PEPPI Study: Identification of Women at Risk for Placental Dysfunction

Cardiovascular Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06115122
• Other study ID #: OuluUH_PEPPI
• Status: Recruiting
• Start date: February 15, 2022
• Est. completion date: December 31, 2041

Study information

• Verified date: October 2023
• Source: Oulu University Hospital
• Contact: Jaana E Nevalainen, Assoc prof
• Phone: +358405801857
• Email: jaana.nevalainen[@]oulu.fi
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3000
• Est. completion date: December 31, 2041
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Eclampsia
• Fetal Growth Retardation
• Hypertension
• Hypertensive Disorder of Pregnancy
• Intrauterine Growth Restriction
• Iron-deficiency
• Polycystic Ovary Syndrome
• Pre-Eclampsia
• Proteinuria
• Proteinuria in Pregnancy
• Toxemia

Intervention

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

Locations

Country	Name	City	State
Finland	The Wellbeing Services County of North Ostrobothnia	Oulu

Sponsors (7)

Lead Sponsor	Collaborator
Oulu University Hospital	Academy of Finland, Finnish Medical Foundation, PerkinElmer, Inc., Roche Diagnostics, Sigrid Jusélius Foundation, University of Oulu

Country where clinical trial is conducted

Finland, 

References & Publications (23)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. Erratum In: Hum Reprod. 2019 Feb 1;34(2):388. — View 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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	The height of the child during the first year of life.	Measurement of height (cm)	At 0, 3 and 6-12 months of age
Primary	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
Primary	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
Primary	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
Primary	Ferritin		At 0, 3 and 6-12 months of age
Primary	Hepcidin		At 0, 3 and 6-12 months of age
Primary	Saturation of transferrin		At 0, 3 and 6-12 months of age
Primary	Hypersensitive-C-reactive protein		At 0, 3 and 6-12 months of age
Primary	Anti-mullerian hormone		At 3 and 6-12 months of age
Primary	Cortisol		At 3 and 6-12 months of age
Primary	Corticotropin		At 3 and 6-12 months of age
Primary	Dehydroepiandrosterone		At 3 and 6-12 months of age
Primary	Progesterone		At 3 and 6-12 months of age
Primary	Inhibin-B		At 3 and 6-12 months of age
Primary	Luteinizing hormone		At 3 and 6-12 months of age
Primary	Follicle stimulating hormone		At 3 and 6-12 months of age
Primary	Testosterone (boys)		At 3 and 6-12 months of age
Primary	Estradioli (girls)		At 3 and 6-12 months of age
Primary	Vitamin D		At 3 and 6-12 months of age
Primary	Calcium		At 3 and 6-12 months of age
Primary	Phosphate		At 3 and 6-12 months of age
Primary	Alkaline phosphatase		At 3 and 6-12 months of age
Primary	Parathyroid hormone		At 3 and 6-12 months of age
Primary	Clinical examination of genitals	Measurement of perineum with centimeters (cm)	At 0, 3 and 6-12 months of age
Primary	Clinical examination of mammary glands	Measurement with millimeters (mm)	At 3 and 6-12 months of age
Primary	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
Primary	Heart auscultation with stethoscope.		At 3 and 6-12 months of age
Primary	Ultrasound scan of the heart (echo)		At 3 and 6-12 months of age
Primary	Birth Weight	Grams	At birth
Primary	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
Primary	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
Primary	Admission to NICU	NICU denotes neonatal intensive care unit.	Delivery through discharge up to 18 weeks
Primary	Apgar Score =3 at 5 Minutes		At birth
Primary	Fetal iron deficiency	Fetal iron deficiency defined by reticulocyte hemoglobin < 29 pg from umbilical cord blood collected at birth	At birth
Primary	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
Primary	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	Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).	HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.	20 weeks through discharge following delivery.
