Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Changing the standardised obstetric care by expanded carrier screening and counselling: a multicentre prospective cohort study.

BACKGROUND: Expanded genetic screening before conception or during prenatal care can provide a more comprehensive evaluation of heritable fetal diseases. This study aimed to provide a large cohort to evaluate the significance of expanded carrier screening and to consolidate the role of expanded genetic screening in prenatal care. METHODS: This multicentre, retrospective cohort study was conducted between 31 December 2019 and 21 July 2022. A screening panel containing 302 genes and next-generation sequencing were used for the evaluation. The patients were referred from obstetric clinics, infertility centres and medical centres. Genetic counsellors conducted consultation for at least 15 min before and after screening. RESULTS: A total of 1587 patients were screened, and 653 pairs were identified. Among the couples who underwent the screening, 62 (9.49%) had pathogenic variants detected on the same genes. In total, 212 pathogenic genes were identified in this study. A total of 1173 participants carried at least one mutated gene, with a positive screening rate of 73.91%. Among the pathogenic variants that were screened, the gene encoding gap junction beta-2 (GJB2) exhibited the highest prevalence, amounting to 19.85%. CONCLUSION: Next-generation sequencing carrier screening provided additional information that may alter prenatal obstetric care by 9.49%. Pan-ethnic genetic screening and counselling should be suggested for couples of fertile age.

Nonlinear Stiffness and Nonlinear Damping in Atomically Thin MoS2 Nanomechanical Resonators.

We report on experimental measurements and quantitative analyses of nonlinear dynamic characteristics in ultimately thin nanomechanical resonators built upon single-layer, bilayer, and trilayer (1L, 2L, and 3L) molybdenum disulfide (MoS2) vibrating drumhead membranes. This synergistic study with calibrated measurements and analytical modeling on observed nonlinear responses has led to the determination of nonlinear damping and stiffness coefficients at cubic and quintic orders for these two-dimensional (2D) resonators operating in the very high frequency (VHF) band (up to ∼90 MHz). We find that the quintic force can be ∼20% of the Duffing force at larger amplitudes, and thus, it generally cannot be ignored in a nonlinear dynamics analysis. This study provides the first quantification of nonlinear damping and frequency detuning characteristics in 2D semiconductor nanomechanical resonators and elucidates their origins and dependency on engineerable parameters, setting a foundation for future exploration and utilization of the rich nonlinear dynamics in 2D nanomechanical systems.

The impact of prenatal screening tests on prenatal diagnosis in Taiwan from 2006 to 2019: a regional cohort study.

BACKGROUND: The purpose of this study is to evaluate the impact of prenatal screening tests on prenatal diagnosis in Taiwan's 14 years from 2006 to 2019. METHODS: The prenatal screening methods evolved from the second-trimester serum screening to combined first-trimester screening (cFTS) and then followed by the non-invasive cell-free DNA prenatal test (NIPT). The data used by the Department of Statistics, the Ministry of Health and Welfare and Department of Household Registration, Ministry of the Interior public website. RESULTS: This regional registry-based cohort retrospective study examined a total of 2,775,792 births from January 2006 to December 2019. The proportion of advanced maternal age (AMA) pregnancies increased from 11.63% in 2006 to 30.94% in 2019. Overall, invasive diagnostic testing was used in 87.22% of AMA pregnancies. The prenatal detection rate of trisomy 21 and 18 increased from 74.1% and 83.3% in 2006 to 96.9% and 98.8% in 2019, respectively. CONCLUSION: During the second-trimester and cFTS periods, the percentage of AMA pregnancies increased every year and the number of invasive procedures also accompany with increased percentage of AMA. However, during the period that NIPT were implemented, the percentage of invasive procedures decreased.

Human amniotic fluid stem cells can improve cerebral vascular remodelling and neurological function after focal cerebral ischaemia in diabetic rats.

Diabetes causes vascular injury and carries a high risk of ischaemic stroke. Human amniotic fluid stem cells (hAFSCs) can enhance cerebral vascular remodelling and have the potential to improve neurological function after stroke in diabetic rats. Five groups of female rats were examined: (1) normal control, (2) type 1 diabetic (T1DM) rats induced by streptozotocin injection (DM), (3) non-DM rats receiving 60-minute middle cerebral artery occlusion (MCAO), (4) T1DM rats receiving 60-minute MCAO (DM + MCAO) and (5) T1DM rats receiving 60-minute MCAO and injection with 5 × 106  hAFSCs at 3 h after MCAO (DM + MCAO + hAFSCs). Neurological function was examined before, and at 1, 7, 14, 21 and 28 days, and cerebral infarction volume and haemorrhage, cerebral vascular density, angiogenesis and inflammatory were examined at 7 and 28 days after MCAO. hAFSCs treatment caused a significant improvement of neurological dysfunction, infarction volume, blood-brain barrier leakage, cerebral arterial density, vascular density and angiogenesis and a reduction of brain haemorrhage and inflammation compared with non-treatment. Our results showed that the effect of hAFSCs treatment against focal cerebral ischaemia may act through the recovery of vascular remodelling and angiogenesis and the reduction of inflammation in ischaemic brain.

