiles in Asian population: multicenter cohort study.

OBJECTIVES: To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. METHODS: This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. RESULTS: In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. CONCLUSIONS: Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Treatment of twin-reversed arterial perfusion sequence using high-intensity focused ultrasound.

We describe our experience of high-intensity focused ultrasound (HIFU) for fetal therapy in twin-reversed arterial perfusion (TRAP) sequence. Six pregnant women underwent HIFU therapy, five before 16 weeks and one at 26 weeks. Two types of HIFU system were used: the first-generation system, which comprised a biaxial transducer and continuous exposure pattern, and the second-generation system, which comprised a coaxial transducer and sequential exposure pattern. The first-generation apparatus was used in four cases and the second-generation apparatus was used in two. In three cases, occlusion of the blood vessels mediating flow to the acardiac twin was achieved by HIFU. Two cases experienced intrauterine fetal death despite vessel occlusion. The total survival rate of pump fetuses 2 years after HIFU was 67% and the efficiency rate (the proportion of cases with occlusion or reduced blood flow on ultrasound after HIFU) was 83%. After more than 2 years of follow-up, the surviving infants had no severe clinical complications and no postnatal developmental problems. There was no significant difference in survival rate compared with TRAP cases managed expectantly. Given that complete occlusion of the blood vessels was not achieved in half of the cases, we could not show that HIFU therapy is superior to other treatments. However, HIFU can reduce the cardiac load of the pump fetus and, as it does not require uterine puncture for fetal therapy, there were no fatal complications, such as bleeding, rupture of membranes or infection. Thus, HIFU therapy may represent a less-invasive treatment for TRAP sequence in early pregnancy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Influenza 2014-2015 among pregnant Japanese women: primiparous vs multiparous women.

This study was performed to determine whether multiparous pregnant women are prone to influenza. A questionnaire survey was conducted at 19 centres located throughout Japan, targeting all 6,694 postpartum women within 7 days after birth before leaving the hospital. All women gave birth during the study period between March 1, 2015, and July 31, 2015. Data regarding vaccination and influenza infection in or after October 2014, age, previous experience of childbirth, and number and ages of cohabitants were collected. Seventy-eight percent (n = 51,97) of women given questionnaires responded. Of these, 2,661 (51 %) and 364 (7.0 %) women reported having been vaccinated and having contracted influenza respectively. Multiparous women had a higher risk of influenza regardless of vaccination status (8.9 % [121/1362] vs 5.7 % [74/1299], relative risk [95 % confidence interval], 1.80 [1.36 to 2.38] for vaccinated and 9.3 % [112/1198] vs 4.3 % [57/1328], 2.18 [1.60 to 2.97] for unvaccinated women) compared to primiparous women. The risk of influenza increased with increasing number of cohabitants: 4.8 % (100/2089), 7.5 %, (121/1618), 9.0 %, (71/785), and 10.4 % (58/557) for women with 1, 2, 3, and ≥4 cohabitants respectively. Family size is a risk factor for influenza infection in pregnancy.

Prediction of early- and late-onset pregnancy-induced hypertension using placental volume on three-dimensional ultrasound and uterine artery Doppler.

OBJECTIVES: To determine whether uterine artery (UtA) Doppler findings and three-dimensional (3D) ultrasound measurement of placental volume during the first trimester allowed prediction of early- and late-onset pregnancy-induced hypertension (early PIH and late PIH). METHODS: Subjects with singleton pregnancy who underwent an ultrasound scan at 11-13 weeks' gestation and delivered between 2011 and 2013 were enrolled prospectively into the study. The UtA Doppler indices and placental volume on 3D ultrasound at 11-13 weeks' gestation in cases that developed early PIH (< 34 weeks) or PIH later in pregnancy (≥ 34 weeks) were compared with values in unaffected pregnancies. RESULTS: Ten cases of early PIH, 67 cases of late PIH and 1285 unaffected pregnancies were analyzed. The UtA pulsatility index (PI) was higher in cases of early PIH than that in unaffected pregnancies (median, 2.35 vs. 1.79; P = 0.043) but did not differ between cases of late PIH and unaffected pregnancies. Placental volume was smaller in cases of early PIH than that in unaffected pregnancies (median, 43 cm3 vs. 62 cm(3) ; P = 0.003) but did not differ between cases of late PIH and unaffected pregnancies. The area under the receiver-operating characteristics curve for the prediction of early PIH, by combining UtA-PI and placental volume, was 0.832 (95% CI, 0.742-0.921), with this combination providing a detection rate for early PIH of 67.5% for a 5% false-positive rate. CONCLUSIONS: High UtA-PI and small placental volume were observed more often in cases of early PIH compared with unaffected pregnancies, but not in cases of late PIH. These results may indicate that there are differences in pathophysiology between early PIH and late PIH.

