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| Name | Class |
|---|---|
| Obstetrics & Gynecology Hospital of Fudan University | OTHER |
| Shanghai First Maternity and Infant Hospital | OTHER |
| West China Second University Hospital | OTHER |
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This is a prospective, multicenter, randomized controlled, double-blind trial of three treatment arms: (1) aspirin 75 mg/day vs. (2) aspirin 150 mg/day vs. (3) aspirin 75 mg/day with metformin 1.5 g/day from the first trimester to compare the incidence of preterm preeclampsia with delivery at <37 week's gestation between the treatment arms, in order to determine the optimal therapeutic intervention for the prevention of preterm preeclampsia among Chinese women at high-risk of preeclampsia.
All women with singleton pregnancies who are attending for their routine hospital visit at 11-13 weeks' gestation will be invited to undergo screening for preeclampsia. We use a Bayes theorem-based method that combines maternal characteristics, medical and obstetric history together with mean arterial pressure (MAP) and serum placental growth factor (PlGF) level. Women who are deemed high-risk following first trimester combined screening (cutoff corresponding to a screen positive rate of 10%, e.g ≥1 in 80) will be invited to participate in the 3-arm randomized controlled trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Aspirin 75 mg and placebo | Experimental | A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery. |
|
| Aspirin 150 mg and placebo | Experimental | Two capsules of 75 mg aspirin to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery. |
|
| Aspirin 75 mg and Metformin 1.5 g | Experimental | A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin capsules (up to 750 mg) to be taken twice per day from enrolment until delivery |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 75 mg acetylsalicylic acid | Drug | 75 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of preterm preeclampsia(<37 weeks) | Preeclampsia will be defined as per the International Society for the Study of Hypertension in Pregnancy.The Proportions of delivery with preterm-preeclampsia between different intervention groups will be measured. | ≥20 weeks to <37 weeks of gestation |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse outcome of pregnancy at <37 weeks. | including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption. | <37 weeks of gestation |
| Adverse outcome of pregnancy at <34 weeks. |
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Inclusion Criteria:
Exclusion Criteria:
All eligible women with singleton pregnancies
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Chiu Yee, Liona Poon, MD | Contact | (852) 3505 1290 | liona.poon@cuhk.edu.hk | |
| Chi Chiu Wang, PhD | Contact | (852) 3505 3099 | ccwang@cuhk.edu.hk |
| Name | Affiliation | Role |
|---|---|---|
| Chiu Yee, Liona Poon, MD | Chinese University of Hong Kong | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Peking University First Hospital | Recruiting | Beijing | Beijing Municipality | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32234176 | Background | Women's Heart Health Group of Chinese Society of Cardiology of Chinese Medical Association; Hypertension Group of Chinese Society of Cardiology of Chinese Medical Association. [Expert consensus on blood pressure management in hypertensive disorders of pregnancy (2019)]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Mar 24;48(3):195-204. doi: 10.3760/cma.j.cn112148-20191024-00652. Chinese. | |
| 10739516 |
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| Peking University First Hospital |
| OTHER |
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PI, participating research doctors, pharmacists at the local clinical trial pharmacy, project managers and others involved in the trial are all blinded to the investigational medicinal product (IMP). The tablets and capsules will be identical, so it will not be possible to distinguish between the different IMPs.
|
| 1.5g Metformin | Drug | up to 1.5 g metformin (C4H11N5, CAS number 657-24-9) daily, Oral Dose increases from 0.5g to 1.0g to 1.5g |
|
|
| 150 mg acetylsalicylic acid | Drug | 150 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral |
|
|
| Placebo of acetylsalicylic acid and Metformin | Drug | Pills with shape, color and smell same with acetylsalicylic acid and metformin, daily, oral |
|
including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption. |
| <34 weeks of gestation |
| Adverse outcome of pregnancy at ≥37 weeks | including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, stillbirth or placental abruption. | ≥37 weeks of gestation |
| Neonatal mortality | A neonatal death is a death during 0-27 days of life. | During the first 28 days of life (0-27days) |
| Neonatal morbidity | Composite neonatal morbidity (any one of the following): >grade II intra-ventricular hemorrhage; neonatal sepsis confirmed by cultures; neonatal anemia requiring transfusion; respiratory distress syndrome requiring surfactant and ventilation; necrotising enterocolitis requiring surgical intervention. | During the first 28 days of life (0-27days) |
| Neonatal birthweight below the 3rd,5th and 10th centile. | Birthweight and birthweight percentile for gestational age at delivery is calculated using a normal range derived in a Chinese population. | At delivery |
| Stillbirth or neonatal death | Stillbirth: the death of a baby before or during birth after 24 weeks of gestation. Neonatal death: the death of a baby within the first 28 days of life. | At delivery |
