Clinical trial NCT05720169: Fetal, Obstetrics and Reproduction Genomics
Official title: Fetal, Obstetrics and Reproduction Genomics
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Preeclampsia
Intrauterine Growth Restriction
Placental Disease
Keywords: Preeclampsia
Intrauterine Growth Restriction
Genomics
Lead sponsor: Fundación Ginemed
Sponsor class: OTHER
Collaborators: name: Hospitales Universitarios Virgen del Rocío
name: University of Seville
name: Clínicas Ginemed
name: FIRST - Fetal, IVF and Reproduction Simulation Training Center
First posted: 2023-02-09
Enrollment: 400
Sex: FEMALE
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Sample

1. Virgen del Rocío Hospital Area: according to the data obtained from the pregnant women who start the pregnancy process in the Andalusian Congenital Anomalies Screening Program (PACAC) in 2021, we expect a total population of 165 pregnant women per year with age at the start of pregnancy equal to or greater than 40 years, and whose pregnancy was obtained through IVF or ovodonation.
2. Clínicas Ginemed: according to the data obtained from the report of Ginemed Clinics for the year 2021, we expect a total population of 150 pregnant women per year with an age at the onset of pregnancy equal to or greater than 40 years old, and whose gestation was obtained through IVF or ovodonation.

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with preeclampsia (PE) during pregnancy
timeFrame: ≥20 weeks to <37 weeks of gestation
measure: Number of fetuses diagnosed with intrauterine growth restriction (IUGR) during pregnancy
timeFrame: ≥20 weeks to <37 weeks of gestation
Secondary outcomes:
measure: Number of fetuses and newborns with severe perinatal morbidity
timeFrame: From birth up to 7 days of life
measure: Cesarean section rate
timeFrame: During birth
measure: Number of Participants with pregnancy-related maternal morbidity
timeFrame: From conception up to 4 days after birth
measure: Maternal experience and psychological impact
timeFrame: From conception up to 4 days after birth
measure: Maternal anxiety and psychological impact
timeFrame: From conception up to 4 days after birth
Other outcomes:
Locations:
Study officials:
References:
citation: Usta IM, Nassar AH. Advanced maternal age. Part I: obstetric complications. Am J Perinatol. 2008 Sep;25(8):521-34. doi: 10.1055/s-0028-1085620. Epub 2008 Sep 4.
citation: Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan E, Vanderpoel S; International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril. 2009 Nov;92(5):1520-4. doi: 10.1016/j.fertnstert.2009.09.009. Epub 2009 Oct 14.
citation: Thoma ME, McLain AC, Louis JF, King RB, Trumble AC, Sundaram R, Buck Louis GM. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril. 2013 Apr;99(5):1324-1331.e1. doi: 10.1016/j.fertnstert.2012.11.037. Epub 2013 Jan 3.
citation: Cedars MI, Taymans SE, DePaolo LV, Warner L, Moss SB, Eisenberg ML. The sixth vital sign: what reproduction tells us about overall health. Proceedings from a NICHD/CDC workshop. Hum Reprod Open. 2017 Jul 12;2017(2):hox008. doi: 10.1093/hropen/hox008. eCollection 2017.
citation: American College of Obstetricians and Gynecologists' Committee on Obstetric Practice; Committee on Genetics; U.S. Food and Drug Administration. Committee Opinion No 671: Perinatal Risks Associated With Assisted Reproductive Technology. Obstet Gynecol. 2016 Sep;128(3):e61-8. doi: 10.1097/AOG.0000000000001643.
citation: 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.
citation: Schieve LA, Cohen B, Nannini A, Ferre C, Reynolds MA, Zhang Z, Jeng G, Macaluso M, Wright VC; Massachusetts Consortium for Assisted Reproductive Technology Epidemiologic Research (MCARTER). A population-based study of maternal and perinatal outcomes associated with assisted reproductive technology in Massachusetts. Matern Child Health J. 2007 Nov;11(6):517-25. doi: 10.1007/s10995-007-0202-7. Epub 2007 Mar 8.
citation: Qin JB, Sheng XQ, Wang H, Chen GC, Yang J, Yu H, Yang TB. Worldwide prevalence of adverse pregnancy outcomes associated with in vitro fertilization/intracytoplasmic sperm injection among multiple births: a systematic review and meta-analysis based on cohort studies. Arch Gynecol Obstet. 2017 Mar;295(3):577-597. doi: 10.1007/s00404-017-4291-2. Epub 2017 Feb 6.
citation: 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.
citation: Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004 Mar;103(3):551-63. doi: 10.1097/01.AOG.0000114989.84822.51.