First successful case of non-invasive in-utero treatment of twin reversed arterial perfusion sequence by high-intensity focused ultrasound.

High-intensity focused ultrasound (HIFU) has excellent potential as a non-invasive therapeutic tool in various fields of medicine. We present a case of twin reversed arterial perfusion sequence, in which non-invasive blood flow occlusion in the acardiac fetus was successfully achieved by means of HIFU exposure from outside the maternal abdomen. HIFU was applied to blood vessels of the acardiac fetus at the point at which the umbilical cord entered the body in a series of four procedures at 3-day intervals starting at 13 weeks' gestation, and in a final procedure with higher power at 17 weeks. The HIFU intensity was set at approximately 2300 W/cm(2) for the initial series of procedures and at 4600 W/cm(2) for the final procedure, with exposure periods of 10 s. As color Doppler examination revealed absence of blood flow to the acardiac fetus after the second round of HIFU exposure, we concluded that complete occlusion of target vessels had been achieved. Delivery was by Cesarean section at 37 weeks' gestation. A male neonate (the pump fetus) was born weighing 1903 g with Apgar scores of 8 and 9 at 1 and 5 min, respectively. At the time of writing, the baby was healthy and growing normally, with the exception of congenital pseudarthrosis.

High-intensity focused ultrasound treatment for twin reversed arterial perfusion sequence.

Twin reversed arterial perfusion (TRAP) sequence is a serious complication of monochorionic twin pregnancies, in which arterioarterial anastomoses allow blood flow from a 'pump' fetus to an acardiac fetus via reversed flow in the latter's umbilical artery. Several trial treatments for TRAP sequence have been reported, but all of these have been invasive. We present a case of TRAP sequence in which high-intensity focused ultrasound (HIFU) was applied to the umbilical artery of the anomalous twin at 26 weeks as a non-invasive fetal therapy. The HIFU intensity was set at approximately 2300 W/cm(2) with exposure periods of 10 s. Color Doppler ultrasound showed a decrease in blood supply to the anomalous twin, although complete occlusion of the targeted vessel was not achieved. Delivery was by Cesarean section at 29 weeks' gestation and the pump twin survived, without severe clinical complications at 6 months.

Location of the placenta or the umbilical cord insertion site in the lowest uterine segment is associated with low maternal blood pressure.

OBJECTIVE: To evaluate whether placental abnormalities and umbilical cord insertion site affect the occurrence of pre-eclampsia and maternal blood pressure. DESIGN: Case-control study. SETTING: Showa University Hospital, Tokyo, Japan. POPULATION: A total of 5722 consecutive women who delivered singleton infants were included in the study. METHODS: The associations of placental abnormalities, the location of the placenta, the location of the cord insertion site, and maternal background with the occurrence of pre-eclampsia and maternal blood pressure at the term of pregnancy were analysed. MAIN OUTCOME MEASURE: Pre-eclampsia and maternal blood pressure at the term of pregnancy. RESULTS: Pre-eclampsia was observed in 236 women (4.1%). Pre-eclampsia was frequently observed in women with placental form abnormalities (odds ratio 3.0) and infarction of the placenta (odds ratio 5.3). Pre-eclampsia was observed in 0 and 4.1% of women with and without placenta praevia, respectively (P = 0.004), and in 0 and 2.5% of women with and without low cord insertion during the first trimester, respectively (P = 0.018). After adjustment for confounding variables, the multivariate regression analyses revealed reductions of 8.4 and 5.0 mmHg in systolic and diastolic blood pressure, respectively, in women with placenta praevia compared with women without placenta praevia, and reductions of 4.3 and 3.1 mmHg in systolic and diastolic blood pressure, respectively, in women with low cord insertion during the first trimester compared with women without low cord insertion. CONCLUSION: Not only placenta praevia but also low cord insertion are associated with low frequencies of pre-eclampsia and low maternal blood pressure.

