PRIOR Study (Pre-eclampsia Risk In Oocyte Recipients) - Investigating Matching, Biomarkers and Outcomes.
Conditions: Pre-eclampsia, Oocyte Donation, Pre-Eclampsia; Complicating Pregnancy, Pre-Eclampsia; Mild, Pre-Eclampsia, Severe, Pre-eclampsia or Eclampsia With Pre-existing Hypertension, ART, Neonatal Morbidity, Neonatal Mortality, Placental Abruption, Gestational Diabetes, Preterm Labor, Post-partum Hemorrhage (PPH), Intrauterine Growth Restriction (IUGR), Hypertensive Disorders of Pregnancy
Sponsor: Copenhagen University Hospital, Hvidovre

 
 
 
Registration at clinicaltrials.gov 
 
PROJECT 
PRIOR: Pre-eclampsia Risk In Oocyte Recipients -  
Investigating matching, biomarkers and outcome 
 
NCT-number 
Not yet applied 
 
Document 
Study protocol 
 
Document date 
07.02.25 
 
Primary supervisor: 
Pernille Fog Svendsen, DMSc, associate professor, Fertility 
Clinic, Dept. of Obstetrics and Gynaecology, Herlev University 
Hospital, University of Copenhagen 
 
Principal investigator: 
Mette Schou Hedegaard, MD, Pd.D. student, Fertility Clinic, Dept 
of Obstetrics and Gynaecology, Herlev University Hospital, Uni-
versity of Copenhagen 
 

 
 
  
VEK-id: H-22068878 
 
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PRIOR: Pre-eclampsia Risk In Oocyte Recipients -  
Investigating matching, biomarkers and outcome 
 
 

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It is hereby declared that the study will be performed according to the latest approved 
study protocol, the “Helsinki Declaration” and local regulatory requirements and 
legislation. 
Sponsors and investigators signatures 
Primary supervisor: 
Pernille Fog Svendsen, DMSc, associate professor, Fertility Clinic, Dept. of 
Obstetrics and Gynaecology, Herlev University Hospital, University of Copenhagen 
 
______________________________________________Date:_______________ 
 
Secondary supervisor: 
Thomas Bergholt, Professor, Dept. of Obstetrics and Gynaecology, Herlev University 
Hospital, University of Copenhagen 
 
______________________________________________Date:_______________ 
 
Associate supervisor: 
Hellen Edwards, MD, Ph.D Dept. of Obstetrics and Gynaecology, Herlev University 
Hospital, University of Copenhagen 
 
______________________________________________Date:_______________ 
 
Associate supervisor: 
Maria Birkvad Rasmussen, MD, Ph.D., Associate Professor, Fertility Clinic, Dept. of 
Obstetrics and Gynaecology, Herlev University Hospital, University of Copenhagen 
 
______________________________________________Date:_______________ 
 
Principal investigator: 
Mette Schou Hedegaard, MD, Pd.D. student, Fertility Clinic, Dept of Obstetrics and 
Gynaecology, Herlev University Hospital, University of Copenhagen 
 
______________________________________________Date:_______________ 

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Primary supervisor 
MD, consultant, DMSc, associate professor 
Pernille Fog Svendsen 
Dept. of Obstetrics and Gynaecology  
Fertility Clinic  
Herlev University Hospital 
Borgmester Ib Juuls Vej 1 
DK-2730 Herlev, Denmark 
 
Secondary supervisor 
MD, Obstetrician, Professor 
Thomas Bergholt 
Dept. of Obstetrics and Gynaecology  
Herlev University Hospital 
Borgmester Ib Juuls Vej 1 
DK-2730 Herlev, Denmark 
 
Study site 
Dept. of Obstetrics and Gynaecology  
Fertility Clinic,  
Herlev University Hospital 
Borgmester Ib Juuls Vej 1 
DK-2730 Herlev, Denmark 
 
E-mail 
HGH-FP-Projekt-PRIOR@regionh.dk 
 
 
 
 
 
 

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Table of content 
BACKGROUND .................................................................................................................................... 6 
OBJECTIVES ......................................................................................................................................... 8 
PRIMARY OBJECTIVES ............................................................................................................................ 9 
SECONDARY OBJECTIVES ........................................................................................................................ 9 
STUDY DESIGN ................................................................................................................................... 9 
PATIENT POPULATION ........................................................................................................................... 9 
RECRUITMENT ........................................................................................................................................ 9 
INCLUSION CRITERIA FOR THE OOCYTE RECIPIENTS ..........................................................................10 
EXCLUSION CRITERIA FOR OOCYTE RECIPIENTS ................................................................................11 
METHODS .............................................................................................................................................11 
BLOOD TESTS .......................................................................................................................................12 
STUDY VISITS ........................................................................................................................................13 
SCHEME OF STUDY VISITS ....................................................................................................................21 
DEFINITION OF PRE-ELAMPSIA ...........................................................................................................23 
DATA MANAGEMENT .....................................................................................................................23 
DATA COLLECTION AND PROCESSING .................................................................................................23 
BIO BANK ..............................................................................................................................................24 
COLLABORATIONS ................................................................................................................................25 
DATA ANALYSIS ....................................................................................................................................26 
POWER ANALYSIS .................................................................................................................................26 
QUALITY CONTROL AND ASSURANCE ..................................................................................................26 
ETHICAL CONSIDERATIONS ........................................................................................................27 
PATIENT DISCOMFORT AND RISKS ......................................................................................................27 
INFORMED CONSENT ............................................................................................................................28 
INSURANCE ...........................................................................................................................................30 
FINANCIAL REMUNERATION ................................................................................................................30 
BUDGET ................................................................................................................................................30 
PUBLICATION PLAN ..............................................................................................................................30 
TIMETABLE ...........................................................................................................................................31 
 
 
 
 
 
 
 
 
 
 

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Abbreviations 
AFC = atrial follicle count 
AMH = anti müllerian hormone 
ART = assisted reproductive therapy 
BMI = body mass index 
BP = blood pressure 
FSH = follicle-stimulating hormone 
FET = frozen embryo transfer 
HCG = human chorionic gonadotropin 
Hgb = hemoglobin 
HR = heart rate 
 
ICSI = intracytoplasmic sperm injection 
IVF = in vitro fertilization  
ICSI = intracytoplasmic sperm injection 
LH = luteinizing hormone  
OD = oocyte donation 
DGD = double gamete donation 
Red Cap = research electronic data capture 
SD = standard deviation 
TSH = thyroid stimulation hormone  
UA = umbillical artery 
 
 
 

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Background 
Maternal age at conception has been continuously rising worldwide and the 
proportion of pregnant women over 35 years of age has increased up to eight times.1 
In 2021, the average maternal age at first birth in Danish women was 30 years 
compared to 24 years in 1970.2 
  
As fecundity decreases with maternal age and rapidly after the age of 35 years, 
there is an increased need for assisted reproductive technology (ART). The success 
rate of ART with autologous oocytes decreases after the age of 40 years, and oocyte 
donation becomes a more relevant option for achieving pregnancy for these women.  
 
