Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Heart and Blood Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Infections

Diabetes Mellitus

Breast Neoplasms

Syndrome

Hypertension

Diabetes, Gestational

Polycystic Ovary Syndrome

Toxemia

Primary Ovarian Insufficiency

Menopause, Premature

Menopause

* Blood sample
* Questionnaires
* Arterial stiffness assessment
* Transthoracic Echocardiogram
* Coronary Computed Tomography Angiography (CTA)
* Cardiac Positron Emission Tomography (PET)

* Blood sample
* Questionnaires
* Arterial stiffness assessment

PET scan

Kerri-Anne Mullen, PhD

The full HER CROWN will be a prospective cohort study to propose a novel, women-specific cardiovascular risk score/ algorithm in the prediction of hard cardiovascular outcomes (myocardial infarction, unstable angina, coronary revascularization, stroke, total and cardiovascular mortality). This future study will be the first longitudinal cohort study, to our knowledge, that is focused entirely on researching the pathophysiology and natural history of cardiovascular disease in women with known female-specific risk factors. Further, the investigators are aiming to recruit a sample that is representative of the ethnic distribution in Canada. The proposed pilot study is a feasibility study as an essential preparatory step for HER CROWN.

Cardiovascular diseases (CVD), including ischemic heart disease (IHD), peripheral vascular disease (PVD), and stroke, remain the leading preventable cause of death among Canadian women, resulting in over 34,000 deaths per year (age-standardized death rate: 25.1%). Nearly 40% of CVD-related deaths in women are due to IHD. Increased awareness efforts and effective treatments have led to an overall decline in CVD mortality among men and women in high income countries over the past few decades; however, alarmingly, an increase in CVD mortality has been observed in women in the most recent 5 to 10 years in Canada and the United States, and an upward trend in rates of AMI among younger women.

CVD in women remains understudied, under-diagnosed, and undertreated. Clinical guidelines are largely based on studies of men. Several existing large longitudinal cohort studies (e.g., the Nurses' Health Study, The Framingham Heart Study, the PURE study) have included women; however, they have not focused recruitment specifically on high-risk cohorts of women or on risk factors that are unique to women, more common in women, or that disproportionately affect women; they have not used novel measures of subclinical disease in women (e.g., coronary computed tomography angiography and cardiac Rb-positive emission tomography); and most have not recruited representative samples of women in terms of ethnicity or socioeconomic status. CVD risk calculators (e.g., Framingham, the American College of Cardiology ASCVD) focus on traditional risk factors (e.g., tobacco smoking, hypertension, diabetes), do not include sex-specific CVD risk factors or factors that disproportionately affect women, and thus tend to underestimate risk in women. Female-specific factors that have been associated with CVD risk include: premature or late menarche, abnormal menses, premature or early menopause, gestational hypertensive disorders, gestational diabetes, preterm delivery, pregnancy loss, hormonal contraceptive use, and polycystic ovarian syndrome. Risk factors that are under-recognized or disproportionately affect women include: rheumatologic inflammatory disorders (RIDs), depression, anxiety, chronic stress, abuse and intimate partner violence, and health literacy. In addition, a more feminine gender role has been shown to be associated with higher risk of reinfarction after premature acute coronary syndrome, but no additional research on gender roles and future cardiovascular risk is available. Importantly, novel cardiovascular risk markers such as measures of arterial stiffness and aging, among others, have not been prospectively evaluated in a female population. As such, additional longitudinal research is needed to understand the natural history of CVD and the impact of these 'non-conventional' risk factors in women.

A recent article published in the Lancet by a multi-national group of women's heart health experts reviewed existing evidence, identified knowledge gaps, and provided specific recommendations related to CVD research, prevention, treatment, and access to care for women. The HER CROWN longitudinal cohort study will respond to three important gaps identified in this review, specifically: 1) describe the pathophysiology and natural history of cardiovascular disease in women; 2) determine the impact of sex-specific, psychosocial, and socioeconomic risk factors on CVD in women; and, 3) improve CVD risk prediction/ risk stratification models for women. The Vanguard phase of the study will evaluate the feasibility of the full study being planned.

The full HER CROWN will be a prospective matched-cohort study to propose a novel, women-specific cardiovascular risk score/ algorithm in the prediction of hard cardiovascular outcomes (myocardial infarction, unstable angina, coronary revascularization, stroke, total and cardiovascular mortality). This future study will be the first longitudinal cohort study, to our knowledge, that is focused entirely on researching the pathophysiology and natural history of cardiovascular disease in women with known female-specific risk factors. Further, the investigators are aiming to recruit a sample that is representative of the ethnic distribution in Canada. The proposed pilot study is a feasibility study as an essential preparatory step for HER CROWN. The study will be cross-disciplinary, including investigators who specialize in the treatment of cardiovascular disease in women, epidemiology and administrative data, cardiovascular imaging, biomarker research, physical activity, nutrition, nicotine addiction, and mental health who will each inform outcomes and sub-studies.

A single-site, two-group, matched-cohort Vanguard study will be completed to test feasibility outcomes to inform a large, multi-site, two-group, longitudinal matched-cohort study.

Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study

Demographics and socioeconomic information

Past, present medical history, medication, and women's health related information

This is calculated by assigning scores of 0, 1, 2, and 3 to the response categories, respectively, of "not at all," "several days," "more than half the days," and "nearly every day." GAD-7 total score for the seven items ranges from 0 to 21.

