Clinical trial NCT06115122: PEPPI Study: Identification of Women at Risk for Placental Dysfunction
Official title: PEPPI Study: Identification of Women at Risk for Placental Dysfunction During the First and Third Trimesters of Pregnancy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Pre-Eclampsia
Intrauterine Growth Restriction
Polycystic Ovary Syndrome
Iron-deficiency
Cardiovascular Diseases
Hypertensive Disorder of Pregnancy
Proteinuria in Pregnancy
Lead sponsor: Oulu University Hospital
Sponsor class: OTHER
Collaborators: name: PerkinElmer, Inc.
name: Roche Diagnostics GmbH
name: Academy of Finland
name: Sigrid Jusélius Foundation
name: Finnish Medical Foundation
name: University of Oulu
First posted: 2023-11-02
Enrollment: 3000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All pregnant women eligible for the study will be invited to participate the study during their first visit to maternity care. Children born to these women and children's fathers will be asked to participate in the study at the labor hospital.

Brief summary: The main purpose of this study is to evaluate Fetal Medicine Foundation's pre-eclampsia risk calculator using maternal characteristics, first trimester serum placental growth factor (PlGF) and mean arterial pressure (MAP) in a Finnish general population.

Condition or disease: pre-eclampsia, intrauterine growth restriction, polycystic ovary syndrome

Detailed description: According to power calculations, altogether 3000 pregnant women will be recruited into PEPPI-study in Oulu area. Women will be recruited during their first visit to maternity care. Women will have blood samples for study purposes at first and third trimester of pregnancy. Participants will be divided into risk-, control- and polycystic ovary syndrome (PCOS) groups according to pre-eclampsia risk calculation program and questionnaire (PCOS: Rotterdam criteria) (N=300/group). Half of the women in risk- and control groups and all women in PCOS group will have a pregnancy ultrasound scan at 30-32 weeks of gestation. Fathers and children will be recruited at the Oulu University Hospital when the child is born.

Studies within PEPPI-study:

PEPPI-offspring: Children born for those 600 women in risk-, control and PCOS groups who have an extra ultrasound at gestational weeks 30-32 during PEPPI-study and children whose mother developed pre-eclampsia during the pregnancy regardless of her study group during PEPPI-study are recruited into PEPPI-offspring study. PEPPI-offspring study investigates the short- and long-term consequences of placental insufficiency/pre-eclampsia on the health of the children.

PEPPI-PCOS: Investigates pregnancy characteristics of women with PCOS. Women with PCOS form PCOS study group, have additional ultrasound scan at gestational weeks 30-32 and their children are recruited into PEPPI-offspring study.

FERPPI: FERPPI study investigates the possible connection between placental insufficiency and iron deficiency with or without anemia in both pregnant women and their children after birth.

Eligibility criteria: Mothers

Inclusion Criteria for PEPPI-study

* Pregnant (first trimester)
* Understands Finnish
* ≥18 years
* Signed informed consent

Exclusion Criteria

* Multiple pregnancy
* Miscarriage/termination of the index pregnancy
* No first trimester blood sampling

Inclusion Criteria for FERPPI-study

* Participates in PEPPI-study (criteria above)
* Blood samples at first and third trimester of pregnancy
* Permits blood sampling from the umbilical cord when the baby is born

Exclusion Criteria

* No first or third trimester blood sampling
* No umbilical cord blood sample after baby is born

Fathers

Inclusion Criteria

* Biological father to the child born for the mother who participated in PEPPI study
* ≥18 years
* Signed informed consent

Exclusion Criteria

• Does not understand Finnish

Children

Inclusion Criteria for PEPPI-study

* Born to mother who participated in PEPPI study
* Signed informed consent from parent(s)

Exclusion Criteria

• No consent from parent(s)

Inclusion Criteria for PEPPI-offspring study • Mother in risk-, control-, or PCOS group during PEPPI-study with ultrasound information at gestational weeks 30-32 or a mother who developed pre-eclampsia during the pregnancy regardless of their study group during PEPPI-study

Exclusion Criteria

• Mother/father declines participation

Inclusion Criteria for FERPPI-study

* Signed informed consent from parent(s)
* Mother has blood samples taken at first and third trimester (iron status)
* Child has blood samples taken at birth and at 3 months of age

Exclusion Criteria

* No consent from parent(s)
* No blood samples from mother
* No blood samples from child

