At High-risk for Pre-eclampsia After Assisted Reproductive Technology
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 1,050
- 试验地点
- 1
- 主要终点
- Total energy expenditure (kcal/day)
研究概览
简要总结
The overarching goal of the project is to unravel PE etiopathogenesis in high-risk patients (PCOS patients and oocyte acceptors) after assisted reproductive technology (ART) to individualize prenatal care following ART and to determine potential targets for new PE prevention options decreasing the morbidity/mortality caused by this pathology. More specifically, the following objectives/work packages (WPs) are put forward:
- WP1 - PRECONCEPTION: Identify preconceptional maternal characteristics associated with in-creased risk of PE in ART patients (1a) and investigate the potential role of the endometrium prior to pregnancy (1b).
- WP2 - DURING PREGNANCY: Evaluate the Fetal Medicine Foundation's (FMF) first trimester PE screening in selected high-risk groups post ART to explore the clinical benefit in this specific context (2a) and investigate the association between parameters during the pregnancy and PE development post-ART.
- WP3 - AT DELIVERY: Identifying placental molecular pathways associated with PE post-ART.
详细描述
Background:
Pre-eclampsia (PE) is a multisystemic syndrome occurring in 4-5% of pregnant women. It is defined by a new-onset hypertension (HT) developing after 20 weeks of gestation in combination with one of the following entities: proteinuria, maternal organ dysfunction and/or uteroplacental insufficiency. The vicious circle of the syndrome can end up in life-threatening complications for mother and child and, today, the only treatment of cure is the induction of delivery. Furthermore, besides the problems in the acute phase of the disease, women who experienced PE have been shown to have an increased lifetime risk of developing cardiovascular disease (CVD) and chronic kidney disease, while the children carry the consequences of their prematurity and, often following intra-uterine growth restriction, also seem to be more prone to develop metabolic disturbances like diabetes, HT and CVD later in life. Research, including data publishes by my own research group, shows that the risk of PE development in subfertile patients undergoing assisted reproductive technology (ART), is more than doubled, with incidences between 8-12%.
ART includes in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), using autologous or heterologous gametes, followed by fresh or frozen embryo transfer. The increased risk of PE within this population has mainly been attributed to known maternal PE risk factors associated with ART like increased maternal age, nulliparity and metabolic disturbances e.g. in patients with polycystic ovary syndrome (PCOS). Recent studies however have shown that ART is an independent risk factor of PE. More specifically, a higher PE incidence is consistently observed when patients have a frozen embryo transfer (FET) in an artificially prepared cycle. Unlike in a natural cycle in which ovulation occurs, an artificial cycle is characterized by the absence of ovulation as the luteal phase is induced by exogenous progesterone administration. It has been put forward that the absence of the corpus luteum, producing vasoactive and angiogenic substances (e.g. VEG-F, relaxin) and thereby orchestrating a correct placental development, could be held responsible for this observation. Other high risk ART patients are recipients of heterologous oocytes (i.e. oocyte recipients) potentially due to immunological conflicts.
In 2016, the ASPRE trial published their results evaluating a new first trimester screening tool developed by the fetal medicine foundation (FMF). This algorithm takes into account a limited number of anamnestic maternal characteristics, maternal blood pressure, the measurement of placental growth factor (PlGF) as a serum biomarker and the ultrasonographic measurement of the pulsatility index of the uterine artery. When an increased risk of PE had been detected (>1/100), aspirin daily is given, starting before 16 weeks' of gestation.