Prediction of pre-eclampsia by an analysis of placenta-derived cellular mRNA in the blood of pregnant women at 15-20 weeks of gestation.

OBJECTIVE: A panel of cellular mRNA markers was used to predict the occurrence of pre-eclampsia in pregnant women at 15-20 weeks of gestation. DESIGN: Prospective cohort study. SETTING: The Department of Obstetrics and Gynaecology, University of Indonesia, Cipto Mangunkusumo National Hospital, Indonesia. SAMPLE: Peripheral blood samples from asymptomatic pregnant women. METHODS: Among 660 women, 62 developed pre-eclampsia at later gestation (pre-eclampsia group) and each case was matched with five controls. Therefore, the RNA expression levels in the cellular component of maternal blood in 62 women with pre-eclampsia were compared with those in 310 controls. MAIN OUTCOME MEASURES: The cellular RNA expression levels of genes related to angiogenesis and oxidative stress were compared between pre-eclampsia and control groups. A receiver operating characteristic (ROC) curve was used to analyse the sensitivity of each available marker. A logistic regression analysis was performed to calculate the odds for each woman to be classified as a case. RESULTS: The univariate ROC analysis identified soluble vascular endothelial growth factor receptor-1 (Flt-1) and endoglin (ENG) as the markers with the highest sensitivity. The best multivariate model was obtained by combining Flt-1, ENG, placental growth factor (PlGF) and parity. The relative ROC curve yielded a sensitivity of 66% at a 10% 1 - specificity rate with an area under the curve of 0.884 (P < 0.001). CONCLUSION: A panel of cellular mRNA markers in maternal blood can predict the development of pre-eclampsia long before clinical onset.

Detection of umbilical venous constriction by Doppler flow measurement at midgestation.

OBJECTIVES: To investigate whether umbilical venous velocity and venous velocity pulsation are associated with umbilical vein diameter, umbilical ring diameter and umbilical cord coiling index at midgestation. METHODS: Two hundred and eighty pregnant women were enrolled in the study at between 18 and 24 weeks of gestation. The diameter of the umbilical cord and internal diameter of the umbilical vein in a free loop and at the ring, and the umbilical coiling index, were measured using ultrasonography. Umbilical venous velocities were measured by Doppler ultrasonography at the umbilical ring and a free loop of the cord. RESULTS: All variables were successfully measured in 92% of the patients. There were negative correlations between the diameters of the umbilical ring and of the umbilical vein at the ring and the venous velocity at the umbilical ring. The venous velocity at the umbilical ring was significantly higher and the umbilical ring diameter was significantly lower in fetuses with umbilical venous pulsation at the free loop. Significant correlations were observed between the venous velocity and amplitude of pulsation. Venous pulsations at the free loop were frequently observed in fetuses with a hypercoiled cord. CONCLUSION: High venous velocity and increased venous pulsation at the umbilical ring may be associated with umbilical cord constriction.

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer.

BACKGROUND: Reduced expression of cluster of differentiation (CD) 133 and cyclo-oxygenase (COX) 2, and increased density of CD8+ tumour-infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts. METHODS: Patients with low rectal cancer who underwent radical resection and preoperative short-term CRT in 2001-2007 (retrospective cohort) and long-term CRT in 2011-2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX-2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival. RESULTS: For 95 patients in the retrospective cohort, the incidence of TRG 3-4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3-4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence-free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively). CONCLUSION: Assessment of CD133, COX-2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.