The first oocyte donation was performed in 1984 to overcome infertility 
caused by premature ovarian failure (POI).3 The indications for OD are however 
heterogenous and include Turner syndrome, prior surgical removal of ovaries, prior 
chemotherapy, or radiation therapy affecting reproductive ability are other diagnoses 
where oocyte donation might be indicated. Other causes of oocyte donation can be 
serious genetic disease in women where preimplantation diagnostic is not an option. 
With oocyte donation, these different groups of women, who were previously 
untreatable, now have a chance to become pregnant. 
 
With increasing age and concomitant decreasing oocyte reserve and oocyte 
quality in women with inability to conceive spontaneously or after ART, the 
technique is nowadays used more widespread. We can now overcome natural peri- 
and postmenopausal infertility, thus theoretically prevail biology, making motherhood 
possible for women in their forties, fifties and even sixties. The success of oocyte 
donation relies more on the donor than the recipients age, however recent studies 
suggest that paternal age might also have an influence.4,5 In Denmark, the age limit 
for the recipient is 46 years, but some women who have crossed this age limit go 
abroad to countries like Spain, Greece, Latvia, Ukraine, Poland, Cypress or Russia to 
have treatment for infertility. In total opposition to this, oocyte donation is prohibited 
in some countries such as Italy, Turkey, Germany, and Luxemburg.  
In Denmark, oocyte donation has been legal since 2007 and double gamete 
donation has been legal since 2018. All healthy and fit women under the age of 36 can 

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donate their eggs either anonymously or non-anonymously, and the ideal age for 
donors is thought to be 23 to 30 years of age.5,6  
 
The request for oocyte donors is steadily increasing. In 2011, 124 oocyte 
donations were performed nationally. In 2022, the number had increased more than 
20-fold to 2782 oocyte donations of which approximately half of the donated eggs 
were given to Danish recipients. With a success rate of around 35%, this led to 756 
deliveries after oocyte donation in Denmark in 2021.7-8 
This increment in numbers of oocyte donations may partly be explained by 
growing request due to increasing age and decreasing fertility in women seeking 
ART, partly by an increase in the compensation for oocyte donation. Because double 
donation is now legal, ageing single women or same sex couples have a new option to 
obtain pregnancy. There is reason to believe that oocyte donation will only increase 
further over the next years, because we still see an increasing trend for maternal age.2  
Few years after the first oocyte donation was performed, studies revealed that 
OD was associated with different obstetrical complications9, and this has been 
documented over the past decades.10–13  
Oocyte recipients have an increased risk of pre-eclampsia (PE), intrauterine 
growth restriction (IUGR), preterm birth, caesarean section, placental abruption, and 
postpartum hemorrhage.10,14 In women who have received double gamete donation 
the risk of obstetrical adverse outcome may be further increased.13 The explanation of 
this increase in obstetrical risk is unknown. Speculations are, that with the use of a 
sperm donor, the recipient’s immune system is exposed to unknown paternal antigens 
which may activate immunological reactions that predispose to PE.  
The increased risk of PE in oocyte pregnancies might be explained by an 
amplification of the pathophysiological changes seen in the development of 
preeclampsia in some spontaneously conceived pregnancies. Women undergoing 
fertility treatment with their own frozen gametes are also at increased risk of pre-
eclampsia but not to the same extent as oocyte recipients. 
 
Preeclampsia is a pregnancy-specific disease that complicates 3–8% of pregnancies.15  
It has been known for centuries and was previously referred to as toxaemia of the 
pregnancy. It is defined as hypertension (systolic blood pressure ≥ 140 mm Hg or 

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diastolic blood pressure ≥ 90 mm Hg) plus proteinuria (300 mg or more over 24 
hours) and/or signs of organ dysfunction after the 20th week of gestation.16  
Though the definition of PE is clear, a wide range of clinical manifestations makes PE 
more syndrome-like than a defined disease, which complicates the clinical diagnosis. 
These manifestations include headache, visual disturbances, chest pain, palpitations, 
upper abdominal pain, oedema, hyperreflexia, and thrombocytopenia. 
Risk factors for PE are previous pre-eclampsia, chronic renal disease, chronic 
hypertension, pre-existing diabetes mellitus, autoimmune disease, multifetal   
gestation, nulliparity, advanced age, high body mass index (albeit at differing cut-
offs), inter-pregnancy interval of > 10 years and family history of preeclampsia.17  
 
Pre-eclampsia is thought to be a spectrum of pregnancy complications that share a 
common pathophysiology centred upon disordered placentation. This spectrum of 
disorders of placentation also includes late spontaneous miscarriage, placental 
abruption, foetal growth restriction, pre-term rupture of the membranes and premature 
delivery.18 
 
The exact etiology of pre-eclampsia remains unclear. However, several potential 
mechanisms related to the placentation including genes, immune response, insulin 
resistance, and maternal vascular disease are suggested to contribute to the 
development of the disease.19 A recent Dutch study finds that the number of HLA 
mismatches between fetus and recipient is related to the risk of pre-eclampsia, and 
especially HLA-DR incompatibility has shown to be related to development of pre-
eclampsia .20,21  
 
We hypothesize that by studying oocyte recipients, whom we know are at increased 
risk of pre-eclampsia, we can get an insight to the mechanisms behind pre-eclampsia. 
The aim of the present study is thus to investigate pathophysiological mechanisms 
involved in development of pre-eclampsia and concomitant obstetrical adverse 
outcomes after oocyte and double gamete donation. 

