Fetal, Obstetrics and Reproduction Genomics

Preeclampsia Clinical Trial

— FORgenomics  

Official title:

Fetal, Obstetrics and Reproduction Genomics

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05720169
• Other study ID #: 0001
• Status: Not yet recruiting
• Start date: October 1, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: September 2023
• Source: Fundación Ginemed
• Contact: Guillermo Antiñolo Gil, PhD, MD
• Phone: 0034955012772
• Email: gantinolo[@]us.es
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to determine the impact of a clinical screening strategy and genomic analysis of the factors involved in Placental Dysfunction (Preeclampsia and IUGR) in women of advanced maternal age undergoing assisted reproduction techniques (ART), specifically, in vitro fertilization (IVF) and oocyte donation.

Description:

Given society's shift towards later childbearing, partly related to increased career development, women are increasingly delaying childbearing and, as a result, face declining biological fertility and increased maternal morbidity and adverse perinatal pregnancy outcomes, as well as increased use of ART. Preeclampsia (PE) complicates 2% of pregnancies and is a leading cause of severe maternal and perinatal complications. There is no curative treatment, and the only recognized beneficial primary prevention is low-dose aspirin. Finding an effective method of predicting and preventing placental dysfunction (PD) in women of advanced maternal age undergoing ART remains a challenge. The investigators believe that maternal and perinatal complications in this group of pregnant women could be detected preclinically and allow early preventive actions. On the other hand, establishing a differentiated genomic pattern in this group of patients would allow preventive actions both pregestational and during gestation. Furthermore, FORgenomics can be used to externally validate a prediction model for the development of PE and IUGR in pregnancy after IVF/ovodon. Our results could be applicable in most healthcare settings and have important implications for maternal-fetal health. The justification and hypothesis of this proposal is: (1) maternal and perinatal complications in this group of pregnant women could be detected preclinically and allow preventive actions by systematic screening based on Doppler ultrasound of uterine arteries and anti-angiogenic factors (sFlt-1/PlGF ratio) at 13, 16, 20 and 26 weeks to identify pregnant women at high risk for developing PE; (2) morphological ultrasound at 13, 16 and 20 weeks would help to establish a standardized procedure for early detection of congenital anomalies and (3) establishing a differentiated genomic pattern in this group of patients would allow preventive actions both pregestational and during gestation.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 400
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Singleton pregnancy
• Age =40 years
• Signed informed consent
• Gestation obtained by IVF or ovodonation

Exclusion Criteria:

• Non-ongoing pregnancy
• Gestation obtained by artificial insemination
• Naturally obtained gestation, without ART
• Multiple pregnancy
• Pregnancies complicated by major fetal abnormality identified at the first-trimester ultrasound
• Age <18 years
• Poor understanding of the Spanish or English languages
• Refusal in informed consent to participate in the study
• Participation in another intervention study that could modify follow-up

Related Conditions & MeSH terms

• Fetal Growth Retardation
• Intrauterine Growth Restriction
• Placenta Diseases
• Placental Disease
• Pre-Eclampsia
• Preeclampsia

Intervention

Diagnostic Test:
• Doppler ultrasound
Doppler ultrasound at 13, 16, 20 and 26 weeks for assessment of uterine arteries according to ISUOG criteria.
• Blood sample
Blood sampling at 13, 16, 20, 26 weeks of gestation to determine the sFlt-1/PlGF ratio
• Blood sample
Blood sampling at week 13 for DNA extraction for genomic studies
• Doppler ultrasound
Fetal morphological ultrasound at 13, 16 and 20 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (5)

Lead Sponsor	Collaborator
Fundación Ginemed	Clínicas Ginemed, FIRST - Fetal, IVF and Reproduction Simulation Training Center, Hospitales Universitarios Virgen del Rocío, University of Seville

References & Publications (45)

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Ciobanu A, Wright A, Panaitescu A, Syngelaki A, Wright D, Nicolaides KH. Prediction of imminent preeclampsia at 35-37 weeks gestation. Am J Obstet Gynecol. 2019 Jun;220(6):584.e1-584.e11. doi: 10.1016/j.ajog.2019.01.235. Epub 2019 Feb 7. — View Citation

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Dall'Asta A, D'Antonio F, Saccone G, Buca D, Mastantuoni E, Liberati M, Flacco ME, Frusca T, Ghi T. Cardiovascular events following pregnancy complicated by pre-eclampsia with emphasis on comparison between early- and late-onset forms: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2021 May;57(5):698-709. doi: 10.1002/uog.22107. — View Citation

Gallo DM, Wright D, Casanova C, Campanero M, Nicolaides KH. Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19-24 weeks' gestation. Am J Obstet Gynecol. 2016 May;214(5):619.e1-619.e17. doi: 10.1016/j.ajog.2015.11.016. Epub 2015 Nov 25. — View Citation