ANTECEDENTES: La expresión reducida de CD133 and COX-2, y un aumento en la densidad de los linfocitos infiltrantes del tumor CD8+ se han asociado recientemente con una respuesta favorable del tumor a la quimiorradioterapia preoperatoria (preoperative chemoradiotherapy, CRT). Este estudio evaluó estos marcadores respecto a la respuesta del tumor tras CRT preoperatoria en dos cohortes de cáncer colorrectal. MÉTODOS: Se analizaron pacientes con cáncer de recto bajo sometidos a resección radical y CRT preoperatoria de corta duración entre 2001-2007 (cohorte retrospectiva) y CRT de larga duración entre 2011-2017 (cohorte prospectiva). Se realizó tinción inmunohistoquímica (immunohistochemical, IHC) con anticuerpos para CD133, COX-2 y CD8 en las biopsias previas al tratamiento. Las características de interés incluyeron la disminución en las expresiones de CD133 y COX-2, y la densidad aumentada de CD8+. Las variables de interés fueron los grados de regresión tumoral (tumour regression grades, TRG) de acuerdo con Rödel, la reducción del estadio tumoral y las supervivencias. RESULTADOS: La cohorte retrospectiva incluyó 95 pacientes. En este subgrupo, la incidencia de TRGs 3-4 fue del 66,7% en pacientes con dos o tres características de la IHC, mientras que solo fue del 20,0% en pacientes con ninguna o con una característica (P < 0,001). Además, la incidencia de disminución del estadio tumoral fue más alta en pacientes que mostraban al menos dos características IHC (43,3%) que en los controles (21,5%; P = 0,029). En la cohorte prospectiva se incluyeron 49 pacientes y la incidencia de estos hallazgos fue similar (TRG 3-4, 76,2% en ≥ 2 características IHC versus 25,0% en los controles, P < 0,001; disminución del estadio tumoral, 57,1% en ≥ 2 características IHC versus 25,0% en los controles, P = 0,022). La supervivencia libre de recidiva local fue similar en las cohortes retrospectiva y prospectiva, cuando se compararon subgrupos de acuerdo con las características IHC (P = 0,058 y 0,387, respectivamente) CONCLUSIÓN: Este estudio sugiere que la evaluación de CD133, COX-2 y CD8 podría ser útil para la predicción de una buena respuesta a la CRT preoperatoria en pacientes con cáncer de recto bajo sometidos a tratamiento neoadyuvante. Se necesitan estudios adicionales para validar los resultados en amplias cohortes e investigar el beneficio en la supervivencia.

Predisposing factors for massive hemorrhage during Cesarean section in patients with placenta previa.

OBJECTIVES: To investigate whether maternal history and ultrasound findings can be predictors for massive hemorrhage during Cesarean section in patients with placenta previa and adherence of the placenta. METHODS: We reviewed 127 singleton pregnancies with placenta previa. Maternal history, antenatal ultrasound findings of the placenta, including location, presence of placental lacunae, lack of a clear zone, presence of sponge-like findings of the cervix and presence of a marginal sinus in cases of placenta previa were reviewed retrospectively, and their association with amount of bleeding during Cesarean section was analyzed. RESULTS: Logistic regression analysis revealed that advanced maternal age (odds ratio (OR), 5.4; 95% CI, 1.8-16.4), previous Cesarean section (OR, 20.4; 95% CI, 4.0-105.2) and sponge-like findings in the cervix (OR, 5.6; 95% CI, 1.8-17.0) were associated with massive bleeding (> 2500 mL). Placental adherence occurred in five cases and was more frequent in cases where the placenta was located at the site of the scar of a previous Cesarean section (OR, 123.1; 95% CI, 4.5-3395.2) and where there was lack of a clear zone (OR, 48.0; 95% CI, 3.8-604.7). CONCLUSIONS: Advanced maternal age, previous Cesarean section and presence of sponge-like findings in the cervix are risk factors for massive bleeding during Cesarean section in cases of placenta previa, regardless of whether placental adherence is present. Placental location on the scar of a previous Cesarean section and lack of a clear zone are risk factors for placental adherence. When these findings are identified preoperatively, management should be tailored accordingly.

Measurement of mRNA of trophoblast-specific genes in cellular and plasma components of maternal blood.