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Objectives 
Primary objectives 
• Investigate the risk of pre-eclampsia in pregnancies obtained after single or 
double gamete donation compared with pregnancies achieved with autologous 
gametes. 
• Investigate immunological, angiogenic biomarkers and HLA tissue type 
markers involved in the development of pre-eclampsia.  
 
Secondary objectives 
• Evaluation of obstetrical and neonatal complications such as pre-eclampsia, 
gestational diabetes, preterm birth, placental abruption, intrauterine growth 
retardation, asphyxia, neonatal morbidity, and mortality in women pregnant 
after oocyte or double donation in Denmark. 
• To establish a database and biobank to enable future studies including follow-
up of the children born after oocyte donation. 
Study design 
Patient population 
Woman undergoing oocyte donation or double gamete donation (OD) and a matched 
(BMI and age) control group undergoing treatment with frozen thawed blastocysts 
after IVF treatment (IVF). Both groups can be included before conception (Pre-Preg 
Cohort) and after conception (Preg Cohort) 
 
Recruitment 
A sub cohort named Pre-Preg cohort will be included preconceptionally, when 
referred for oocyte or double donation at Herlev University Hospital. This is one of 
two public hospitals in the Central Region of Denmark, where oocyte donation is 
performed. 
 

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The rest of the participants named Preg cohort are followed from early pregnancy and 
can be recruited from two paths: 
1) Most women will be recruited when they become pregnant and are seen for an 
early pregnancy scan around gestational week 7-8. The staff at the fertility 
clinic will shortly introduce the study verbally, and if the woman accepts, her 
information (name, cpr number, contact information) is given to the PI. She 
will then be contacted by the study group with more detailed information 
about the study. This is preferably done in person during a visit at the clinic 
(women at Herlev Hospital), where a printed copy of the patient information 
in handed out. For patients from other clinics (Rigshospitalet, Sellmer 
Fertility, Aleris Hamlet, and Trianglen), the patient information is given by 
telephone and written patient information is sent to the woman’s secure e-mail 
(e-boks).  
2) Others from the Preg cohort will be recruited when they are referred from the 
general practitioner to the obstetrical department in early pregnancy around 
gestational week 10. The visitation office will inform the PI about a possible 
study participant (name, cpr number, contact information). Written 
information about the study will be sent to her secure e-mail (e-boks) 
including information that she will receive a phone call within the following 
days. Here the woman will be informed about the study in more detail.  
If the woman is still interested in participation after receiving oral and written 
information, an inclusion visit is scheduled. The woman is informed, that she can 
bring an assessor.  At the inclusion visit, the patient information is repeated in 
person, possible questions are answered, and the patient is offered at least 24 
hours to consider if she wants to sign the consents. 
 
Inclusion criteria for the oocyte recipients 
• Referred to (Pre-Preg cohort) or pregnant after (Preg cohort) oocyte or double 
gamete donation 
• Age > 18 years  
• BMI < 35 kg/m2 
• Normal wet smear within the past three years 

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• Both nulli- and multiparous 
• Singletons and multiple gestations 
 
Exclusion criteria for oocyte recipients  
These criteria correspond to the general criteria for treatment with oocyte donation in 
the fertility clinics: 
• Age < 18 years 
• BMI > 35 kg/m2 
• HIV/ hepatitis 
• Essential hypertension 
• Chronic kidney disease 
• Undiagnosed vaginal bleeding 
• Uterine malformations 
• Persisting ovarian cysts 
• Tumors in hypothalamus, pituitary, thyroid, or adrenal glands. 
• Previous breast cancer 
• Known BRCA 1 or 2 gene 
• Unregulated thyroid disease 
• Cardiovascular disease 
• Breast feeding 
• Present or previous chemotherapy/radiation therapy 
• Present or previous malignant disease 
• Smoking 
• Alcohol/drug abuse 
 
Methods 
Routine measures for study subjects (background): 
• General physical examination: Height, weight, blood pressure, heart rate (at 
visit 1 for Pre-Preg cohort participants or visit 4 for Preg cohort participants). 
• Questionnaire (Age, ethnicity, previous medical history, fertility history, 
alcohol, smoking ect.) 

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• Transvaginal ultrasound at inclusion (At visit 1 for Pre-Preg cohort 
participants to examine the endometrium. At visit 4 for the Preg cohort, to 
confirm a viable pregnancy) 
• Check that routine blood-tests are already taken: p-thyroid stimulation 
hormone (p-TSH),  p-thyroid peroxidase antibody (p-TPO), p-anti-Mullerian 
hormone (p-AMH), Rubella, Syphilis, Hepatitis, and HIV.  
 
Blood tests 
In the section below, the following group of blood tests will be referred to as pre-
eclampsia markers: 
• Growth markers involved in early pregnancy (PAPP-A, IGF, PlGF, PGF and 
VEGFR) 
• Pro- and anti-inflammatory cytokines (Interleukins, TNF-α and interferon-γ) 
• Metabolic markers (Adiponectin, Leptin and Resistin) 
• Complement and thrombocyte activation markers (Selectin and BF-4) 
• Markers for coagulation and fibrinolysis (Thrombin/antithrombin complexes 
and ex vivo fibrinogenesis/fibrinolysis)  
• miRNA markers (Broad array including previously described PE-associated 
mi-RNAs in the Danish population. That is miR-181b-5p, miR-323a-3p, miR-
518b, miR-363-3p, miR-20a-5p, miR-291-3p and miR-142-3p) 
 
An estimated 37 ml of blood will be collected in total from study participants per visit. 
To specify, this includes two 9 mL EDTA tube (purple color), two 6 mL serum tube 
(red color), and two 3,5 mL sodium citrate glass (blue color). Blood will be separated 
and stored according to specific requirements for each analyte, as per procedures 
available at Statens Serum Institut and Depts. of Clinical Biochemistry at Herlev 
Hospital, Glostrup/Rigshospitalet and Aarhus University Hospital 
In addition, HLA type Pre-Preg cohort participants will be tested with one extra 
blood test (6 mL EDTA tube) taken post-partum. 
A total of 376 mL of blood will be drawn from the Pre-Preg cohort participants 
whereas 222 mL of blood will be drawn from the Preg cohort participants. 
 