As of May 2021, the FMF first trimester screening for PE is offered in the Brussels IVF fertility clinic to all the above-described high-risk patients pregnant following ART (PCOS and oocyte recipients included). Preliminary data confirm a high incidence of positive screening with an overall risk of 18%, reaching upto 27% in oocyte recipients (compared to the reported 10% in the general population following spontaneous conception). To the best of our knowledge, the applicability of the screening tool and aspirin administration for PE prevention has never been specifically evaluated post-ART. PE etiopathogenesis is complex and the exact molecular causative processes are still being unraveled. PE has a wide range of clinical presentations and it is currently unknown what drives these differences. Of critical importance for instance is the difference between early onset pre-eclampsia (EOPE), defined as PE occurring before 34 weeks of gestation and late onset pre-eclampsia (LOPE), defined as PE occurring at or after 34 weeks of gestation. In EOPE, which is mainly a placental disease, the impaired invasion of the spiral arteries by the extravillous cytotrofoblast cells has been put forward as the key pathophysiological component. This in contrary to LOPE, which is seen as a maternal disease, where there is a discrepancy between fetal growth, aging of the placenta an the maternal supply and cardiovascular reserve. Further, single-cell RNA sequencing on placentas confirmed the extensive different expressed genes between EOPE and LOPE. Also, the role of different serum markers (PlGF, sFLT-1, VEGF, leptin, annexin...) have been studied, but their contribution to EOPE and LOPE still remains unclear.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 48 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •First time oocyte acceptors Or Nulliparous PCOS patients undergoing ART (IVF/ICSI)
- •Criteria for PCOS: two out of the three following criteria must be present:
- •Oligo-or anovulation: a menstrual cycle >35 days
- •Hyperandrogenism:
- •Clinically: the presence of hirsutism and/ or severe acne in combination with alopecia confirmed hyperandrogenism Or
- •Biochemically: serum total testosterone >52 ng/dl or calculated free testosterone >0,64 ng/dl
- •Polycystic ovaries:
- •Follicle number per ovary (FNPO) ≥ 12 on both ovaries Or
- •Ovarian volume ≥ 10 ml in both ovaries Or
- •One ovary with ≥ 20 follicles (Using endovaginal US transducers with a frequency bandwidth that includes 8 MHz) Or
- •AMH ≥ 4,9 ng/ml
排除标准
- •Known essential hypertension or development of a new-onset hypertension before 20 weeks' gestation
- •Hypertension is defined as a systolic blood pressure ≥ 140 or a diastolic blood pressure ≥ 90 on two separate measurements with at least 20 minutes in between, taken when the patients is in a seated position Or
- •The patient is known with hypertension, diagnosed by a certified doctor
- •Known diabetes type 1 or 2 before pregnancy
- •Diagnosis of diabetes is confirmed when one of the following is present:
- •Fasting glucose ≥ 126 mg/dl
- •A 2-hour plasma glucose level ≥ 200 mg/dL during a 75-g oral glucose tolerance test Or
- •The patient is known with diabetes (type 1 or 2), diagnosed by a certified doctor
- •Thyroid dysfunction not under control with medication:
- •Hyperthyroidism, the diagnoses is made when:
- •Peripheral blood TSH <0,5 mIU/L and fT4 >1,9 ng/dl Or
- •When the patient is known with hyperthyroidism diagnosed by a certified physician
- •Hypothyroidism, the diagnosis is made when:
- •Peripheral blood TSH >5 mIU/L and fT4 <0,7 ng/dl Or
- •When the patient is known with hypothyroidism diagnosed by a certified physician
- •Other endocrinological disorder (including Cushing syndrome, Adrenal insufficiency, acromegaly): for diagnosis we will trust the opinion of the certified endocrinologist
- •Cardiovascular diseases (including coronary artery disease, arrhythmia, heart valve disease and heart failure): for diagnosis we will trust the opinion of the certified cardiologist
- •Renal disease/insufficiency: for diagnosis we will trust the opinion of the certified nephrologist
- •Systemic lupus erythematosus: for diagnosis we will trust the opinion of the certified internal medicine doctor
- •Antiphospholipid syndrome: for diagnosis we will trust the opinion of the certified internal medicine doctor
- •Liver dysfunction/disease: for diagnosis we will trust the opinion of the certified gastroenterologist
- •History of prior pre-eclampsia
- •Women pregnant with a fetus with known abnormalities such chromosomal anomalies, structural deformities of limbs or organs or any other prebirth diagnosed syndromes or defects
- •Multiple pregnancy
结局指标
主要结局
Total energy expenditure (kcal/day)
时间窗: 1 year
Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
BMI (kg/m2)
时间窗: 1 year
measurement of height en weight. Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