Current update of first trimester preeclampsia screening in Asia.

In consideration of high prevalence of preeclampsia, enormous studies attempted to look for strategies in early gestation. Hence, a powerful screening should be built up in first trimester. Then, Aspirin could be administrated for proper prevention. The objective of this article is reviewing the screening for preeclampsia in first trimester recently. To identify the high-risk group precisely, an effective model should be recommended to Asian population. Articles related to first trimester screening of PE in Asia from databases of PubMed, ScienceDirect and Scopus were searched for this narrative review. The criteria included randomized clinical trials, observational prospective and retrospective cohort studies, case-control studies, systematic review and meta-analysis and professional review articles. Screening models combining maternal factors, biophysical factors, ultrasound studies and biochemical factors achieved high predictive performance of preeclampsia. In Asia, the detection rate of the Fetal Medicine Foundation is superior to those of the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. Consequently, this effective model from the Fetal Medicine Foundation should be continuously used for screening in first trimester for the Asian.

A Taiwan's experience: A case report and review of literature of successful early intrauterine treatment with radiofrequency ablation in twin reversed arterial perfusion (TRAP) sequence.

Acardiac twin or twin reversed arterial perfusion (TRAP) sequence is a rare medical complication of Monozygotic twins. Taiwanese Obstetricians usually treat TRAP sequence conservatively. Occasionally, repeated amnio-reduction is performed to decompress the polyhydramnios caused by the TRAP sequence, even though there was no correction of the pathophysiologic mechanism. Radiofrequency ablation is a minimally invasive, percutaneous technique that can effectively obliterate blood supply to an acardiac twin to preserve and protect the pump twin. This recent technique has never been used before for the treatment of the TRAP sequence in Taiwan. This article reported the first-hand experience of acardiac twin management with RFA in Taipei Chang Gung Memorial Hospital.

Taiwanese Clinical Experience with Noninvasive Prenatal Testing for DiGeorge Syndrome.

OBJECTIVE: DiGeorge syndrome (DGS) is associated with microdeletions of chromosome 22q11. It is the second most common cause of congenital heart disease and is an important consideration whenever a conotruncal cardiac anomaly is identified. The availability of noninvasive prenatal testing (NIPT) is altering the practice of prenatal genetics and maternal-fetal medicine, resulting in a decline in invasive testing. Antenatal ultrasound and other biomarkers have their own limitation. NIPT was proposed to screen DGS with cell-free DNA in Taiwan. Here, we present our experience of prenatal diagnosis of DGS in our center. METHODS: This was a retrospective study between November 1, 2019, and August 31, 2020, in Taiwan. Data were collected from 7,826 pregnant women self-referred for DGS screening with massive parallel shotgun sequencing-based NIPT. High-risk cases subsequently received amniocentesis for array comparative genomic hybridization (aCGH) to confirm the diagnosis. Characteristics of pregnancies were documented when participants received the test. Report of NIPT was completed 2 weeks after the test. Follow-up on high-risk cases was completed by telephone interview on January 30, 2021. RESULTS: Thirteen cases showed high risk by NIPT, and 7 cases were confirmed by aCGH. The sensitivity and specificity were 100% (95% confidence interval [CI] 64.57-100.00%) and 99.92% (95% CI 99.83-99.96%). The prevalence of DGS was 1 in 1,118 pregnancies. The positive predictive rate was 53.85% (95% CI 29.14-76.79%). One true positive (TP) showed US anomaly, and 5 TPs selected termination. DISCUSSION/CONCLUSION: NIPT demonstrated good performance in DGS screening. Detection of 22q11.2 deletion could be combined with routine screening to facilitate proper intervention.

Fetal surgery and stem cell therapy for meningomyelocele.

PURPOSE OF REVIEW: To review the advance of maternal--fetal surgery, the research of stem cell transplantation and tissue engineering in prenatal management of fetal meningomyelocele (fMMC). RECENT FINDINGS: Advance in the imaging study provides more accurate assessment of fMMC in utero. Prenatal maternal--fetal surgery in fMMC demonstrates favourable postnatal outcome. Minimally invasive fetal surgery minimizes uterine wall disruption. Endoscopic fetal surgery is performed via laparotomy-assisted or entirely percutaneous approach. The postnatal outcome for open and endoscopic fetal surgery shares no difference. Single layer closure during repair of fMMC is preferred to reduce postnatal surgical intervention. All maternal--fetal surgeries impose anesthetic and obstetric risk to pregnant woman. Ruptured of membrane and preterm delivery are common complications. Trans-amniotic stem cell therapy (TRASCET) showed potential tissue regeneration in animal models. Fetal tissue engineering with growth factors and dura substitutes with biosynthetic materials promote spinal cord regeneration. This will overcome the challenge of closure in large fMMC. Planning of the maternal--fetal surgery should adhere to ethical framework to minimize morbidity to both fetus and mother. SUMMARY: Combination of endoscopic fetal surgery with TRASCET or tissue engineering will be a new vision to achieve to improve the outcome of prenatal intervention in fMMC.

Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population.

BACKGROUND: The administration of aspirin <16 weeks gestation to women who are at high risk for preeclampsia has been shown to reduce the rate of preterm preeclampsia by 65%. The traditional approach to identify such women who are at risk is based on risk factors from maternal characteristics, obstetrics, and medical history as recommended by the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. An alternative approach to screening for preeclampsia has been developed by the Fetal Medicine Foundation. This approach allows the estimation of patient-specific risks of preeclampsia that requires delivery before a specified gestational age with the use of Bayes theorem-based model. OBJECTIVE: The purpose of this study was to examine the diagnostic accuracy of the Fetal Medicine Foundation Bayes theorem-based model, the American College of Obstetricians and Gynecologists, and the National Institute for Health and Care Excellence recommendations for the prediction of preterm preeclampsia at 11-13+6 weeks gestation in a large Asian population STUDY DESIGN: This was a prospective, nonintervention, multicenter study in 10,935 singleton pregnancies at 11-13+6 weeks gestation in 11 recruiting centers across 7 regions in Asia between December 2016 and June 2018. Maternal characteristics and medical, obstetric, and drug history were recorded. Mean arterial pressure and uterine artery pulsatility indices were measured according to standardized protocols. Maternal serum placental growth factor concentrations were measured by automated analyzers. The measured values of mean arterial pressure, uterine artery pulsatility index, and placental growth factor were converted into multiples of the median. The Fetal Medicine Foundation Bayes theorem-based model was used for the calculation of patient-specific risk of preeclampsia at <37 weeks gestation (preterm preeclampsia) and at any gestation (all preeclampsia) in each participant. The performance of screening for preterm preeclampsia and all preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and placental growth factor (triple test) was evaluated with the adjustment of aspirin use. We examined the predictive performance of the model by the use of receiver operating characteristic curve and calibration by measurements of calibration slope and calibration in the large. The detection rate of screening by the Fetal Medicine Foundation Bayes theorem-based model was compared with the model that was derived from the application of American College of Obstetricians and Gynecologists and National Institute for Health and Care Excellence recommendations. RESULTS: There were 224 women (2.05%) who experienced preeclampsia, which included 73 cases (0.67%) of preterm preeclampsia. In pregnancies with preterm preeclampsia, the mean multiples of the median values of mean arterial pressure and uterine artery pulsatility index were significantly higher (mean arterial pressure, 1.099 vs 1.008 [P<.001]; uterine artery pulsatility index, 1.188 vs 1.063[P=.006]), and the mean placental growth factor multiples of the median was significantly lower (0.760 vs 1.100 [P<.001]) than in women without preeclampsia. The Fetal Medicine Foundation triple test achieved detection rates of 48.2%, 64.0%, 71.8%, and 75.8% at 5%, 10%, 15%, and 20% fixed false-positive rates, respectively, for the prediction of preterm preeclampsia. These were comparable with those of previously published data from the Fetal Medicine Foundation study. Screening that used the American College of Obstetricians and Gynecologists recommendations achieved detection rate of 54.6% at 20.4% false-positive rate. The detection rate with the use of National Institute for Health and Care Excellence guideline was 26.3% at 5.5% false-positive rate. CONCLUSION: Based on a large number of women, this study has demonstrated that the Fetal Medicine Foundation Bayes theorem-based model is effective in the prediction of preterm preeclampsia in an Asian population and that this method of screening is superior to the approach recommended by American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. We have also shown that the Fetal Medicine Foundation prediction model can be implemented as part of routine prenatal care through the use of the existing infrastructure of routine prenatal care.

Bifurcation Generated Mechanical Frequency Comb.

We demonstrate a novel response of a nonlinear micromechanical resonator when operated in a region of strong, nonlinear mode coupling. The system is excited with a single drive signal and its response is characterized by periodic amplitude modulations that occur at timescales based on system parameters. The periodic amplitude modulations of the resonator are a consequence of nonlinear mode coupling and are responsible for the emergence of a "frequency-comb" regime in the spectral response. By considering a generic model for a 1∶3 internal resonance, we demonstrate that the novel behavior results from a saddle node on an invariant circle (SNIC) bifurcation. The ability to control the operating parameters of the micromechanical structures reported here makes the simple micromechanical resonator an ideal test bed to study the dynamic response of SNIC behavior demonstrated in mechanical, optical, and biological systems.