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Urine dip stix is performed at some visits to check for proteinuria as a sign of 
pre-eclampsia. 
The intention is to gather placentas from the 50 Pre-Preg participants to send 
for pathology. Pathologists will look for pathoanatomical signs of pre-eclampsia such 
as infarcts, increased syncytial knots, hypovascularity of the villi, cytotrophoblastic 
proliferation, thickening of the trophoblastic membrane, obliterative enlarged 
endothelial cells in the fetal capillaries, and atherosis of the spiral arteries. 
 
Study visits 
According to the national guideline, all oocyte recipients in Denmark are 
recommended to take 150 mg of acetylsalicylic acid from approximately week 10-12 
in order reduce the risk of pre-eclampsia.22  
Later in pregnancy, the control-program for women pregnant after oocyte 
donation differs among the hospitals in the Capital Region of Denmark. In three out 
of four hospitals, women pregnant after oocyte donation are not per se offered extra 
ante-natal care compared to women who have become spontaneously pregnant. 
Unless any problem evolves during pregnancy, they are only seen for routine visits 
with nucleal translucency scan (GA 12), malformation scan (GA 18-20) and routine 
midwife consultations. This is at Rigshospitalet, Hvidovre Hospital, and Hillerød 
Hospital.  
At Herlev Hospital, women pregnant after oocyte donation are routinely 
offered a control program. Initially they also have nucheal translucency scan (GA 12) 
and malformation scan (GA 18-20). Later they are monitored with blood pressure 
measurements sent to the hospital using telemedicine every second week from GA 24 
and physical visits at the hospital with ultrasound and doctors’ appointments (GA 28, 
GA 34, and GA 38). In Denmark we recommend induction of labor at week 40+0 for 
oocyte recipients.  
To standardize, we gained permission to offer all pregnant oocyte recipients, 
to be transferred to Herlev Hospital, in case of pregnancy. If transferred to Herlev 
Hospital, they would be followed according to the above-mentioned routine control 
program. This model was accepted by the visitation office for deliveries in the Capital 
Region of Denmark (“Central Visitation for Fødsler”). 
In case the woman declines transfer to Herlev Hospital during her pregnancy, 

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she can still be included in the study. However, she would then have to visit Herlev 
Hospital three times during her pregnancy to have an introduction to telemedicine 
(GA 28) and two times for ultrasound examinations (GA 34 + 38). During these 
visits, blood to test for pre-eclampsia markers will be drawn. 
In the Pre-Preg cohort, the placenta is sent for pathology examination and a 
post-partum study visit with their newborn will be arranged. 
 
For controls who are pregnant after IVF-treatment, study participation will be 
similar. Of course, they are still seen pre-pregnancy when they undergo fertility 
treatment either at Herlev Hospital (Pre-Preg and Preg cohorts) or if they have fertility 
treatment elsewhere (Preg cohort). Some will be included before the fertility 
treatment starts (Pre-Preg cohort, study visit 1-3) and others in their early pregnancy 
(Preg cohort, study visit 4). Women pregnant after IVF will have the routine nuchal 
translucency scan in week 12 and malformation scan in week 18-20. In relation to 
these already scheduled visits, study participants will also have blood drawn for this 
study (named study visit 5 and 6). Unless something in their pregnancy rises concern, 
they would not have extra ultrasound examinations or doctor’s appointments. Thus 
visit 1 to 3 (see below) which are in relation to fertility treatment, are already routine 
for IVF-pregnancies. However, the pre-eclampsia marker blood tests taken in relation 
to routine visits, the inclusion visit in early pregnancy and visit 7-8 are extra for 
women pregnant after IVF. Additionally, they will report urine dip stix and blood 
pressure measured at home every second week from gestational age 28 until delivery. 
Instructions on the use of telemedicine will be given at a visit in week 28 by study 
personal. These IVF women will be recommended induction of labor at gestational 
age 41+5, which is standard treatment for all pregnant women in Denmark. 
 
 
 
 
 
 
 
 

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Contacts with oocyte recipients 
For Pre-Preg cohort participants, a woman who calls the fertility clinic to start 
fertility treatment will have a brief introduction to the study by the doctor/nurse in 
charge of their treatment.  After acceptance, her information (CPR number, name, 
type of treatment, contact information) is given to the PI. She will then be contacted 
by telephone with more detailed information about the study and written information 
in her secure e-mail (e-boks). The woman in this Pre-Preg cohort needs to be 
thoroughly informed about the study before her visit to the clinic, as inclusion and the 
first blood tests have to be on the day she visits the clinic, as the first blood tests must 
be drawn before she starts her fertility medication later the same day. 
 
The Preg cohort participant is also briefly introduced to the study by the doctor in 
charge of their treatment during one of the physical visits in the one of the fertility 
clinics. After acceptance, her information (name, CPR number, contact information) 
is given to the PI. For a woman who becomes pregnant at Herlev Hospital, detailed 
information about the study is given in person during a physical visit in the clinic and 
a printed copy of the patient information is handed out. For a woman who becomes 
pregnant at the other clinics (Rigshospitalet, Sellmer Fertility, Aleris Fertility, and 
Trianglen) this information is given by telephone and written patient information is 
sent to her secure e-mail (e-boks).  
 
If the patient is still interested after oral and written information is given as described 
above, an inclusion visit is arranged.  
 
During the inclusion visit, the patient information will be repeated as needed. The 
woman is offered at least 24 hours to consider participation. After signed consent, the 
woman can be included as described below. Information about the age of the donor 
will be retracted from patient files in “Formatex” 
 
Pre-conception – inclusion of Pre-Preg cohort participants (Study visit 1) 
• Informed consent obtained by primary investigator, or trained study nurse. 
Study subjects are given the opportunity for another consideration period 
if needed before signing the consents. 