BACKGROUND: Placental mRNA in maternal plasma is suitable for quantitative analysis regardless of fetal gender and genetic polymorphism status. METHODS: We obtained 155 blood samples from pregnant women to compare human placental lactogen (hPL) and beta-subunit of human chorionic gonadotropin (beta hCG) mRNA and protein levels between the cellular and plasma components of maternal blood. To assess clearance of hPL mRNA expression, we obtained blood samples from nine women immediately before and after delivery by caesarean section. mRNA was extracted from the cellular and plasma components of all samples, and hPL and beta hCG mRNA expression was analysed by reverse transcription-PCR assay. RESULTS: The concentration of beta hCG mRNA in the cellular component positively correlated with the plasma concentration of beta hCG protein and beta hCG mRNA (p = 0.001 for both). The concentration of hPL protein in the plasma correlated with the hPL mRNA concentration of the cellular component (p<0.05). For both hPL and beta hCG, the mRNA concentration of the cellular component was greater than that of the plasma component (22.9-fold higher for hPL and 4.3-fold higher for beta hCG). The half life of hPL mRNA clearance was significantly longer for the cellular fraction (mean half life = 203.8 min, range 150-3465 min) than for the plasma fraction (mean half life = 32.2 min, range 15-385 min) (p = 0.008). CONCLUSION: The present findings indicate that the concentration of hPL and beta hCG mRNA is significantly higher in the cellular component of maternal blood samples than in the plasma component. Cellular mRNA in maternal blood is useful for non-invasive evaluation of placental function.

Placenta previa with early opening of the uterine isthmus is associated with high risk of bleeding during pregnancy, and massive haemorrhage during caesarean delivery.

OBJECTIVE: To demonstrate the relationship between the timing of opening of the uterine isthmus and bleeding during pregnancy and caesarean section in patients with placenta previa. METHODS: A prospective observational study was conducted at a single perinatal centre. All patients with placenta previa, diagnosed between 20 and 22 weeks of gestation, who were followed up at the study hospital and underwent caesarean section were enrolled. The condition of the uterine isthmus was examined every 2 weeks. The timing (in gestational weeks) of complete opening of the uterine isthmus was determined. Patients were divided into two groups: patients in whom the uterine isthmus opened before 25 weeks of gestation (EO-previa), and patients in whom the uterine isthmus opened after 25 weeks of gestation (LO-previa). The frequency of bleeding during pregnancy and the amount of intra-operative bleeding were compared between the two groups. RESULTS: Forty-four cases of EO-previa and 55 cases of LO-previa were analysed. Complete placenta previa at delivery was observed more frequently in the EO-previa group than in the LO-previa group (88.6% vs 47.3%, p<0.001). An emergency caesarean section due to active bleeding was performed more frequently in the EO-previa group (48%) than in the LO-previa group (25%) (p=0.021). The frequency of massive haemorrage (>2500ml) during caesarean section was higher in the EO-previa group than in the LO-previa group (25% vs 9%, p=0.033). CONCLUSION: Placenta previa was associated with a high risk of bleeding leading to emergency caesarean section during pregnancy, and massive haemorrhage during caesarean section in patients in whom the uterine isthmus opened before 25 weeks of gestation.

Velamentous cord insertion and atypical variable decelerations with no accelerations.

OBJECTIVES: To examine intrapartum fetal heart rate (FHR) patterns in the presence of velamentous cord insertion (VCI). METHODS: The site of cord insertion was determined in 1460 women on antenatal ultrasonographic and postnatal examinations. Each of 24 women with pregnancies complicated with VCI was matched at the onset of labor with 10 women who had a normal pregnancy, and FHR patterns were analyzed for both cases and controls. RESULTS: Compared with controls, cases of variable decelerations with no accelerations (VDNA) during the first and second stages of labor were more frequent in women with VCI (first stage: 25% vs. 5.1%, second stage: 65.0% vs. 21.7%, P < 0.001). The adjusted odds ratio associated with VDNA occurrence in women with VCI was 3.83 (95% confidence interval [CI]: 1.51-9.72, P = 0.005). The mean odds ratio associated with length of aberrant vessels in women with VCI plus VDNA was 1.38 (95% CI: 1.04-1.83, P = 0.026). CONCLUSION: Pregnancies complicated with VCI are associated with a higher rate of VDNA.