Structural optimization for nonlinear dynamic response.

Much is known about the nonlinear resonant response of mechanical systems, but methods for the systematic design of structures that optimize aspects of these responses have received little attention. Progress in this area is particularly important in the area of micro-systems, where nonlinear resonant behaviour is being used for a variety of applications in sensing and signal conditioning. In this work, we describe a computational method that provides a systematic means for manipulating and optimizing features of nonlinear resonant responses of mechanical structures that are described by a single vibrating mode, or by a pair of internally resonant modes. The approach combines techniques from nonlinear dynamics, computational mechanics and optimization, and it allows one to relate the geometric and material properties of structural elements to terms in the normal form for a given resonance condition, thereby providing a means for tailoring its nonlinear response. The method is applied to the fundamental nonlinear resonance of a clamped-clamped beam and to the coupled mode response of a frame structure, and the results show that one can modify essential normal form coefficients by an order of magnitude by relatively simple changes in the shape of these elements. We expect the proposed approach, and its extensions, to be useful for the design of systems used for fundamental studies of nonlinear behaviour as well as for the development of commercial devices that exploit nonlinear behaviour.

The properties of absorbable scaffold harvested with human amniotic fluid stem cells on rat model: an innovation for pelvic reconstruction surgery.

The current practice of restoring the anatomical structure in the treatment of pelvic floor dysfunction includes implantation of synthetic sling, which carries potential complications. This study aimed to develop biological substitutes to improve tissue function using scaffolds as a support to the host cells, through formation of new tissue. Human amniotic fluid stem cells (hAFSCs) were seeded on synthetic mesh-scaffold of AlloDerm Regenerative Tissue Matrix (RTM), Poly-DL-lactico-glycolic acid (PLGA) mesh (VICRYL) and Polydioxanone (PDS) meshes. In vitro study evaluates the metabolic activity of hAFSCs seeded mesh-scaffolds. In vivo study involving Sprague-Dawley rats was performed by assigning into 7 groups of sham control with fascia operation, AlloDerm implant, PDS implant, PLGA implant, AlloDerm harvest with hAFSC (AlloDerm-SC), PDS harvest with hAFSC(PDS-SC) and PLGS harvest with hAFSC (PGLA-SC). In vitro study reveals cell viability and proliferation of hAFSC on mesh scaffolds varies between meshes, with AlloDerm growing the fastest. The biomechanical properties of tissue-mesh-complex tension strength declined over time, showing highest tension strength on week-1, deteriorated similar to control group on week-12. All hAFSC-seeded mesh provides higher tension strength, compared to without. This study shed the potential of synthetic mesh as a scaffold for hAFSC for the surgical treatment of pelvic floor dysfunction.

Influence of gestational hypertension and maternal air pollutant exposure on birth outcomes.

The relationship between exposure to air pollutants and fetal growth outcomes has shown inconsistency, and only a limited number of studies have explored the impact of air pollution on gestational hypertension and birth outcomes. This study aimed to evaluate how maternal exposure to air pollutants and blood pressure could influence fetal birth outcomes. A total of 55 women with gestational hypertension and 131 healthy pregnant women were enrolled in this study. Data pertaining to personal characteristics, prenatal examinations, outdoor air pollutant exposure, and fetal birth outcomes were collected. The study revealed that fetal birth weight and abdominal circumference exhibited a significant reduction among women with gestational hypertension compared to healthy pregnant women, even after adjustments for body mass index, gestational age, and exposure to air pollutants had been made. Moreover, maternal exposure to outdoor air pollutants displayed a notable correlation with decreased birth length of fetuses. Consequently, the study concluded that maternal blood pressure and exposure to outdoor air pollutants during pregnancy potentially stand as pivotal factors influencing fetal birth outcomes.

Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

OBJECTIVES: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. RESULTS: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). CONCLUSION: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

Controllable branching of robust response patterns in nonlinear mechanical resonators.

In lieu of continuous time active feedback control in complex systems, nonlinear dynamics offers a means to generate desired long-term responses using short-time control signals. This type of control has been proposed for use in resonators that exhibit a plethora of complex dynamic behaviors resulting from energy exchange between modes. However, the dynamic response and, ultimately, the ability to control the response of these systems remains poorly understood. Here, we show that a micromechanical resonator can generate diverse, robust dynamical responses that occur on a timescale five orders of magnitude larger than the external harmonic driving and these responses can be selected by inserting small pulses at specific branching points. We develop a theoretical model and experimentally show the ability to control these response patterns. Hence, these mechanical resonators may represent a simple physical platform for the development of springboard concepts for nonlinear, flexible, yet robust dynamics found in other areas of physics, chemistry, and biology.