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Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004 Jan 31;328(7434):261. doi: 10.1136/bmj.37957.560278.EE. Epub 2004 Jan 23. — View Citation

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Kenny LC, Lavender T, McNamee R, O'Neill SM, Mills T, Khashan AS. Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort. PLoS One. 2013;8(2):e56583. doi: 10.1371/journal.pone.0056583. Epub 2013 Feb 20. — View Citation

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Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012 Sep-Oct;18(5):485-503. doi: 10.1093/humupd/dms018. Epub 2012 May 19. — View Citation

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Qin J, Liu X, Sheng X, Wang H, Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril. 2016 Jan;105(1):73-85.e1-6. doi: 10.1016/j.fertnstert.2015.09.007. Epub 2015 Oct 9. — View Citation

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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. — View Citation

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* Note: There are 45 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with preeclampsia (PE) during pregnancy	Defined as systolic blood pressure = 140mmHg or diastolic blood pressure = 90mmHg with an interval of at least 4 h after 20 weeks' gestation plus any of the following: (i) proteinuria (>300 mg/24 h) or a urine protein/creatinine ratio > 0.3 mg/mmol); (ii) end-organ dysfunction: systolic blood pressure > 160 mmHg, diastolic blood pressure >110 mmHg, platelet count <100x109/L, blood alanine and aspartate transaminases >70 IU/L, serum creatinine >1. 1 mg/dL, lactate dehydrogenase >700 IU/L, right upper quadrant or epigastric pain, dyspnea and/or cerebral/visual disturbances. Or (iii) utero-placental dysfunction (estimated fetal weight <3rd centile or <10th centile with abnormal uterine or umbilical Doppler [pulsatility index >95th centile]) as defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP) with minor adaptations for study purposes.	=20 weeks to <37 weeks of gestation
Primary	Number of fetuses diagnosed with intrauterine growth restriction (IUGR) during pregnancy	IUGR will be defined by the following criteria: Estimated fetal weight (EFW) between percentile (p) 3 and p 10 with Doppler alteration (uterine arteries > p 95 or cerebroplacental index < p 5, or middle cerebral artery < p 5, or umbilical artery > p 95). PFE < p 3 independently of feto-maternal Doppler.	=20 weeks to <37 weeks of gestation
Secondary	Number of fetuses and newborns with severe perinatal morbidity	Defined by a composite including any of the following: premature placental abruption, severe fetal growth restriction (birth weight <3rd centile), perinatal mortality, an Apgar score at 5'< 7.0, arterial pH less than 7.10, need for respiratory support within 72 hours of birth, neonatal intraventricular hemorrhage grade III/IV, necrotizing, periventricular leukomalacia, sepsis, bronchopulmonary dysplasia or encephalopathy due to hypoxic ischemic enterocolitis. Days of admission to ICU.	From birth up to 7 days of life
Secondary	Cesarean section rate	Type of delivery and cesarean section rate will be recorded.	During birth
Secondary	Number of Participants with pregnancy-related maternal morbidity	defined by a composite including any of the following: (i) HELLP syndrome (lactate dehydrogenase [LDH] >700 IU/L, AST at twice normal values, and platelet count <100x109/L); (ii) central nervous system dysfunction (eclampsia, Glasgow Coma Score <13, stroke, reversible ischemic neurologic deficit, or cortical blindness); (iii) hepatic dysfunction (INR >1. 2 in the absence of disseminated intravascular coagulation, MELD score >10, or hepatic hematoma or rupture); (iv) renal dysfunction (dialysis, serum creatinine concentration greater than 150 µmol/L, or diuresis <0.5 mL/kg/h for 12 hours, according to renal failure by RIFLE criteria; or need for furosemide treatment to maintain diuresis >0. 5 mL/kg/h for 3 hours); (v) respiratory dysfunction (pulmonary edema, need for invasive or noninvasive mechanical ventilation, need for oxygen concentration greater than 50% for more than 1 hour, or severe respiratory distress [without pulmonary edema criteria but with presence of dyspnea,	From conception up to 4 days after birth
Secondary	Maternal experience and psychological impact	It will be assessed by: - WHO Five Well-Being Index (WHO), Spanish version of 1998, applied at week 26. A brief self-assessment questionnaire on a person's perception of well-being over a specific period of time.	From conception up to 4 days after birth
Secondary	Maternal anxiety and psychological impact	It will be assessed by: - Spielberger State-Trait Anxiety Questionnaire (STAI), in its Spanish adaptation applied in the 26th week of gestation. One of the first instruments validated in Spain and one of the most widely used by many researchers, it comprises two differentiated self-assessment scales: State Anxiety (SA), referring to a transitory anxious state that a person may feel in specific situations; and Trait Anxiety (RA), which characterizes a more or less stable anxious tendency that distinguishes people in their tendency to perceive situations as threatening.	From conception up to 4 days after birth