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• Assessment of study in- and exclusion criteria. 
• Questionnarie  
• Demography (age, ethnicity, family status), medical history (history of 
concomitant disease, hereditary diseases, and fertility history). 
• Concomitant medication. 
• Smoking and alcohol habits. 
• Physical examination 
• Height and weight. 
• Ultrasound of the ovaries. 
• Blood pressure and heart rate sitting position. 
• Check for routine measures in the patient file 
• Smear, TSH, TPO, AMH, HIV, hepatitis, syphilis, and rubella (These are 
standard tests for all fertility patients) 
• Blood test for the study 
• Blood samples for measuring pre-eclampsia markers. 
 
Ovulatory women will be instructed to sign up for treatment on the second to third 
day of their menstrual cycle. Anovulatory women with an endometrial thickness > 4 
mm measured by transvaginal ultrasound will be given Gestagen tablets 10 mg daily 
for 10 days. They are instructed to sign up for treatment on the second day of the 
withdrawal bleeding. 
 
During the beginning of stimulation, women will have a transvaginal ultrasound with 
measurement of endometrial thickness (< 4 mm) and evaluation of ovarian 
morphology. They will be instructed to administer estradiol with 6 tablets a day.  
 
At stimulation day 10, women will have repeated transvaginal ultrasound with 
measurement of endometrial thickness (> 7 mm) and evaluation of ovarian 
morphology. Embryo transfer will be planned and instructions on progesterone 
administration with 1200 mg daily (400 mg vaginally + 400 mg vaginally + 400 mg 
rectally) 4 days before embryo transfer. 
 
Transfer of blastocyst - only PrePreg cohort (Study visit 2) 

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• Transfer of a frozen thawed blastocyst.  
• Blood samples for measuring pre-eclampsia markers. 
 
Women will have an HCG blood test approximately 10 days after the transfer to test 
for pregnancy. If the test is positive, an early pregnancy ultrasound is planned at the 
fertility clinic. 
 
 
Gestational week (GW) 7-8, test for pregnancy - only Pre-Preg cohort (Study visit 3) 
• Early pregnancy ultrasound to confirm a viable pregnancy. 
• Blood samples for measuring pre-eclampsia markers. 
 
Part of the Preg cohort will be included directly from the fertility clinics (Herlev 
Hospital, Rigshospitalet, Sellmer Fertility, Trianglen, Aleris Fertility). Recruitment 
will happen when the woman becomes pregnant and is at the fertility clinic for an 
early pregnancy scan in approximately gestational week 7 to confirm a viable 
pregnancy. The doctor/nurse at the clinic will briefly inform the patient about the 
study and ask for acceptance for the study group to contact the patient. If the patient 
wants to participate after both oral (preferably in person or else by telephone) and 
written information (preferably handed out or else in e-boks), the above-mentioned 
inclusion visit will be arranged. The woman is informed, that she can bring an 
assessor. At the inclusion visit, the patient information will be repeated. 
 
Lastly, we will include women in the Preg cohort who have become pregnant after 
oocyte donation performed in other Danish fertility clinics or outside Denmark. These 
women will be identified for possible inclusion, when referred from the general 
practitioner to Dept. of Obstetrics and Gynecology in early pregnancy around 
gestational week 6-10. The possible participant will receive a secure e-mail (e-boks) 
with written information about the study and information that she will receive a phone 
call within the following days. The mail also tells her how to write or call in case she 
does not want any further information.  The possible participant is given a few days to 
read the material, after which she will receive a phone call with oral information 
about the study. If she is still interested, an inclusion visit is arranged. Here the patient 
information will be repeated, and she is offered time (at least 24 hours) to consider 

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participation.  
 
GW10 – inclusion – Preg cohort only (Study visit 4) 
• Informed consent obtained by primary investigator, or trained study nurse.  
• Assessment of study in- and exclusion criteria. 
• Questionnarie  
• Demography (age, ethnicity, family status), medical history (history of 
concomitant disease, hereditary diseases, and fertility history). 
• Concomitant medication. 
• Smoking and alcohol habits. 
• Physical examination 
• Height and weight. 
• Ultrasound of the ovaries. 
• Blood pressure and heart rate sitting position. 
• Check for routine measures in the patient file 
• Smear, TSH, TPO, AMH, HIV, hepatitis, syphilis, and rubella (These are 
standard tests for all fertility patients) 
• Blood test for the study 
• Blood samples for measuring pre-eclampsia markers. 
 
GeW12, Nucheal translucency scan – Pre-Preg+Preg cohorts (Study visit 5) 
• Nuchal translucency scan  
• Blood samples for measuring pre-eclampsia markers 
 
GW18-20, Malformation scan  – Pre-Preg+Preg cohorts (Study visit 6) 
• Malformation scan  
• Blood samples for measuring pre-eclampsia markers. 
 
GW24 - Pre-Preg + Preg cohorts  
• OD (Herlev): Introduction to telemedicine. 
 
GW26 – Pre-Preg + Preg cohorts 

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• OD (Herlev): Telemedicine. 
  
GW28 – Pre-Preg + Preg cohorts (Study visit 7) 
• OD (Herlev): Telemedicine, ultrasound, obstetrical check-up and pre-
eclampsia markers. 
• IVF + OD (other hospitals): Introduction to telemedicine and pre-
eclampsia markers. 
 
GW30 – Pre-Preg + Preg cohorts 
• All participants: Telemedicine. 
 
GW32 – Pre-Preg + Preg cohorts 
• All participants: Telemedicine 
 
GW34 – Pre-Preg + Preg cohorts (Study visit 8) 
• All participants: Telemedicine, ultrasound, obstetrical check-up and pre-
eclampsia markers. 
 
GW36 – Pre-Preg + Preg cohorts 
• All participants: Telemedicine 
 
GW38 – Pre-Preg + Preg cohorts (Study visit 9) 
• All participants: Telemedicine, ultrasound, obstetrical check-up, and pre-
eclampsia markers. 
 
GW40 – Pre-Preg + Preg cohorts 
• OD (Herlev): Telemedicine and induction of labor, if not delivered yet. 
• IVF + OD (other hospitals): Telemedicine. 
 
Delivery – Pre-Preg cohort only (Study visit 10) 
• Delivery blood samples with pre-eclampsia markers and including 
umbilical cord samples. 
• Placenta pathological examination. 

