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Implementation of first-trimester screening and prevention of preeclampsia: a stepped wedge cluster-randomized trial in Asia FORECAST (FORECAST)

Implementation of first-trimester screening and prevention of preeclampsia (FORECAST)

5653

Patients who met all inclusion criteria and none of the exclusion criteria defined below were enrolled in the study. (1) Inclusion criteria: 1) 18 years or older, 2) singleton pregnancy, 3) viable fetus. (2) Exclusion criteria: 1) multiple pregnancy, 2) major fetal disease at evaluation at 11-13 weeks gestation, 3) non-viable fetus (spontaneous abortion or stillbirth). (3) Target population for low-dose aspirin administration (162 mg/day in Japan): The study subjects enrolled in the intervention period, who were screened for preterm-PE during the first trimester (11 to 13 weeks of gestation) with a combination test of maternal factors, MAP, UtA-PI and PIGF for preterm-PE, and who was identified to be a high-risk pregnancy for preterm-PE. (4) Discontinuation criteria: 1) if the study subject declines to participate in the study or withdraws consent; 2) if the subject is found to be not eligible after enrolment; 3) miscarriage; 4) if a serious adverse event or illness occurs for which a causal link to low-dose aspirin cannot be denied (except for small amounts of genital bleeding, for which continued administration of low-dose aspirin is deemed acceptable); 5) when it is deemed appropriate to discontinue the study for other reasons.

(1) Study design: A multicenter study Stepped Wedge Cluster Randomized Trial (Stepped Wedge CRT) involving birth/diagnosis units from eight regions in Asia. (2) Process and period of clinical research, recruitment of research participants, randomization: Divide eight regions and facilities in Asia into seven clusters (seven groups), randomize the timing of intervention at the cluster level, and sequentially shift from the observation period to the intervention period (intervention is applied sequentially by staggering the introduction period). This study includes non-intervention periods in all recruitment units, i.e. regular antenatal care and regular periods (every 6 weeks). One cluster will be randomized to transition from the non-intervention group to the intervention group. In the intervention arm, first-trimester screening for preterm-PE by the Fetal Medicine Foundation Bayes theorem-based model (maternal factors, MAP, UtA-PI and PlGF) was performed to calculate the patient-specific risk for preterm PE. In high-risk women, low-dose aspirin (150 mg/night if > 40 kg; 150 or 162 mg (only in Japan)/night for those weighing 40 kg or more, from less than 15 weeks to 36 weeks and 0 day, or until the onset of labor if labor is begun) is started. All clusters are randomized with computer-generated random numbers, and the start of randomization for each cluster is kept confidential until 3 weeks prior to its date. Randomization is performed by a trial statistician. (2) Specific procedures in clinical research 1) [Non-intervention group] Consent acquisition and follow-up Among pregnant women who visited the hospital with the chief complaint of pregnancy, pregnant women who had a normal intrauterine pregnancy at less than 11 weeks of gestation and whose expected delivery date was confirmed, used the explanatory document about this study at 11 to 13 weeks of gestation, Give a detailed explanation. Gestational weeks (X weeks and Y days) are determined by the due date calculator at the participating institution or by ultrasonography results. For pregnant women who agreed to participate in the study, the presence or absence of labor at the time of delivery, gestation period and mode of delivery, indication for medical delivery intervention, fetal sex and birth weight, Apgar score, NICU hospitalization for 24 hours or more, and during pregnancy Explain that information on the presence or absence of hypertensive complications will be obtained from the electronic medical record of our hospital. 2) [Intervention group] Explanation about screening and obtaining informed consent Brief information that the study was conducted between 11 and 13 weeks of gestation for pregnant women who visited the hospital with the chief complaint of pregnancy and who had a normal intrauterine pregnancy before 11 weeks' gestation and had a confirmed due date. Provide in advance. Gestational weeks (X weeks and Y days) are determined by the due date calculator at the participating institution or by ultrasonography results. After that, when the patient visits the hospital during the 11th to 13th week of pregnancy, a detailed explanation about the research will be given using the informed consent form for this research. Maternal information (pregnancy history, obstetric history, medical history and drug history including aspirin intake) was collected from pregnant women who agreed to participate in the study at that time, and a part of the case report (blood test request form and case registration form) was collected. ) and mail it to the person in charge of data management. 3) Blood sample collection and ultrasound examination An ultrasound examination and a blood test will be performed on the same day as consent is obtained. Maternal MAP and UtA-PI are measured according to standardized protocols 12,13). In order to measure the PlGF level in serum, blood was collected in advance using a 6 mL Terumo Venoject II vacuum blood collection tube (with separation material) distributed by Ritz Medical Co., Ltd., and promptly stored at 4 C. After sending the blood collection tube, request form, and checklist to Ritz Medical Co., Ltd. by courier, we will notify you by email that the sample has been sent. Ritz Medical Co., Ltd. will confirm the receipt of the sample and reply by email to the effect that it has been received and whether there are any deficiencies in the case report form. Ritz Medical Co., Ltd. will contact each facility by e-mail regarding the determination of PE risk. 4) PE risk assessment and administration of low-dose aspirin The risk of preterm-PE for individual study participants is calculated using Bayesian methods. Pregnant women at high risk of PE (top 10 % of screening population) should be invited for a follow-up visit for counseling and encouraged to take low-dose aspirin from < 15 weeks' gestation until 36 weeks' gestation. Pregnant women who accept PE prophylaxis with low-dose aspirin are prescribed low-dose aspirin. Subsequent visits will follow the antenatal care schedule of participating sites and will be treated similarly to those not taking low-dose aspirin. 5) Follow up Data on participating sites and maternal demographics were recorded, maternal demographics including maternal age, BMI, racial background, obstetric history, and medical history. When you visit the hospital for antenatal care, check your dosing diary to make sure you are taking low-dose aspirin. Presence or absence of labor at delivery, gestational period and mode of delivery, indication for iatrogenic delivery, fetal sex and birth weight, Apgar score, NICU hospitalization for 24 hours or more, presence or absence of hypertensive complications during pregnancy, and during pregnancy Collect information such as low-dose aspirin intake (dosage and indications), as well as collect a dosing diary. The observation period for safety evaluation is from study participation to 1 month after parturition. Patients at high risk of PE will be followed up according to protocol at participating institutions. To evaluate a series of processes to assess whether early pregnancy screening for preterm-PE is performed according to standards and to assess the uptake and safety of prophylactic low-dose aspirin in high-risk pregnant women. Quality assurance of biomarkers (MAP, UtA-PI and PlGF) must be assessed using target plots and cumulative sum control charts every 3 months at all participating centers. Pregnant women's acceptance of PE screening and low-dose aspirin prophylaxis will also be assessed by the proportion of all pregnant women who consent to PE screening and those at high risk of PE who consent to start low-dose aspirin prophylaxis. Regarding compliance and abnormalities during pregnancy, at follow-up visits at 16-20 weeks gestation, 28-32 weeks gestation and around 30 days after delivery or after final low-dose aspirin administration (supplemented by telephone interview if necessary) , with a dosing diary provided to study participants (a diary recording daily low-dose aspirin self-administration and side effects). The safety of low-dose aspirin will also be assessed by the percentage of pregnant women who experienced low-dose aspirin-related adverse side effects (allergic reactions, nausea, vomiting, upper or lower gastrointestinal symptoms, fever, etc.) during the study period.