Primary outcomes:
measure: Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate
timeFrame: 20 weeks through discharge following delivery
measure: Severe Hypertension
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32-34-37 Weeks of Gestation Owing to Hypertension-related Disorders
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the - 2 SD) Adjusted for Sex and Race or Ethnic Group
timeFrame: 20 weeks through discharge following delivery
measure: Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death
timeFrame: 20 weeks through discharge or prior to discharge following delivery admission
measure: Prevalence of high pre-eclampsia risk score in women with PCOS compared to non-PCOS women
timeFrame: at 13 gestational weeks
measure: 11. All the above mentioned outcomes (1-10) in PCOS group compared to non-PCOS group.
timeFrame: 13 gestational weeks through discharge following delivery
measure: The height of the child during the first year of life.
timeFrame: At 0, 3 and 6-12 months of age
measure: The weight of the child during the first year of life.
timeFrame: At 0, 3 and 6-12 months of age
measure: The body mass index (BMI) of the child during the first year of life.
timeFrame: At 0, 3 and 6-12 months of age
measure: Basic blood count
timeFrame: At 0, 3 and 6-12 months of age
measure: Ferritin
timeFrame: At 0, 3 and 6-12 months of age
measure: Hepcidin
timeFrame: At 0, 3 and 6-12 months of age
measure: Saturation of transferrin
timeFrame: At 0, 3 and 6-12 months of age
measure: Hypersensitive-C-reactive protein
timeFrame: At 0, 3 and 6-12 months of age
measure: Anti-mullerian hormone
timeFrame: At 3 and 6-12 months of age
measure: Cortisol
timeFrame: At 3 and 6-12 months of age
measure: Corticotropin
timeFrame: At 3 and 6-12 months of age
measure: Dehydroepiandrosterone
timeFrame: At 3 and 6-12 months of age
measure: Progesterone
timeFrame: At 3 and 6-12 months of age
measure: Inhibin-B
timeFrame: At 3 and 6-12 months of age
measure: Luteinizing hormone
timeFrame: At 3 and 6-12 months of age
measure: Follicle stimulating hormone
timeFrame: At 3 and 6-12 months of age
measure: Testosterone (boys)
timeFrame: At 3 and 6-12 months of age
measure: Estradioli (girls)
timeFrame: At 3 and 6-12 months of age
measure: Vitamin D
timeFrame: At 3 and 6-12 months of age
measure: Calcium
timeFrame: At 3 and 6-12 months of age
measure: Phosphate
timeFrame: At 3 and 6-12 months of age
measure: Alkaline phosphatase
timeFrame: At 3 and 6-12 months of age
measure: Parathyroid hormone
timeFrame: At 3 and 6-12 months of age
measure: Clinical examination of genitals
timeFrame: At 0, 3 and 6-12 months of age
measure: Clinical examination of mammary glands
timeFrame: At 3 and 6-12 months of age
measure: Sebum measurement
timeFrame: At 3 and 6-12 months of age
measure: Heart auscultation with stethoscope.
timeFrame: At 3 and 6-12 months of age
measure: Ultrasound scan of the heart (echo)
timeFrame: At 3 and 6-12 months of age
measure: Birth Weight
timeFrame: At birth
measure: Small for Gestational Age
timeFrame: At birth
measure: Large for gestational age
timeFrame: At birth
measure: Admission to NICU
timeFrame: Delivery through discharge up to 18 weeks
measure: Apgar Score ≤3 at 5 Minutes
timeFrame: At birth
measure: Fetal iron deficiency
timeFrame: At birth
measure: Iron deficiency during third trimester of pregnancy
timeFrame: At 30-32 weeks of gestation
measure: Severe iron deficiency during third trimester of pregnancy
timeFrame: At 30-32 weeks of gestation
Secondary outcomes:
measure: Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).
timeFrame: 20 weeks through discharge following delivery.
measure: Superimposed Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).
timeFrame: 20 weeks through discharge following delivery.
measure: Pregnancy Associated Hypertension.
timeFrame: 20 weeks through discharge following delivery.
measure: Medically Indicated Delivery Because of Hypertension.
timeFrame: 20 weeks through discharge following delivery.
measure: Fetal Weight Estimation under 3rd percentile at gestational weeks 30-32 ultrasound scan.