citation: McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A; Knowledge Synthesis Group. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol. 2009 Oct;146(2):138-48. doi: 10.1016/j.ejogrb.2009.05.035. Epub 2009 Jul 4.
citation: 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.
citation: Kawwass JF, Monsour M, Crawford S, Kissin DM, Session DR, Kulkarni AD, Jamieson DJ; National ART Surveillance System (NASS) Group. Trends and outcomes for donor oocyte cycles in the United States, 2000-2010. JAMA. 2013 Dec 11;310(22):2426-34. doi: 10.1001/jama.2013.280924.
citation: Jeve YB, Potdar N, Opoku A, Khare M. Donor oocyte conception and pregnancy complications: a systematic review and meta-analysis. BJOG. 2016 Aug;123(9):1471-80. doi: 10.1111/1471-0528.13910. Epub 2016 Feb 8.
citation: Jacobsson B, Ladfors L, Milsom I. Advanced maternal age and adverse perinatal outcome. Obstet Gynecol. 2004 Oct;104(4):727-33. doi: 10.1097/01.AOG.0000140682.63746.be.
citation: 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.
citation: Yogev Y, Melamed N, Bardin R, Tenenbaum-Gavish K, Ben-Shitrit G, Ben-Haroush A. Pregnancy outcome at extremely advanced maternal age. Am J Obstet Gynecol. 2010 Dec;203(6):558.e1-7. doi: 10.1016/j.ajog.2010.07.039. Epub 2010 Oct 20.
citation: Reddy UM, Ko CW, Willinger M. Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol. 2006 Sep;195(3):764-70. doi: 10.1016/j.ajog.2006.06.019.
citation: Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis. PLoS One. 2017 Oct 17;12(10):e0186287. doi: 10.1371/journal.pone.0186287. eCollection 2017.
citation: Wennberg AL, Opdahl S, Bergh C, Aaris Henningsen AK, Gissler M, Romundstad LB, Pinborg A, Tiitinen A, Skjaerven R, Wennerholm UB. Effect of maternal age on maternal and neonatal outcomes after assisted reproductive technology. Fertil Steril. 2016 Oct;106(5):1142-1149.e14. doi: 10.1016/j.fertnstert.2016.06.021. Epub 2016 Jul 9.
citation: Wen J, Jiang J, Ding C, Dai J, Liu Y, Xia Y, Liu J, Hu Z. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril. 2012 Jun;97(6):1331-7.e1-4. doi: 10.1016/j.fertnstert.2012.02.053. Epub 2012 Apr 3.
citation: Boulet SL, Kirby RS, Reefhuis J, Zhang Y, Sunderam S, Cohen B, Bernson D, Copeland G, Bailey MA, Jamieson DJ, Kissin DM; States Monitoring Assisted Reproductive Technology (SMART) Collaborative. Assisted Reproductive Technology and Birth Defects Among Liveborn Infants in Florida, Massachusetts, and Michigan, 2000-2010. JAMA Pediatr. 2016 Jun 6;170(6):e154934. doi: 10.1001/jamapediatrics.2015.4934. Epub 2016 Jun 6.
citation: Giorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A, Sigismondi C, Tiberio F, Cavoretto P. Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018 Jan;51(1):33-42. doi: 10.1002/uog.18932.
citation: Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org; Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012). Am J Obstet Gynecol. 2020 Oct;223(4):B2-B17. doi: 10.1016/j.ajog.2020.05.010. Epub 2020 May 12.
citation: Gordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, Baschat AA, Baker PN, Silver RM, Wynia K, Ganzevoort W. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016 Sep;48(3):333-9. doi: 10.1002/uog.15884.
citation: Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, Harper A, Hulbert D, Lucas S, McClure J, Millward-Sadler H, Neilson J, Nelson-Piercy C, Norman J, O'Herlihy C, Oates M, Shakespeare J, de Swiet M, Williamson C, Beale V, Knight M, Lennox C, Miller A, Parmar D, Rogers J, Springett A. Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG. 2011 Mar;118 Suppl 1:1-203. doi: 10.1111/j.1471-0528.2010.02847.x.
citation: 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.
citation: Roberts LM, Davis GK, Homer CS. Pregnancy with gestational hypertension or preeclampsia: A qualitative exploration of women's experiences. Midwifery. 2017 Mar;46:17-23. doi: 10.1016/j.midw.2017.01.004. Epub 2017 Jan 10.
citation: Bergink V, Laursen TM, Johannsen BM, Kushner SA, Meltzer-Brody S, Munk-Olsen T. Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study. Psychol Med. 2015 Dec;45(16):3481-9. doi: 10.1017/S0033291715001385. Epub 2015 Aug 5.