Secondary	Superimposed Pre-eclampsia (Mild, Severe, HELLP Syndrome, Eclampsia).	Women with Hypertension before pregnancy week 20. HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.	20 weeks through discharge following delivery.
Secondary	Pregnancy Associated Hypertension.	Women with Hypertension after pregnancy week 20.	20 weeks through discharge following delivery.
Secondary	Medically Indicated Delivery Because of Hypertension.		20 weeks through discharge following delivery.
Secondary	Fetal Weight Estimation under 3rd percentile at gestational weeks 30-32 ultrasound scan.		30-32 weeks.
Secondary	Abnormal uterine artery pulsatility index at gestational weeks 30-32 ultrasound scan	According to calculator provided by Fetal Medicine Foundation (https://fetalmedicine.org/research/utpi).	At 30-32 weeks.
Secondary	Aspartate Aminotransferase =100 U/Liter.		20 weeks through discharge.
Secondary	Creatinine =90 µmol/l.		20 weeks through discharge.
Secondary	Massive postpartum hemorrhage.	Massive postpartum hemorrhage defined= 1000ml blood loss within 24 hours after child birth.	From delivery to 24 hours after child birth
Secondary	Premature Rupture of Membranes.	If the water breaks before the 37th week of pregnancy, it is called preterm premature rupture of membranes (PPROM).	From 22nd gestational week until delivery
Secondary	Placental Abruption.	Defined as the placenta separates from the inner wall of the uterus before birth.	From 22nd gestational week until delivery
Secondary	Gestational Diabetes.	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).	From gestation until delivery
Secondary	Cesarean Delivery.		At Birth.
Secondary	Vacuum Extraction Delivery.		At Birth.
Secondary	Maternal Death.		During pregnancy or within 42 days after delivery
Secondary	Postpartum Pulmonary Edema.		Within 42 days after delivery
Secondary	Hematocrit =24% With Transfusion.		Within 42 days after delivery
Secondary	Maternal Hospital Stay.	Duration of the time spend at the hospital after delivery (measured as days and weeks)	Within 42 days after delivery
Secondary	Gestational Age at Delivery.		At Delivery.
Secondary	Perineal Lacerations.	Defined as first, second, third or fourth degree lacerations during birth.	At Birth.
Secondary	Number of Visits to Maternity Health Care During Pregnancy.		From gestation until delivery, on average during 9 months
Secondary	Number of Visits at Tertiary Maternity Care Hospital.		From gestation until delivery, on average during 9 months
Secondary	Fetal Death.		From 22nd gestational week until delivery
Secondary	Neonatal Death.		Birth until 4 weeks' of age
Secondary	Respiratory Distress Syndrome.		Birth until 4 weeks' of age
Secondary	Intraventricular Hemorrhage, Grade III or IV.		Birth until 4 weeks' of age
Secondary	Neonatal sepsis.		Birth until 4 weeks' of age
Secondary	Necrotizing Enterocolitis.		Birth until 4 weeks' of age
Secondary	Retinopathy of Prematurity.		Birth until 4 weeks' of age
Secondary	Neonatal Hospital Stay.		Birth until 18 weeks' of age
Secondary	Umbilical artery pulsatility index	Measured with Doppler ultrasound	At 30-32 gestational weeks
Secondary	Mean cerebral artery pulsatility index	Measured with Doppler ultrasound	At 30-32 gestational weeks
Secondary	Ductus venousus pulsatility index	Measured with Doppler ultrasound	At 30-32 gestational weeks
Secondary	Fetal weight estimation	Measured with ultrasound using fetal BPD, HC, AC and FL measurements (Hadlock)	At 30-32 gestational weeks
Secondary	Amniotic fluid measurement	Ultrasound measurements of maximum velocity pocket (cm) and amniotic fluid index (cm)	At 30-32 gestational weeks
Secondary	Estimation of fetal movement during ultrasound scan	Estimated as a whole with inspection of body movements, limb movements and breathing movement	At 30-32 gestational weeks
Secondary	Apgar Score =7 at 5 minutes.		At birth.
Secondary	Blood transfusion.	Defined as red blood cell transfusion received by patient (mother or child).	From 22nd pregnancy week until four weeks after delivery

External Links

•   Finnish maternity and child care webpage
•   PEPPI-study's webpage