PEPPI Study: Identification of Women at Risk for Placental Dysfunction

NCT06115122 | Recruiting

• 1 other identifier: OuluUH_PEPPI
• Study Type: observational
• Target: 3,000
• Locations: 1 country
• Sites: 1

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

Conditions

Pre-Eclampsia; Intrauterine Growth Restriction; Polycystic Ovary Syndrome; Iron-deficiency; Cardiovascular Diseases; Hypertensive Disorder of Pregnancy; Proteinuria in Pregnancy

Outcome Measures

Primary Outcomes (47)

• Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate

  Severe hypertension (blood pressure \[BP\]≥ 160/110) or mild hypertension (BP≥140/90) ≥ 20 weeks gestation in conjunction with one of the following: elevated liver enzymes, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, an indicated preterm birth before 32 weeks of gestation owing to hypertension-related disorders, a fetus that was small for gestational age (SGA, below 3rd percentile) adjusted for sex and race or ethnic group, fetal death after 20 weeks of gestation, or neonatal death

  20 weeks through discharge following delivery

• Severe Hypertension

  Women who had severe hypertension only and those who had severe hypertension with elevated liver enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or fetal death after 20 weeks of gestation, or neonatal death.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels

  Elevated liver enzyme levels are specified as an aspartate aminotransferase level of ≥ 100 U/l. Women who met more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia

  Thrombocytopenia defined as a platelet count of \<100 × 109/l. Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level

  Elevated serum creatinine defined as ≥90 µmol/l. Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure

  Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32-34-37 Weeks of Gestation Owing to Hypertension-related Disorders

  Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• 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

  Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge following delivery

• Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death

  Women who meet more than one component of the primary outcome are counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.

  20 weeks through discharge or prior to discharge following delivery admission

• Prevalence of high pre-eclampsia risk score in women with PCOS compared to non-PCOS women

  Pre-eclampsia risk score is calculated with LifeCycle risk calculation program and a risk of 1:100 or higher is considered as high risk for pre-eclampsia.

  at 13 gestational weeks

• 11. All the above mentioned outcomes (1-10) in PCOS group compared to non-PCOS group.

  As described above.

  13 gestational weeks through discharge following delivery

• The height of the child during the first year of life.

  Measurement of height (cm)

  At 0, 3 and 6-12 months of age

• The weight of the child during the first year of life.

  Measurement of weight (g, kg)

  At 0, 3 and 6-12 months of age

• The body mass index (BMI) of the child during the first year of life.

  Measurements of height (cm) and weight (kg) combined as BMI (kg/m2)

  At 0, 3 and 6-12 months of age

• Basic blood count

  B-Hb, B-Leuk, B-Hkr, B-Eryt, E-MCV, E-RDW, E-MCH, E-MCHC, B-Trom

  At 0, 3 and 6-12 months of age

• Ferritin

  At 0, 3 and 6-12 months of age

• Hepcidin

  At 0, 3 and 6-12 months of age

• Saturation of transferrin

  At 0, 3 and 6-12 months of age

• Hypersensitive-C-reactive protein

  At 0, 3 and 6-12 months of age

• Anti-mullerian hormone

  At 3 and 6-12 months of age

• Cortisol

  At 3 and 6-12 months of age

• Corticotropin

  At 3 and 6-12 months of age

• Dehydroepiandrosterone

  At 3 and 6-12 months of age

• Progesterone

  At 3 and 6-12 months of age

• Inhibin-B

  At 3 and 6-12 months of age

• Luteinizing hormone

  At 3 and 6-12 months of age

• Follicle stimulating hormone

  At 3 and 6-12 months of age

• Testosterone (boys)

  At 3 and 6-12 months of age

• Estradioli (girls)

  At 3 and 6-12 months of age

• Vitamin D

  At 3 and 6-12 months of age

• Calcium

  At 3 and 6-12 months of age

• Phosphate

  At 3 and 6-12 months of age

• Alkaline phosphatase

  At 3 and 6-12 months of age

• Parathyroid hormone

  At 3 and 6-12 months of age

• Clinical examination of genitals

  Measurement of perineum with centimeters (cm)

  At 0, 3 and 6-12 months of age

• Clinical examination of mammary glands

  Measurement with millimeters (mm)

  At 3 and 6-12 months of age

• Sebum measurement

  Measurement is done with Sebumeter ®. The cassette is placed on the skin for a defined length of time and then returned to the aperture. The change in the amount of light transmission represents the sebum content of the tape, which is displayed in units from 0-350.

  At 3 and 6-12 months of age

• Heart auscultation with stethoscope.

  At 3 and 6-12 months of age

• Ultrasound scan of the heart (echo)

  At 3 and 6-12 months of age

• Birth Weight

  Grams

  At birth

• Small for Gestational Age

  A baby whose birth weight is less than the - 2 standard deviations is considered to be small for gestational age (adjusted for sex and race or ethnic group)

  At birth

• Large for gestational age

  A baby whose birth weight is more than the + 2 standard deviations is considered to be small for gestational age (adjusted for sex and race or ethnic group)

  At birth

• Admission to NICU

  NICU denotes neonatal intensive care unit.

  Delivery through discharge up to 18 weeks

• Apgar Score ≤3 at 5 Minutes

  At birth

• Fetal iron deficiency

  Fetal iron deficiency defined by reticulocyte hemoglobin \< 29 pg from umbilical cord blood collected at birth

  At birth

• Iron deficiency during third trimester of pregnancy

  Iron deficiency defined as serum ferritin \< 30 µg/l at gestational weeks 30-32 with or without anemia defined as Hb ≤ 110 g/l.