0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety

Several days = 1 More than half the days = 2 Nearly every day = 3

1-4 Minimal depression 5-9 Mild depression 10-14 Moderate depression 15-19 Moderately severe depression 20-27 Severe depression

PSS scores are obtained by reversing responses (e.g., 0 = 4, 1 = 3, 2 = 2, 3 = 1 \& 4 = 0) to the four positively stated items (items 4, 5, 7, \& 8) and then summing across all scale items. A short 4 item scale can be made from questions 2, 4, 5 and 10 of the PSS 10 item scale.

Both the ISA-P and ISA-NP scores range from 0 to 100 where a low score indicates the relative absence of abuse and the higher scores represent the presence of a greater degree or amount of abuse.

Responses are measured on a 5-point Likert scale (1 = never true, 2 = rarely true, 3 = sometimes true, 4 = often true, 5 = very often true). Each subscale is represented by five questions with a score range from 5 to 25; scores fall into four categories: none to low trauma exposure, low to moderate trauma exposure, moderate to severe trauma exposure and severe to extreme trauma exposure for each scale.

Respondents are asked to rate how bothered they have been by each of 20 items in the past month on a 5- point Likert scale ranging from 0-4. Items are summed to provide a total severity score (range = 0-80). 0 = Not at all 1 = A little bit 2 = Moderately 3 = Quite a bit 4 = Extremely

SF-12v2 items are scored so that a higher score indicates a better health state. For example, functioning items are scored so that a high score indicates better functioning, and the pain item is scored so that a high score indicates freedom from pain. After data entry, items are scored in three steps:

1. item recoding for the four items that require recoding;
2. computing scale scores by summing across items in the same scale (raw scale scores); and,
3. transforming raw scale scores to a 0-100 scale (transformed scale scores).

Nicotine, alcohol, cannabis use measure questionnaire. No score.

Scoring a HIGH level of physical activity on the IPAQ means your physical activity levels equate to approximately one hour of activity per day or more at least a moderate intensity activity level. Scoring a MODERATE level of physical activity on the IPAQ means you are doing some activity more than likely equivalent to half an hour of at least moderate intensity physical activity on most days. Scoring a LOW level of physical activity on the IPAQ means that you are not meeting any of the criteria for either MODERATE of HIGH levels of physical activity.

Score by giving 1 point for each correct answer (maximum 6 points). Score of 0-1 suggests high likelihood (50% or more) of limited literacy. Score of 2-3 indicates the possibility of limited literacy. Score of 4-6 almost always indicates adequate literacy.

Coronary artery calcium, plaque presence and plaque characteristics

Coronary perfusion and microvascular function

CBC, electrolytes, creatinine, fasting lipids, fasting glucose, HbA1c, hs-troponin, NT-proBNP, Lipoprotein (a), LH, FSH, estradiol, progesterone, additional sample for biobanking βhCG test for subsamples participating in PET and Coronary CTA

participant satisfaction and acceptability questionnaire. No score.

Ottawa Heart Institute Research Corporation

Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Anemia, Iron-Deficiency

Iron Deficiencies

Pre-Eclampsia

Proteinuria

Eclampsia

Fetal Growth Retardation

Sepsis

Metabolic Diseases

Iron Metabolism Disorders

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Hypertension, Pregnancy-Induced

Urination Disorders

Urologic Diseases

Male Urogenital Diseases

Urological Manifestations

Fetal Diseases

Growth Disorders

Vascular Diseases

Communicable Diseases

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

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

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

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

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).

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

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

Pre-eclampsia screening program

Jaana E Nevalainen, Assoc prof

Terhi Piltonen, Professor

Jaana E Nevalainen, Assoc Prof

Marja Ojaniemi, Assoc Prof

Liisa Laatio, PhD

Hilkka Nikkinen, PhD

Pekka Pinola, PhD

Tiina Kantomaa, MD

Jaana Nevalainen, Assoc prof

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

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.

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.

Participants recruited for PEPPI are pregnant women (females), their partners (males) and babies (female/male).

PEPPI Study: Identification of Women at Risk for Placental Dysfunction

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

Data will deposited into Oulu University Hospital's and Oulu University's data bank.

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

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.

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.

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.

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.

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.

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.

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

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

Measurement of perineum with centimeters (cm)

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.

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)

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)

NICU denotes neonatal intensive care unit.

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

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

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

HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.

Women with Hypertension before pregnancy week 20. HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.

Women with Hypertension after pregnancy week 20.

According to calculator provided by Fetal Medicine Foundation (https://fetalmedicine.org/research/utpi).

Massive postpartum hemorrhage defined≥ 1000ml blood loss within 24 hours after child birth.

If the water breaks before the 37th week of pregnancy, it is called preterm premature rupture of membranes (PPROM).

Defined as the placenta separates from the inner wall of the uterus before birth.

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).

Duration of the time spend at the hospital after delivery (measured as days and weeks)

Defined as first, second, third or fourth degree lacerations during birth.

Measured with ultrasound using fetal BPD, HC, AC and FL measurements (Hadlock)

Ultrasound measurements of maximum velocity pocket (cm) and amniotic fluid index (cm)

Estimated as a whole with inspection of body movements, limb movements and breathing movement

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study	NCT05632601	Cardiovascular ...	PET scan	25 Years - 55 Years	Ottawa Heart Institute Research Corporation
Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study	NCT05632601	Cardiovascular ...	PET scan	25 Years - 55 Years	Ottawa Heart Institute Research Corporation
PEPPI Study: Identification of Women at Risk for Placental Dysfunction	NCT06115122	Pre-Eclampsia Intrauterine Gr... Polycystic Ovar... Iron-deficiency Cardiovascular ... Hypertensive Di... Proteinuria in ...	Pre-eclampsia s...	-	Oulu University Hospital

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