| <34 weeks and <37 weeks spontaneous preterm delivery | Spontaneous delivery at <34 weeks(early preterm) and at <37 weeks(total preterm) includes those with spontaneous onset of labor and those with preterm pre-labor rupture of membranes (PPROM). | At spontaneous delivery |
| Gestational age | Gestation is the period of time between conception and birth. During this time, the baby grows and develops inside the mother's womb. Gestational age is the common term used during pregnancy to describe how far along the pregnancy is. It is measured in weeks, from the first day of the woman's last menstrual cycle to the current date. A normal pregnancy can range from 38 to 42 weeks. | At delivery |
| Guangzhou Women and Children's Medical Center | Withdrawn | Guangzhou | Guangdong | China |
| The Third Affiliated Hospital of Guangzhou Medical University | Not yet recruiting | Guangzhou | Guangdong | China |
|
| Obstetrics and Gynecology Hospital of Fudan University | Recruiting | Shanghai | Shanghai Municipality | China |
|
| Shanghai First Maternity and Infant Hospital | Recruiting | Shanghai | Shanghai Municipality | China |
|
| West China Second University Hospital, Sichuan University | Recruiting | Chengdu | Sichuan | China |
|
| Background |
| Witlin AG, Saade GR, Mattar F, Sibai BM. Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks' gestation. Am J Obstet Gynecol. 2000 Mar;182(3):607-11. doi: 10.1067/mob.2000.104224. |
| 11719411 | Background | Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001 Nov 24;323(7323):1213-7. doi: 10.1136/bmj.323.7323.1213. |
| 12908998 | Background | von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143-8. doi: 10.1081/PRG-120021060. |
| 31589866 | Background | Chaemsaithong P, Pooh RK, Zheng M, Ma R, Chaiyasit N, Tokunaka M, Shaw SW, Seshadri S, Choolani M, Wataganara T, Yeo GSH, Wright A, Leung WC, Sekizawa A, Hu Y, Naruse K, Saito S, Sahota D, Leung TY, Poon LC. Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population. Am J Obstet Gynecol. 2019 Dec;221(6):650.e1-650.e16. doi: 10.1016/j.ajog.2019.09.041. Epub 2019 Oct 4. |
| 21210481 | Background | Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. 2011 Jan;31(1):66-74. doi: 10.1002/pd.2660. |
| 17512048 | Background | Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0. |
| 28657417 | Background | Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28. |
| 20664402 | Background | Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010 Aug;116(2 Pt 1):402-414. doi: 10.1097/AOG.0b013e3181e9322a. |
| 22441437 | Background | Roberge S, Villa P, Nicolaides K, Giguere Y, Vainio M, Bakthi A, Ebrashy A, Bujold E. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther. 2012;31(3):141-6. doi: 10.1159/000336662. Epub 2012 Mar 21. |
| 27640943 | Background | Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017 Feb;216(2):110-120.e6. doi: 10.1016/j.ajog.2016.09.076. Epub 2016 Sep 15. |
| 20175340 | Background | Caron N, Rivard GE, Michon N, Morin F, Pilon D, Moutquin JM, Rey E. Low-dose ASA response using the PFA-100 in women with high-risk pregnancy. J Obstet Gynaecol Can. 2009 Nov;31(11):1022-1027. doi: 10.1016/S1701-2163(16)34346-8. |
| 21440360 | Background | Rey E, Rivard GE. Is testing for aspirin response worthwhile in high-risk pregnancy? Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):38-42. doi: 10.1016/j.ejogrb.2011.02.026. Epub 2011 Mar 25. |
| 32375429 | Background | Hypertensive Disorders in Pregnancy Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. [Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China（2020）]. Zhonghua Fu Chan Ke Za Zhi. 2020 Apr 25;55(4):227-238. doi: 10.3760/cma.j.cn112141-20200114-00039. Chinese. |
| 26721779 | Background | Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016 Mar;214(3):356.e1-356.e15. doi: 10.1016/j.ajog.2015.12.019. Epub 2015 Dec 22. |
| 26840133 | Background | Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med. 2016 Feb 4;374(5):434-43. doi: 10.1056/NEJMoa1509819. |
| 26165398 | Background | Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE, Walker BR, Quenby S, Wray S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman JE. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015 Oct;3(10):778-86. doi: 10.1016/S2213-8587(15)00219-3. Epub 2015 Jul 9. |
| 30575675 | Background | ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):1. doi: 10.1097/AOG.0000000000003018. |
| 22846512 | Background | Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH. Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther. 2012;32(3):156-65. doi: 10.1159/000338655. Epub 2012 Jul 26. |
| 28888591 | Background | Wright D, Poon LC, Rolnik DL, Syngelaki A, Delgado JL, Vojtassakova D, de Alvarado M, Kapeti E, Rehal A, Pazos A, Carbone IF, Dutemeyer V, Plasencia W, Papantoniou N, Nicolaides KH. Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J Obstet Gynecol. 2017 Dec;217(6):685.e1-685.e5. doi: 10.1016/j.ajog.2017.08.110. Epub 2017 Sep 6. |
| 38631826 | Derived | Liu J, Shen L, Nguyen-Hoang L, Zhou Q, Wang CC, Lu X, Sahota D, Chong KC, Ying H, Gu W, Zhou R, Yang H, Jiang Y, Chen D, Li X, Poon L. Aspirin versus metformin in pregnancies at high risk of preterm pre-eclampsia in China (AVERT): protocol for a multicentre, double-blind, 3-arm randomised controlled trial. BMJ Open. 2024 Apr 17;14(4):e074493. doi: 10.1136/bmjopen-2023-074493. |
| ID | Term |
|---|---|
| D011225 | Pre-Eclampsia |
| ID | Term |
|---|---|
| D046110 | Hypertension, Pregnancy-Induced |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D001241 | Aspirin |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
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