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Gestational week 41+3-5 
• OD (Herlev) + OD (other hospitals): Hopefully already delivered. 
• IVF: Induction of labor, if not delivered yet. 
 
Four weeks post-partum – Pre-Preg cohort only (Study visit 11) 
• Blood test to identify HLA tissue type 
• Buccal swap on new-borns to identify HLA tissue type 
Blood samples for measuring pre-eclampsia markers. 
 
Scheme of study visits 
  
  
Pre-
Preg  
cohort 
Preg  
cohort 
Pre-conception - inclusion Pre-Preg cohorte (Study visit 1) 
  
  
  
Information about the study and signed consent from Pre-Preg cohort 
X 
  
  
Questionaire about previous medical history 
X 
  
  
Physical examination with height, weight, and blood pressure 
X 
  
  
Check routine blood tests (TSH, TPO, AMH) 
X 
  
  
Check routine blood tests (Syphilis, Rubella, HIV, and Hepatitis) 
X 
  
  
Transvaginal ultrasound 
X 
  
  
Blood tests (PE-markers) 
X 
  
Transfer of blastocyst (Study Visit 2) 
  
  
  
Ultrasound examination (Transfer of blastocyst) 
X 
  
  
Blood tests (PE-markers) 
X 
  
Early pregnancy GW 7-8 (Study Visit 3) 
  
  
  
Ultrasound examination (Viable pregnancy?) 
X 
  
 
Blood tests (PE-markers) 
X 
  
Inclusion of Preg cohorte (GW 8-11) (Study Visit 4) 
  
  
  
Information about the study and signed consent from Pre-Preg cohort 
  
X 
  
Questionaire about previous medical history 
  
X 
  
Physical examination with height, weight and blood pressure 
  
X 
  
Check routine blood tests (TSH, TPO, AMH) 
  
X 
  
Check routine blood tests (Syphilis, Rubella, HIV, and Hepatitis) 
  
X 
  
Transvaginal ultrasound to check for a viable pregnancy 
  
X 
  
Blood tests (PE-markers) 
  
X 
Nucheal Translucency Scan (GW12) (Study visit 5) 
  
  
  
Ultrasound examination (Nuchal translucency scan) 
X 
X 
  
Blood tests (PE-markers) 
X 
X 

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Malformation scan (GW 18-20) (Study Visit 6) 
  
  
  
Ultrasound examination (Malformation scan) 
X 
X 
  
Blood tests (PE-markers) 
X 
X 
GW 24 
  
  
  
Introduction to telemedicine (Only OD) (Blood pressure, urine dip stix)  
X 
X 
GW 26 
  
  
  
Telemedicine (Only OD) (Blood pressure, urine dip stix)  
X 
X 
GW 28 (Study visit 7) 
  
  
  
Fetal growth scan (Only OD) 
X 
X 
  
Obstetrical check-up (Only OD) 
X 
X 
  
Introduction to telemedicine (Only IVF) (Blood pressure, urine dip stix)  
X 
X 
  
Blood tests (PE-markers) 
X 
X 
GW 30 
  
  
  
Telemedicine (Blood pressure, urine dip stix) 
X 
X 
GW 32 
  
  
  
Telemedicine (Blood pressure, urine dip stix) 
X 
X 
GW 34 (Study Visit 8) 
  
  
  
Fetal growth scan 
X 
X 
  
Obstetrical check-up 
X 
X 
  
Telemedicine (Blood pressure, urine dip stix)  
X 
X 
  
Blood tests (PE-markers) 
X 
X 
GW 36 
  
  
  
Telemedicine (Blood pressure, urine dip stix) 
X 
X 
GW 38 (Study Visit 9) 
  
  
  
Fetal growth scan 
X 
X 
  
Obstetrical check-up 
X 
X 
  
Telemedicine (Blood pressure, urine dip stix)  
X 
X 
  
Blood tests (PE-markers) 
X 
X 
GW 40 
  
  
  
Telemedicine (Blood pressure, urine dip stix)  
X 
X 
  
Induction of labor at 40+0 (Only OD) 
X 
X 
Delivery (Study visit 10) 
  
  
  
Placental tests 
X 
  
  
Umbillical cord samles 
X 
  
4 weeks post-partum (Study visit 11) 
  
  
  
HLA-type on newborn (buccal swap) 
X 
  
  
Blood tests (PE-markers + HLA type on mother) 
X 
  
 
 
 
 
 

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Definition of pre-elampsia 
In this study, pre-eclampsia is defined as: 
- 
Hypertension after GA 20 weeks with SBT >= 140 and/or DBT >=90. 
 
and either one or both of 
 
- 
Proteinuria >= 0,3 g / 24 hours 
- 
Signs of organ dysfunction (thrombocytopenia, affection of kidney or liver 
function, lung oedema, neurological complications, utero-placental 
dysfunction) 
Data management 
Data collection and processing 
Source data will be recorded in the patient record or on specific worksheets. Data will 
be stored in Redcap. A Case Report Form (CRF) will be constructed for data capture. 
Data will be stored in coded form for 15 years according to recommendations from” 
Videnscenter for dataanmeldelser”, Rigshospitalet. Afterwards it will be transmitted to 
“Rigsarkivet.”  
Data on which women have undergone oocyte donation (cases) will be 
retrieved from the visitation papers from the general practitioner to hospital 
department in early pregnancy (Preg cohort), to identify possible study participants. 
This information about CPR number, contact details and mode of conception will be 
passed on to principal investigator before consent from the patient in accordance with 
the Danish Health Act paragraph 46. The possible study participant will receive a 
secure e-mail (e-boks) with written information about the study and that study 
personal will call her within a few days and how to call or write in case she does not 
want additional information. Otherwise, she will receive a phone call with 
information about the study. If still interested, she can either accept participation or 
have a consideration period after which she will be contacted again a few days later. 
If the interest persists, an initial visit will be arranged. Here, the woman will again 
receive detailed information about the study and sign consents. After signed consents, 
prior hospitalizations, chronic disease, and medication will be obtained from patient 

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files “Sundhedsplatformen” as well as the age of the patient’s oocyte donor from the 
patient’s journal in “Formatex”. Later in the study, information on gestational age at 
delivery, mode of delivery, birth weight, fetal malformations, obstetrical 
complications (preeclampsia, gestational diabetes, intrauterine growth retardation, 
post-partum haemorrhage) will be obtained from patient files “Sundhedsplatformen”.  
Signed consent allows for principal investigator, supervisors, and other study 
staff to access the information from the patient and children’s files. This consent is 
crucial to monitor, control and complete the study. 
 