citation: Chesley LC, Cooper DW. Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women. Br J Obstet Gynaecol. 1986 Sep;93(9):898-908. doi: 10.1111/j.1471-0528.1986.tb08006.x.
citation: Skjaerven R, Vatten LJ, Wilcox AJ, Ronning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005 Oct 15;331(7521):877. doi: 10.1136/bmj.38555.462685.8F. Epub 2005 Sep 16.
citation: Williams PJ, Broughton Pipkin F. The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011 Aug;25(4):405-17. doi: 10.1016/j.bpobgyn.2011.02.007. Epub 2011 Mar 22.
citation: Valenzuela FJ, Perez-Sepulveda A, Torres MJ, Correa P, Repetto GM, Illanes SE. Pathogenesis of preeclampsia: the genetic component. J Pregnancy. 2012;2012:632732. doi: 10.1155/2012/632732. Epub 2011 Dec 1.
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.
citation: 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.
citation: Rodriguez-Calvo J, Villalain C, Gomez-Arriaga PI, Quezada MS, Herraiz I, Galindo A. Prediction of perinatal survival in early-onset fetal growth restriction: role of placental growth factor. Ultrasound Obstet Gynecol. 2023 Feb;61(2):181-190. doi: 10.1002/uog.26116.
citation: Crovetto F, Triunfo S, Crispi F, Rodriguez-Sureda V, Roma E, Dominguez C, Gratacos E, Figueras F. First-trimester screening with specific algorithms for early- and late-onset fetal growth restriction. Ultrasound Obstet Gynecol. 2016 Sep;48(3):340-8. doi: 10.1002/uog.15879.
citation: Andrietti S, Silva M, Wright A, Wright D, Nicolaides KH. Competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 35-37 weeks' gestation. Ultrasound Obstet Gynecol. 2016 Jul;48(1):72-9. doi: 10.1002/uog.15812. Epub 2016 May 30.
citation: 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.
citation: Llurba E, Crispi F, Verlohren S. Update on the pathophysiological implications and clinical role of angiogenic factors in pregnancy. Fetal Diagn Ther. 2015;37(2):81-92. doi: 10.1159/000368605. Epub 2015 Feb 3.
citation: Velez MP, Hamel C, Hutton B, Gaudet L, Walker M, Thuku M, Cobey KD, Pratt M, Skidmore B, Smith GN. Care plans for women pregnant using assisted reproductive technologies: a systematic review. Reprod Health. 2019 Jan 29;16(1):9. doi: 10.1186/s12978-019-0667-z.
citation: Bhide A, Acharya G, Bilardo CM, Brezinka C, Cafici D, Hernandez-Andrade E, Kalache K, Kingdom J, Kiserud T, Lee W, Lees C, Leung KY, Malinger G, Mari G, Prefumo F, Sepulveda W, Trudinger B. ISUOG practice guidelines: use of Doppler ultrasonography in obstetrics. Ultrasound Obstet Gynecol. 2013 Feb;41(2):233-39. doi: 10.1002/uog.12371. No abstract available.
citation: Lucas-Carrasco R. Reliability and validity of the Spanish version of the World Health Organization-Five Well-Being Index in elderly. Psychiatry Clin Neurosci. 2012 Oct;66(6):508-13. doi: 10.1111/j.1440-1819.2012.02387.x.
citation: Pena-Chilet M, Roldan G, Perez-Florido J, Ortuno FM, Carmona R, Aquino V, Lopez-Lopez D, Loucera C, Fernandez-Rueda JL, Gallego A, Garcia-Garcia F, Gonzalez-Neira A, Pita G, Nunez-Torres R, Santoyo-Lopez J, Ayuso C, Minguez P, Avila-Fernandez A, Corton M, Moreno-Pelayo MA, Morin M, Gallego-Martinez A, Lopez-Escamez JA, Borrego S, Antinolo G, Amigo J, Salgado-Garrido J, Pasalodos-Sanchez S, Morte B; Spanish Exome Crowdsourcing Consortium; Carracedo A, Alonso A, Dopazo J. CSVS, a crowdsourcing database of the Spanish population genetic variability. Nucleic Acids Res. 2021 Jan 8;49(D1):D1130-D1137. doi: 10.1093/nar/gkaa794.
citation: Plagnol V, Curtis J, Epstein M, Mok KY, Stebbings E, Grigoriadou S, Wood NW, Hambleton S, Burns SO, Thrasher AJ, Kumararatne D, Doffinger R, Nejentsev S. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics. 2012 Nov 1;28(21):2747-54. doi: 10.1093/bioinformatics/bts526. Epub 2012 Aug 31.