PEPPI Study: Identification of Women at Risk for Placental Dysfunction

Sponsor

Oulu University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT06115122

Collaborator

PerkinElmer, Inc. (Industry), Roche Diagnostics (Industry), Academy of Finland (Other), Sigrid Jusélius Foundation (Other), Finnish Medical Foundation (Other), University of Oulu (Other)

3,000

Enrollment

Location

238.5

Anticipated Duration (Months)

12.6

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Pre-Eclampsia Intrauterine Growth Restriction Polycystic Ovary Syndrome Iron-deficiency Cardiovascular Diseases Hypertensive Disorder of Pregnancy Proteinuria in Pregnancy	Other: Pre-eclampsia screening program

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.

Study Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

3000 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

PEPPI Study: Identification of Women at Risk for Placental Dysfunction During the First and Third Trimesters of Pregnancy

Actual Study Start Date :

Feb 15, 2022

Anticipated Primary Completion Date :

Dec 31, 2026

Anticipated Study Completion Date :

Dec 31, 2041

Arms and Interventions

Arm	Intervention/Treatment
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 Pregnant women will be devided into risk-, control- and PCOS groups according to first trimester 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 Pregnant women will be devided into risk-, control- and PCOS groups according to first trimester 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 Pregnant women will be devided into risk-, control- and PCOS groups according to first trimester screening program.
Follow up group Approximately 2100 women who are not enrolled into risk-, control- or PCOS groups.	Other: Pre-eclampsia screening program Pregnant women will be devided into risk-, control- and PCOS groups according to first trimester 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.

Outcome Measures

Primary Outcome Measures

Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate [20 weeks through discharge following delivery]
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
Severe Hypertension [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32-34-37 Weeks of Gestation Owing to Hypertension-related Disorders [20 weeks through discharge following delivery]
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.
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 [20 weeks through discharge following delivery]
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.
Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death [20 weeks through discharge or prior to discharge following delivery admission]
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.
Prevalence of high pre-eclampsia risk score in women with PCOS compared to non-PCOS women [at 13 gestational weeks]
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.
11. All the above mentioned outcomes (1-10) in PCOS group compared to non-PCOS group. [13 gestational weeks through discharge following delivery]
As described above.
The height of the child during the first year of life. [At 0, 3 and 6-12 months of age]
Measurement of height (cm)
The weight of the child during the first year of life. [At 0, 3 and 6-12 months of age]
Measurement of weight (g, kg)
The body mass index (BMI) of the child during the first year of life. [At 0, 3 and 6-12 months of age]
Measurements of height (cm) and weight (kg) combined as BMI (kg/m2)
Basic blood count [At 0, 3 and 6-12 months of age]
B-Hb, B-Leuk, B-Hkr, B-Eryt, E-MCV, E-RDW, E-MCH, E-MCHC, B-Trom
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 [At 0, 3 and 6-12 months of age]
Measurement of perineum with centimeters (cm)
Clinical examination of mammary glands [At 3 and 6-12 months of age]
Measurement with millimeters (mm)
Sebum measurement [At 3 and 6-12 months of age]
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.
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 [At birth]
Grams
Small for Gestational Age [At birth]
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)
Large for gestational age [At birth]
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)
Admission to NICU [Delivery through discharge up to 18 weeks]
NICU denotes neonatal intensive care unit.
Apgar Score ≤3 at 5 Minutes [At birth]
Fetal iron deficiency [At birth]
Fetal iron deficiency defined by reticulocyte hemoglobin < 29 pg from umbilical cord blood collected at birth
Iron deficiency during third trimester of pregnancy [At 30-32 weeks of gestation]
Iron deficiency defined as serum ferritin < 30 µg/l at gestational weeks 30-32 with or without anemia defined as Hb ≤ 110 g/l.
Severe iron deficiency during third trimester of pregnancy [At 30-32 weeks of gestation]
Iron deficiency defined as serum ferritin < 15 µg/l at gestational weeks 30-32 with or without anemia defined as Hb ≤ 110 g/l.