timeFrame: 30-32 weeks.
measure: Abnormal uterine artery pulsatility index at gestational weeks 30-32 ultrasound scan
timeFrame: At 30-32 weeks.
measure: Aspartate Aminotransferase ≥100 U/Liter.
timeFrame: 20 weeks through discharge.
measure: Creatinine ≥90 µmol/l.
timeFrame: 20 weeks through discharge.
measure: Massive postpartum hemorrhage.
timeFrame: From delivery to 24 hours after child birth
measure: Premature Rupture of Membranes.
timeFrame: From 22nd gestational week until delivery
measure: Placental Abruption.
timeFrame: From 22nd gestational week until delivery
measure: Gestational Diabetes.
timeFrame: From gestation until delivery
measure: Cesarean Delivery.
timeFrame: At Birth.
measure: Vacuum Extraction Delivery.
timeFrame: At Birth.
measure: Maternal Death.
timeFrame: During pregnancy or within 42 days after delivery
measure: Postpartum Pulmonary Edema.
timeFrame: Within 42 days after delivery
measure: Hematocrit ≤24% With Transfusion.
timeFrame: Within 42 days after delivery
measure: Maternal Hospital Stay.
timeFrame: Within 42 days after delivery
measure: Gestational Age at Delivery.
timeFrame: At Delivery.
measure: Perineal Lacerations.
timeFrame: At Birth.
measure: Number of Visits to Maternity Health Care During Pregnancy.
timeFrame: From gestation until delivery, on average during 9 months
measure: Number of Visits at Tertiary Maternity Care Hospital.
timeFrame: From gestation until delivery, on average during 9 months
measure: Fetal Death.
timeFrame: From 22nd gestational week until delivery
measure: Neonatal Death.
timeFrame: Birth until 4 weeks' of age
measure: Respiratory Distress Syndrome.
timeFrame: Birth until 4 weeks' of age
measure: Intraventricular Hemorrhage, Grade III or IV.
timeFrame: Birth until 4 weeks' of age
measure: Neonatal sepsis.
timeFrame: Birth until 4 weeks' of age
measure: Necrotizing Enterocolitis.
timeFrame: Birth until 4 weeks' of age
measure: Retinopathy of Prematurity.
timeFrame: Birth until 4 weeks' of age
measure: Neonatal Hospital Stay.
timeFrame: Birth until 18 weeks' of age
measure: Umbilical artery pulsatility index
timeFrame: At 30-32 gestational weeks
measure: Mean cerebral artery pulsatility index
timeFrame: At 30-32 gestational weeks
measure: Ductus venousus pulsatility index
timeFrame: At 30-32 gestational weeks
measure: Fetal weight estimation
timeFrame: At 30-32 gestational weeks
measure: Amniotic fluid measurement
timeFrame: At 30-32 gestational weeks
measure: Estimation of fetal movement during ultrasound scan
timeFrame: At 30-32 gestational weeks
measure: Apgar Score ≤7 at 5 minutes.
timeFrame: At birth.
measure: Blood transfusion.
timeFrame: From 22nd pregnancy week until four weeks after delivery
Other outcomes:
Locations:
city: Oulu
country: Finland
facility: The Wellbeing Services County of North Ostrobothnia
Study officials:
affiliation: The Wellbeing Services County of North Ostrobothnia
name: Jaana Nevalainen, Assoc prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ashraf UM, Hall DL, Rawls AZ, Alexander BT. Epigenetic processes during preeclampsia and effects on fetal development and chronic health. Clin Sci (Lond). 2021 Oct 15;135(19):2307-2327. doi: 10.1042/CS20190070.
citation: Bahri Khomami M, Joham AE, Boyle JA, Piltonen T, Silagy M, Arora C, Misso ML, Teede HJ, Moran LJ. Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity-A systematic review, meta-analysis, and meta-regression. Obes Rev. 2019 May;20(5):659-674. doi: 10.1111/obr.12829. Epub 2019 Jan 23.
citation: Becker M, Hesse V. Minipuberty: Why Does it Happen? Horm Res Paediatr. 2020;93(2):76-84. doi: 10.1159/000508329. Epub 2020 Jun 29.
citation: Binder NK, Evans J, Salamonsen LA, Gardner DK, Kaitu'u-Lino TJ, Hannan NJ. Placental Growth Factor Is Secreted by the Human Endometrium and Has Potential Important Functions during Embryo Development and Implantation. PLoS One. 2016 Oct 6;11(10):e0163096. doi: 10.1371/journal.pone.0163096. eCollection 2016.