Bio bank  
Initial blood tests with hormones and infection markers are always taken routinely as 
part of fertility treatment and analyzed immediately, as they are needed in relation to 
fertility treatment. Urine dip stix will be analyzed immediately and destroyed 
afterwards. The entire placenta will be sent for pathology just after delivery from Pre-
Preg cohorte to check for maternal hypofusion (e.g. placental weight, thickness of 
umibillical cord, decidual vasculopathy of the spiral arteries, infarcts, hypermature 
villi). A small proportion of the placenta (a cotyledon) will be stored in the biobank for 
possible future research. Our buccal swap tests and blood samples (pre-eclampsia 
markers) will be gathered and frozen consecutively over a long inclusion-period, as 
they need to be analyzed at several different places and over a longer time span.  
Most blood samples at a total of 28 mL will be stored in a research bio bank and 
analyzed for the present study and additional 9 mL will be drawn and stored in a 
biobank for possible future studies. In case there is excess blood out of the 28 mL drawn 
for the present study, they will also be stored in the same research biobank for possible 
future studies. Blood samples from the bio bank for future studies will be stored for 30 
years provided patient acceptance with signed consent now. Estimated date for 
termination of the biobank for future studies is first of June 2054.  Termination of the 
biobank for the present study is estimated to first of June 2029.  
The data protection rules are still complied with in accordance with The Data 
Protection regulation and the law of data protection. After 30 years, the material will 
be destroyed. This will open to the possibility of future studies including studies on the 
later outcomes of children born after oocyte donation. 
Additional or future analyses will only be performed after renewed approval from the 

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Ethics Committee and the material will not be transported out of the country. Later 
genetic data will be handled according to ethics and data regulation at the time of use 
of the samples.  
The patients can participate in the study without having biologic material stored 
in the bio bank. If a patient does not want blood to be stored for future research, this 
will be registered in RedCap and the consent for this will not be signed. Blood samples 
that are not stored for future research, will be destroyed immediately after analysis.  
 
Collaborations 
We collaborate with stakeholders that specialize in different fields that are all relevant 
to this subject. Thus, blood tests will be analyzed at four different locations: 
 
1) “Statens Serum Institut” (SSI), which is a government public health and research 
institution under the Danish Ministry of Health. We collaborate with Michael 
Christiansen, Professor (adj) and chief physician and Dr. Paula Hedley, as well as 
biochemists and genetics, “Department for Congenital Disorders”, SSI. They have 
previously been involved in research with pre-eclampsia markers and have a special 
interest in miRNA’s and to establish a biobank for possible future “-omics”-studies. 
2) Department of Clinical Biochemistry, Rigshospitalet/Glostrup. We collaborate with 
Line Rode, M.D., Ph.D., who dedicated her work-life to screening in early pregnancy, 
including screening for possible biomarkers. 
3) Department of Clinical Biochemistry, Aarhus University Hospital. This is in 
collaboration with Julie Brogaard Larsen, M.D., Ph.D. Her previous research area has 
been medical conditions with altered thrombosis or complement-activation, such as 
pre-eclampsia.  
4) Department of Clinical Immunology, Rigshospitalet. We collaborate with Anne 
Werner Hauge, M.D., Ph.D.. The department specializes in tissue type HLA and HLA 
antibodies, primarily used in transplantation, transfusions, and diagnostics.  
 
 
 

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Data analysis 
The per protocol population will consist of all patients who completed the study without 
any major protocol violations. 
 
Normally distributed variables will be presented as mean ±SD, non-parametric statistics 
and appropriate log-transformation will be performed if assumption of normality is not 
met. After log transformation the parameter will be further tested for normality 
distribution as indicated. A two-tailed p value of 0.05 or less is considered statistically 
significant. Comparisons between treatment groups will be performed by an unpaired 
two-sample t-test, Mann-Whitney test, or Chi-squared test as appropriate. Analysis for 
non-linear relations will be performed using ML methods, e.g. symbolic regression in 
the QLattice formulation.  
 
Additional analysis due to loss of follow-up: 
Data from the Intention to Treat Population will be analyzed to determine the validity 
of the conclusions of the Per Protocol population. Analysis will include duration in 
study and reason for discontinuation as co-variables. 
 
Power analysis 
A statistical power analysis was performed for sample size estimation, based on data 
from previous studies regarding oocyte donation and risk of preeclampsia. Previous 
studies showed odds ratios for pre-eclampsia among oocyte recipients ranging from 
2,11 to 3,99.10,23 We used the more conservative estimate with an aOR of 2,11.  
Using the clinically relevant effect size of 20% absolute increase in risk of PE among 
oocyte recipients with a two-sided significance level of 0.05 and with 
80% power, the projected sample size needed is N = 250 women. To allow for an 
estimated drop-out or major protocol deviations rate of 5 % we will need to include263 
patients in each arm of this study. Dropouts will be replaced by new patients. 
 
Quality control and assurance 
The study will be carried out in accordance with the Helsinki Declaration, after 
approval by the Regional Scientific Ethics Committee Agency and the “Videnscenter 

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for dataanmeldelse”, Rigshospitalet. It is Sponsors responsibility to ensure that data 
protection rules are complied with in accordance with The Data Protection regulation 
and the law of data protection. 
 