  At 30-32 weeks of gestation

• Severe iron deficiency during third trimester of pregnancy

  Iron deficiency defined as serum ferritin \< 15 µg/l at gestational weeks 30-32 with or without anemia defined as Hb ≤ 110 g/l.

  At 30-32 weeks of gestation

Secondary Outcomes (38)

• Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).

  20 weeks through discharge following delivery.

• Superimposed Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).

  20 weeks through discharge following delivery.

• Pregnancy Associated Hypertension.

  20 weeks through discharge following delivery.

• Medically Indicated Delivery Because of Hypertension.

  20 weeks through discharge following delivery.

• Fetal Weight Estimation under 3rd percentile at gestational weeks 30-32 ultrasound scan.

  30-32 weeks.

Study Arms (6)

Pre-eclampsia risk group

Approximately 300 women will be enrolled into a risk group according to a pre-eclampsia risk calculator.

Other: Pre-eclampsia screening program

PCOS group

Women enrolled into study who fulfill ≥2 Rotterdam criteria. Women with PCOS may be included in risk- or control groups.

Other: Pre-eclampsia screening program

Control group

Approximately 300 women in low risk for pre-eclampsia according to a pre-eclampsia risk calculator.

Other: Pre-eclampsia screening program

Follow up group

Approximately 2100 women who are not enrolled into risk-, control- or PCOS groups.

Other: Pre-eclampsia screening program

Children

Mothers and fathers will be asked for permission to follow the child's health information from national registers until the age of 15 years. Approximately 300 children will be recruited to PEPPI-offspring follow up study (including also PCOS offspring).

Fathers

The role of fathers in the development of pregnancy complications and on the health of the offspring.

Interventions

Pre-eclampsia screening program OTHER

Pregnant women will be devided into risk-, control- and PCOS groups according to first trimester screening program.

Control group; Follow up group; PCOS group; Pre-eclampsia risk group

Eligibility Criteria

• Gender Eligibility Details: Participants recruited for PEPPI are pregnant women (females), their partners (males) and babies (female/male).
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• Multiple pregnancy
• Miscarriage/termination of the index pregnancy
• No first trimester blood sampling
• 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
• No first or third trimester blood sampling
• No umbilical cord blood sample after baby is born
• Fathers
• Biological father to the child born for the mother who participated in PEPPI study
• ≥18 years
• Signed informed consent
• Does not understand Finnish
• Children
• Born to mother who participated in PEPPI study

Sponsors & Collaborators

• Oulu University Hospital: lead
• PerkinElmer, Inc.: collaborator
• Roche Diagnostics GmbH: collaborator
• Academy of Finland: collaborator
• Sigrid Jusélius Foundation: collaborator
• Finnish Medical Foundation: collaborator
• University of Oulu: collaborator

Study Sites (1)

The Wellbeing Services County of North Ostrobothnia

Oulu, 90100, Finland

RECRUITING

Related Publications (23)

• Maeda K, Naganuma M, Fukuda M, Matsunaga J, Tomita Y. Effect of pituitary and ovarian hormones on human melanocytes in vitro. Pigment Cell Res. 1996 Aug;9(4):204-12. doi: 10.1111/j.1600-0749.1996.tb00110.x.

  PMID: 8948502 BACKGROUND

• 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.

  PMID: 30674081 BACKGROUND

• 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.

  PMID: 32599600 BACKGROUND

• 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.

  PMID: 27711226 BACKGROUND

• 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.

  PMID: 3612404 BACKGROUND

• 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.

  PMID: 29070565 BACKGROUND

• 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.

  PMID: 19464502 BACKGROUND

• 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.

  PMID: 17443552 BACKGROUND

• 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.

  PMID: 32613730 BACKGROUND

• 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.

  PMID: 27144974 BACKGROUND

• 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.

  PMID: 24783354 BACKGROUND

• 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.

  PMID: 26498178 BACKGROUND

• 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.

  PMID: 28964327 BACKGROUND

• 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.

  PMID: 28593875 BACKGROUND

• 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.

  PMID: 27354081 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.

  PMID: 28657417 BACKGROUND

• 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.

  PMID: 29235557 BACKGROUND

• 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.

  PMID: 30232399 BACKGROUND

• 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.

  PMID: 23014493 BACKGROUND

• 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.

  PMID: 25141961 BACKGROUND

• 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.

  PMID: 29536574 BACKGROUND

• 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.

  PMID: 30052961 BACKGROUND

• 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.

  PMID: 25633269 BACKGROUND

Related Links

• PEPPI-study's webpage

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples will be taken at first and third trimesters from pregnant women. At birth, blood samples will be taken from umbilical cord, placental samples and umbilical cord samples will be taken also. DNA samples from mothers, fathers and children will be taken. Approximately 900 children will have blood samples at the age of 3 and 6-12 months.

MeSH Terms

Conditions

Pre-Eclampsia; Fetal Growth Retardation; Polycystic Ovary Syndrome; Anemia, Iron-Deficiency; Cardiovascular Diseases; Toxemia

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Growth Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Anemia, Hypochromic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Iron Deficiencies; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Infections

Study Officials

• Jaana Nevalainen, Assoc prof

  The Wellbeing Services County of North Ostrobothnia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jaana E Nevalainen, Assoc prof

CONTACT

+358405801857; jaana.nevalainen@oulu.fi

Terhi Piltonen, Professor

CONTACT

+358405008266; terhi.piltonen@oulu.fi

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 15 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor

Study Record Dates

• First Submitted: November 28, 2022
• First Posted: November 2, 2023
• Study Start: February 15, 2022
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2041
• Last Updated: August 5, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data is available on request 10 years from study completion
• Access Criteria: Data available according to policies of the Oulu University Hospital and Oulu University.

Locations

FI (1)