1) Mild adverse events (those with unclear causal relationship to low dose aspirin): 23 cases 2) Serious adverse events (those with a clear causal relationship to low dose aspirin): 2 cases (1 case of bleeding from the cervix, 1 case of bleeding from placenta previa/placenta low lying)

Primary outcome Incidence of preeclampsia before 37 weeks of gestation (preterm-PE) : Non-intervention period: 0.71 %; intervention period: 0.85 % The incidence of preterm-PE remained similar and did not decrease with low-dose aspirin intervention . However, it delayed the onset of preterm-PE by approximately 4 weeks. During pregnancy, PE was actually diagnosed in 17 cases (6.23 %) in the non-intervention period and 32 cases (7.54 %) in the intervention period. Non-Intervention phase (17 cases) Diagnosis of PE (Weeks) < 34wks >=34, <37wks >=37wks Number of cases 9 1 7 Gestational Weeks of Diagnosis (Average) 28.79 34.29 38.67 Gestational Weeks of Diagnosis (Median) 30.71 34.29 38.86 Diagnosis of weeks <37 Wks Number of cases 10 Gestational Weeks of Diagnosis (Average) 29.34 Gestational Weeks of Diagnosis (Median) 30.86 Intervention phase (32 cases) Diagnosis of weeks <34wks >=34, <37wks >=37wks Number of cases 11 15 6 Gestational Weeks of Diagnosis (Average) 30.65 35.47 38.00 Gestational Weeks of Diagnosis (Median) 32.00 35.43 38.14 Diagnosis of weeks <37 Wks Number of cases 26 Gestational Weeks of Diagnosis (Average) 33.43 Gestational Weeks of Diagnosis (Median) 34.86 Secondary Outcome Birth weight (grams) and mean/median values (grams) of babies born to pregnant women diagnosed with PE at less than 37 weeks of gestation (non-intervention period, intervention period) Birth weight (average) (median) Non-intervention period 1721g 1891g Intervention period 2067g 2090g

This Japan-only analysis shows that for pregnant women diagnosed as high-risk for preterm PE by screening at 11-13 weeks' gestation, low-dose aspirin administered as early as possible may delay the onset of early-onset PE by approximately 2 weeks and may also delay the onset of preterm-PE by delaying the onset of PE by approximately 4 weeks, which may result in a birth weight of approximately 200-300 g heavier. low-dose aspirin treatment may contribute to improving the prognosis of both.

Sept. 30, 2023

No

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs041190035

Shiozaki Arihiro

Toyama University Hospital

2630 Sugitani, Toyama

s33shio@med.u-toyama.ac.jp

Shiozaki Arihiro

Toyama University Hospital

2630 Sugitani, Toyama

+81-76-434-7357

s33shio@med.u-toyama.ac.jp

Complete

May. 30, 2019

Interventional

non-randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

Singleton pregnancy

Multiple pregnancy, Major fetal defects identified at 11-13 weeks of assessment, Non-viable fetus

Female

High-risk pregnancy for preterm-preeclampsia identified by screening at 11-13 weeks

Low-dose aspirin is prescribed every night from before 15 weeks to 36 weeks of gestation to prevent PE in a woman who is at the age of 18 and older, who was screened for PE in an intervention period, and who was identified as a PE high-risk woman.

preeclampsia

Delivery with preeclampsia at < 37 weeks of gestation

Abnormal pregnancy outcome (preeclampsia, gestational hypertension, low birth weight infant (SGA; less than 5th percentile of birth weight), stillbirth, placental abruption) at less than 34 weeks of gestation, 34 to 37 weeks of gestation, 37 weeks of gestation or later

+81-76-415-8857

May. 14, 2019

Hong Kong/China/Taiwan/Thailand/Singapore/Philippines/Vietnam