The study will be registered on www.clinicaltrials.gov  
Ethical considerations 
Patient discomfort and risks 
Participation in the study involves more visits in pregnancy than routinely. This 
specifically applies for IVF-controls and OD cases from other hospitals than Herlev, 
who would not by default routinely be examined by a doctor nor have extra ultrasound 
examinations in their pregnancy. This also applies for women, who agree to be 
transferred to Herlev Hospital from one of the other three hospitals. Some women will 
find these visits to be a safety, whereas other might think of it as a burden.  
Overall, we find that participation in this study poses the women at minimal risk 
compared to the information that this study might give us. Information about the 
pathophysiological mechanisms behind pre-eclampsia might not only benefit women 
pregnant after oocyte donation but possibly benefit all the 3-8% of women who develop 
pre-eclampsia during pregnancy. Using telemedicine, we will most probably at an 
earlier stage identify some IVF controls and OD cases from the other hospitals, who 
develop pre-eclampsia, because they will be screened for continuously from gestational 
week 28. 
Transvaginal and abdominal ultrasound are non-invasive procedures without 
any known side effect from the sound waves used. The procedure can be associated 
with minor discomfort in some women and there is a minimal risk of allergic reaction 
to the examination gel. 
Since this study is an evaluation of standard procedures for OD recipients 
belonging to Herlev Hospital, additional discomfort for these oocyte recipients is 
limited to extra blood sampling during pregnancy and buccal swap on newborn.  
An estimated 37 ml of blood will be collected in total from study participants 
per visit. This amount of blood drawn is not thought to affect the participants, though 
we are aware that blood will be drawn several times, but over a period of months. Blood 

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will be separated and stored according to specific requirements for each analyte, as per 
procedures available at both dept. of Clinical Biochemistry (Aarhus and 
Rigshospitalet/Glostrup) and dept. of Clinical Immunology, Rigshospitalet   
Blood sampling can have side effects such as hematoma, superficial 
thrombophlebitis, and infection, but the risk is generally considered low. 
 
To identify fetal HLA tissue type on Pre-Preg cohort participants’ newborn, a 
buccal swap will be performed 4 weeks post-partum. This is done by sweeping two 
cotton swaps on the mucous membranes on the inside of the newborn’s cheeks for 20 
seconds. This may be associated with a bit of discomfort for the newborn. The method 
is already used in newborn in the case of paternity tests. HLA type for oocyte recipient 
in Pre-Preg cohort will be tested with an extra blood test (6 mL EDTA tube) taken 
during the same visit four weeks post-partum. Considerations of inclusion of newborn 
have been made, as these are incompetent to consent to participation, so consent must 
be given from both parents in case of shared custody. However, the buccal swap must 
evidently be taken on their own offspring to look at the possible HLA mismatch, which 
can contribute to induction of pre-eclampsia. HLA tissue type does however not change 
over years, so in theory, it could be taken once the child gets older. However, this would 
delay the study and the results for years. We find it crucial to investigate this relation 
now, as the usage of oocyte donation is rapidly increasing these years and possible 
adverse side effects, or long-term effects of the treatment need to be examined.  
 
Informed consent 
Subjects recruited will attend an outpatient clinic at the study center. The investigator 
will ensure, that the subject is adequately informed about the study background and 
design, verbally and in writing. 
 
Pre-Preg cohort participants will initially be informed briefly about the study in relation 
to their treatment at the fertility clinics. They will also more thorough information by 
telephone and written information in their secure e-mail (e-boks). Patient information 
will be repeated during the inclusion visit. 
 
 

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For Preg cohort participants, oral information will be given either in person or by 
telephone. The written patient information will be handed out during a visit to the 
fertility clinic or sent by e-mail along with the brochure “Forsøgspersoners rettigheder 
I et biomedicinsk forskningsprojekt” and “Før du beslutter dig” (Your rights as a 
participant in biomedical research).  
 
For interested subjects (both Pre-Preg and Preg cohort), a subsequent inclusion will be 
scheduled. This is called visit 1 for Pre-Preg cohort participants and visit 4 for Preg 
cohort participants (even though it is their first visit). Verbal information will be given 
be repeated as needed by the principal investigator or a specially trained study nurse in 
a quiet environment. The subject will have the opportunity to ask questions and bring 
a companion to the interview. 
 
Before signing the consent form, the subject will be offered to reflect at least 24 hours. 
Should the patient need further time, a follow-up will be scheduled. In case of 
participation, the informed consent is signed prior to inclusion in the study. 
 
Parents cannot consent on behalf of the child before birth. Thus, consent for buccal 
swap on newborn must be signed at the study visit 4 weeks post-partum, where the 
buccal swap is performed on newborn (only Pre-Preg cohort participants). 
 
The subjects are informed that they may, at any time, withdraw their informed consent 
to participate in the study without it having consequences for subsequent care. 
No study-related examinations will be conducted until after the informed consent has 
been obtained. 
 
Termination of the entire study before time could happen in case legislation in the field 
of oocyte donation is changed.  
 
 
 
 

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Insurance 
Patients are covered under “Patienterstatningen” (The patient compensation 
association). 
 
Financial Remuneration 
 
The study subjects will receive no financial remuneration for participation in the study, 
as all the treatments investigated are standard treatments.  
 
Initiative to the study was taken by the sponsor Pernille Fog Svendsen. 
 
We received funding from the private sector with a research grant of 600.000 DKR 
from Ferring and a research grant of 200.000 DKR from Gedeon Richter. All 
members of the study group do not have any affiliations with neither Ferring nor 
Gedeon Richter. Financial support is paid out to the Department of Obstetrics and 
Gynaecology, Herlev Hospital, who will administer the funding.  
 
Neither principal investigators nor supervisors have any financial interest in the 
project.  
 
Budget 
See appendix 1. 
 
Publication plan 
Positive, negative, and inconclusive study results will be published in international peer 
reviewed scientific journals and made publicly available at www.clinicaltrials.gov.  
 
The Ph.D. student, Mette Schou Hedegaard, will be first author and Pernille F. 
Svendsen last author. 
 
 

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Timetable 
Procedure 
Timeframe 
Approval from the Ethics Committee 
and the Danish Data Protection Agency 
July 2024  
Preparation of study sites 
August 2024 
PhD enrollment 
January 2024 
Start inclusion (First patient’s first visit) October 2024  
Completion of study (Last patient’s last 
visit) 
September 2026  
Specialized analysis / Pre-eclampsia 
markers 
October 2026  
Data analysis 
October to December 2026   
Publications 
January to august 2027  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Ginsburg ES, George JS. Older but not wiser: the impact of increasing 
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