Secondary Outcome Measures

Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia). [20 weeks through discharge following delivery.]
HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.
Superimposed Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia). [20 weeks through discharge following delivery.]
Women with Hypertension before pregnancy week 20. HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.
Pregnancy Associated Hypertension. [20 weeks through discharge following delivery.]
Women with Hypertension after pregnancy week 20.
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.]
Abnormal uterine artery pulsatility index at gestational weeks 30-32 ultrasound scan [At 30-32 weeks.]
According to calculator provided by Fetal Medicine Foundation (https://fetalmedicine.org/research/utpi).
Aspartate Aminotransferase ≥100 U/Liter. [20 weeks through discharge.]
Creatinine ≥90 µmol/l. [20 weeks through discharge.]
Massive postpartum hemorrhage. [From delivery to 24 hours after child birth]
Massive postpartum hemorrhage defined≥ 1000ml blood loss within 24 hours after child birth.
Premature Rupture of Membranes. [From 22nd gestational week until delivery]
If the water breaks before the 37th week of pregnancy, it is called preterm premature rupture of membranes (PPROM).
Placental Abruption. [From 22nd gestational week until delivery]
Defined as the placenta separates from the inner wall of the uterus before birth.
Gestational Diabetes. [From gestation until delivery]
Defined as abnormal glucose tolerance test during pregnancy (≥ 5.3 mmol/l (0 h), ≥ 10.0 mmol/l (1 h) and/or ≥ 8.6 mmol/l (2 h). Treatment either with diet or medicine (metformin and/or insulin therapy).
Cesarean Delivery. [At Birth.]
Vacuum Extraction Delivery. [At Birth.]
Maternal Death. [During pregnancy or within 42 days after delivery]
Postpartum Pulmonary Edema. [Within 42 days after delivery]
Hematocrit ≤24% With Transfusion. [Within 42 days after delivery]
Maternal Hospital Stay. [Within 42 days after delivery]
Duration of the time spend at the hospital after delivery (measured as days and weeks)
Gestational Age at Delivery. [At Delivery.]
Perineal Lacerations. [At Birth.]
Defined as first, second, third or fourth degree lacerations during birth.
Number of Visits to Maternity Health Care During Pregnancy. [From gestation until delivery, on average during 9 months]
Number of Visits at Tertiary Maternity Care Hospital. [From gestation until delivery, on average during 9 months]
Fetal Death. [From 22nd gestational week until delivery]
Neonatal Death. [Birth until 4 weeks' of age]
Respiratory Distress Syndrome. [Birth until 4 weeks' of age]
Intraventricular Hemorrhage, Grade III or IV. [Birth until 4 weeks' of age]
Neonatal sepsis. [Birth until 4 weeks' of age]
Necrotizing Enterocolitis. [Birth until 4 weeks' of age]
Retinopathy of Prematurity. [Birth until 4 weeks' of age]
Neonatal Hospital Stay. [Birth until 18 weeks' of age]
Umbilical artery pulsatility index [At 30-32 gestational weeks]
Measured with Doppler ultrasound
Mean cerebral artery pulsatility index [At 30-32 gestational weeks]
Measured with Doppler ultrasound
Ductus venousus pulsatility index [At 30-32 gestational weeks]
Measured with Doppler ultrasound
Fetal weight estimation [At 30-32 gestational weeks]
Measured with ultrasound using fetal BPD, HC, AC and FL measurements (Hadlock)
Amniotic fluid measurement [At 30-32 gestational weeks]
Ultrasound measurements of maximum velocity pocket (cm) and amniotic fluid index (cm)
Estimation of fetal movement during ultrasound scan [At 30-32 gestational weeks]
Estimated as a whole with inspection of body movements, limb movements and breathing movement
Apgar Score ≤7 at 5 minutes. [At birth.]
Blood transfusion. [From 22nd pregnancy week until four weeks after delivery]
Defined as red blood cell transfusion received by patient (mother or child).

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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