number of laps of 6MWT (number)
时间窗: 1 year
6 minute walking test Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
pulse beginning and end of 6MWT
时间窗: 1 year
6 minute walking test Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
LV mass (indexed) mg/m2
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
Deceleration time (ms)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
Lateral wall e' (cm/s)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
TAPSE (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of right ventricle and RV systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
Saturation beginning and end of 6MWT (%)
时间窗: 1 year
6 minute walking test Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
Effective maximal handgrip strength (KPa)
时间窗: 1 year
Hangrip strenght Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
Time until 50% of effective handgrip strenght (s)
时间窗: 1 year
Hangrip strenght Work package 1: preconceptional, metabolic analysis Work package 2: during pregnancy, metabolic analysis
LVEDD (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
IVSd (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
PWTd (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
IVSs (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
PWTs (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
LVESD (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
LVEF (visual, manual modified Simpson's biplane, auto-EF) (%)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
Septal wall e' (cm/s)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
Estimated fetal weight (g)
时间窗: 1 year
ultrasound Work package 2: during pregnancy
LV GLS (LV MW) (-%)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle and left ventricle systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
A-wave velocity (cm/s)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
E/A ratio
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
E-wave velocity (cm/s)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
E/e' ratio
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
La strain (-%)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left atrium Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
RV s' (cm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of right ventricle and RV systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
PRL production (ng/ml)
时间窗: 3 months
ELISA Work package 1: preconception
IGFBP1 (pg/ml)
时间窗: 3 months
ELISA Endometrial tissue Work package 1: preconception
Septal e'/lateral e' ratio
时间窗: 1 year
Transthoracic ultrasound Evaluation of left ventricle diastolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
LAESVi (mL/M2)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left atrium Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
RV GLS (RV MW) (-%)
时间窗: 1 year
Transthoracic ultrasound Evaluation of right ventricle and RV systolic function Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
(sub)endometrial flow (1,2,3)
时间窗: 1 year
ultrasound Work package 1: preconception Work package 2: during pregnancy
LA AP diameters (mm)
时间窗: 1 year
Transthoracic ultrasound Evaluation of left atrium Work package 1: preconceptional, Work package 2: during pregnancy, cardiac evaluation
systolic, diastolic bloodpressure and mean arterial pressure (mmHg)
时间窗: 1 year
Blood pressure measurement device. Work package 1: preconception Work package 2: during pregnancy
Pulsatility index of the uterine artery
时间窗: 1 year
ultrasound Work package 1: preconception Work package 2: during pregnancy
PRL mRNA expression
时间窗: 3 months
RNA sequencing Work package 1: preconception
sENG (ng/ml)
时间窗: 3 months
blood sample Work package 1: preconception Work package 2: during pregnancy
incidence of PE (%)
时间窗: 1 year
work package 2: during pregnancy
IGFBP1 mRNA expression
时间窗: 3 months
RNA sequencing Endometrial tissue Work package 1: preconception
sFLT1 (pg/ml)
时间窗: 3 months
blood sample Work package 1: preconception Work package 2: during pregnancy
Incidence of positive PE screening (%)
时间窗: 6 months
Fetal medicine foundation screening algorithm. Work package 2: during pregnancy
severity of PE (mild/severe)
时间窗: 1 year
work package 2: during pregnancy
gestational age at delivery (weeks)
时间窗: 1 year
work package 3: at delivery
different expressed genes (DEGs) of placenta's
时间窗: 1 year
work package 3: at delivery RNA sequencing
PlGF (pg/ml)
时间窗: 3 months
blood sample Work package 1: preconception Work package 2: during pregnancy
PI umbilical artery
时间窗: 1 year
ultrasound Work package 2: during pregnancy
PI uterine artery
时间窗: 1 year
ultrasound Work package 2: during pregnancy
gestational age at diagnoses PE (weeks)
时间窗: 1 year
work package 2: during pregnancy
birth weight (grams)
时间窗: 1 year
work package 3: at delivery
APGAR scores of baby after 1, 5 and 10 minutes (1-10)
时间窗: 1 year
work package 3: at delivery
次要结局
未报告次要终点
研究者
Mackens Shari
Prof. Dr.
CRG UZ Brussel