citation: Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA, Georgieff MK. Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia. J Pediatr. 1987 Aug;111(2):283-6. doi: 10.1016/s0022-3476(87)80088-4.
citation: Dewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017 Dec;106(Suppl 6):1694S-1702S. doi: 10.3945/ajcn.117.156075. Epub 2017 Oct 25.
citation: Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009 Jun;33(3):130-7. doi: 10.1053/j.semperi.2009.02.010.
citation: Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004659. doi: 10.1002/14651858.CD004659.pub2.
citation: Guy GP, Leslie K, Diaz Gomez D, Forenc K, Buck E, Khalil A, Thilaganathan B. Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study. BJOG. 2021 Jan;128(2):149-156. doi: 10.1111/1471-0528.16361. Epub 2020 Jul 1.
citation: Henley D, Brown S, Pennell C, Lye S, Torpy DJ. Evidence for central hypercortisolism and elevated blood pressure in adolescent offspring of mothers with pre-eclampsia. Clin Endocrinol (Oxf). 2016 Oct;85(4):583-9. doi: 10.1111/cen.13092. Epub 2016 May 26.
citation: Kalousova M, Muravska A, Zima T. Pregnancy-associated plasma protein A (PAPP-A) and preeclampsia. Adv Clin Chem. 2014;63:169-209. doi: 10.1016/b978-0-12-800094-6.00005-4.
citation: Koster MP, de Wilde MA, Veltman-Verhulst SM, Houben ML, Nikkels PG, van Rijn BB, Fauser BC. Placental characteristics in women with polycystic ovary syndrome. Hum Reprod. 2015 Dec;30(12):2829-37. doi: 10.1093/humrep/dev265. Epub 2015 Oct 25.
citation: Nevalainen J, Korpimaki T, Kouru H, Sairanen M, Ryynanen M. Performance of first trimester biochemical markers and mean arterial pressure in prediction of early-onset pre-eclampsia. Metabolism. 2017 Oct;75:6-15. doi: 10.1016/j.metabol.2017.07.004. Epub 2017 Jul 18.
citation: Nevalainen J, Skarp S, Savolainen ER, Ryynanen M, Jarvenpaa J. Intrauterine growth restriction and placental gene expression in severe preeclampsia, comparing early-onset and late-onset forms. J Perinat Med. 2017 Oct 26;45(7):869-877. doi: 10.1515/jpm-2016-0406.
citation: O'Gorman N, Wright D, Rolnik DL, Nicolaides KH, Poon LC. Study protocol for the randomised controlled trial: combined multimarker screening and randomised patient treatment with ASpirin for evidence-based PREeclampsia prevention (ASPRE). BMJ Open. 2016 Jun 28;6(6):e011801. doi: 10.1136/bmjopen-2016-011801.
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: Santos DCC, Angulo-Barroso RM, Li M, Bian Y, Sturza J, Richards B, Lozoff B. Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months. Eur J Clin Nutr. 2018 Mar;72(3):332-341. doi: 10.1038/s41430-017-0015-8. Epub 2017 Nov 6.
citation: Shanmugalingam R, Hennessy A, Makris A. Aspirin in the prevention of preeclampsia: the conundrum of how, who and when. J Hum Hypertens. 2019 Jan;33(1):1-9. doi: 10.1038/s41371-018-0113-7. Epub 2018 Sep 19.
citation: Shao J, Lou J, Rao R, Georgieff MK, Kaciroti N, Felt BT, Zhao ZY, Lozoff B. Maternal serum ferritin concentration is positively associated with newborn iron stores in women with low ferritin status in late pregnancy. J Nutr. 2012 Nov;142(11):2004-9. doi: 10.3945/jn.112.162362. Epub 2012 Sep 26.
citation: Tal R, Seifer DB, Grazi RV, Malter HE. Follicular fluid placental growth factor is increased in polycystic ovarian syndrome: correlation with ovarian stimulation. Reprod Biol Endocrinol. 2014 Aug 20;12:82. doi: 10.1186/1477-7827-12-82.
citation: Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D, Singh M, Greco E, Wright A, Maclagan K, Poon LC, Nicolaides KH. Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE. Ultrasound Obstet Gynecol. 2018 Jun;51(6):743-750. doi: 10.1002/uog.19039. Epub 2018 Mar 14.
citation: Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018 Sep 1;33(9):1602-1618. doi: 10.1093/humrep/dey256.
citation: Yliniemi A, Nurkkala MM, Kopman S, Korpimaki T, Kouru H, Ryynanen M, Marttala J. First trimester placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in the prediction of early-onset severe pre-eclampsia. Metabolism. 2015 Apr;64(4):521-6. doi: 10.1016/j.metabol.2014.12.008. Epub 2014 Dec 26.