4 MATERIALS AND METHODS
6.4 Future aspects
Further studies in the prediction of pre-eclampsia are needed:
- The present screening methods do not detect late-onset pre-eclampsia accurately enough, which still causes most of the pre-eclampsia morbidity among women, at least in high-income countries. Biomarkers of maternal factors may play a key role in this respect, e.g., studies on proteomics and metabolomics of pre-eclampsia may shed light on the issue.
- Better ways to predict pre-eclampsia in nullipara women are needed, since current methods are poor in this subgroup of women.
- In summary: screening should be developed towards more individualised risk assessment. This may become easier along with the implementation of artificial intelligence.
Future study on aspirin
- To increase our understanding of mechanisms by which aspirin affects in preventing or alleviating pre-eclampsia, the effect of aspirin on serum or plasma concentrations of other (than PlGF) biochemical markers should be investigated.
Future studies in the Hb scavenger system and pre-eclampsia are needed:
- Studies on the normal values of A1M and Hpx during pregnancy are needed.
- There are no studies on the Hb scavenger system and pre-eclampsia conducted in prospective screening cohorts. In such a study, maternal cardiac function should be evaluated simultaneously with the concentration of haem, and markers of oxidative stress in maternal circulation should be included to further clarify whether the suggested mechanism presented in our study has clinical relevance.
- Future research may be focused on A1M as a biomarker of pre-eclampsia in the first trimester or as a biomarker of developing SGA/IUGR in women with hypertensive disorders of pregnancy.
- Promising results of an animal study suggest that A1M could be used as a treatment for pre-eclampsia (399). Further studies are needed to clarify its use in human pregnancy complicated with pre-eclampsia.
7 CONCLUSIONS
1. The multivariate model including maternal risk factors, previously tested biomarkers and biophysical measurements combined with hCG-h or %hCG-h and built with regularised logistic regression did not meet the requirements of a clinically useful screening test.
2. We found that there is an association between LDA started before 14 weeks of gestation and higher increase in serum PlGF concentration.
3. We found that high-risk women who do not develop pre-eclampsia have higher plasma A1M concentrations at 26–28 weeks of gestation. There was no difference in Hpx concentrations between three different study groups:
high-risk women who did and did not develop pre-eclampsia and low-risk women.
4. Our study showed that plasma Hpx was higher in high-risk women who developed pre-eclampsia from 12–14 to 26–28 weeks of gestation when compared to low-risk women or high-risk women who did not develop eclampsia. It appeared that high-risk women who did not develop pre-eclampsia had a unique profile of haem scavenger proteins during pregnancy: Firstly, unlike in high-risk women with subsequent pre-eclampsia and in low-risk women, their plasma concentration of Hpx did not change during the study period and it was lower during the first half of the pregnancy when compared to the other two groups. Secondly, the A1M concentration increased during the first half of the pregnancy and stayed at the higher level thereafter when compared to the other two groups. The change during the first half of the pregnancy was opposite to the change seen in high-risk women with subsequent pre-eclampsia, while there was no change in plasma A1M concentration in low-risk women. We also found that women who subsequently developed pre-eclampsia and gave birth to an SGA newborn had consistently higher plasma levels of A1M than women who developed pre-eclampsia and gave birth to an AGA newborn. The difference was significant from mid-gestation onwards.
8 ACKNOWLEDGEMENTS
This study was carried out at the Department of Obstetrics and Gynaecology of University of Helsinki. I express my gratitude to the current and former head of the Department of Obstetrics and Gynaecology Professor Oskari Heikinheimo and Professor Juha Tapanainen, respectively, as well as to the administrative head of the Department of Obstetrics and Gynaecology professor Seppo Heinonen.
I am honoured that Professor Leea Keski-Nisula from the University of Eastern Finland accepted the invitation to be my opponent. I warmly thank the pre-examiners Professor Ganesh Acharya from Karolinska Institutet and Professor Olli Vuolteenaho from the University of Oulu for their valuable remarks and suggestions for improving the manuscript of this thesis.
I wish to express my sincere gratitude to all of the following:
Hannele Laivuori. My supervisor whose superior experience in the field of pre-eclampsia research has given me a secure umbrella under which it has been a great joy to conduct this thesis project. Your capacity, experience and perspective are amazing, and I never stop honouring you. Thank you for all the feedback and encouragement I have received during these years. You have enlightened me with the power of a multi-professional research group and the importance of international connections and collaboration.
Pia Villa. My supervisor whose constant and unreserved support through all the obstacles and difficulties has been a solid base for my path to the doctoral degree. Your commitment and support have been incredible. You were there for me when I had the tightest deadlines and the most stressful moments during my thesis project. You are my role model.
PREDO board. Professor Esa Hämäläinen, Professor Eero Kajantie, Professor Katri Räikkönen and Professor Anu-Katriina Pesonen are the co-authors and unsurpassed professionals of science and research. Thank you for your expert guidance and contribution on our articles.
Co-authors. Grigorios Kalapotharakos, Professor Stefan Hansson, Professor Bo Åkerström, Jaakko Matomäki, Tero Vahlberg, Elina Keikkala, Piia Vuorela, and Professor Ulf-Håkan Stenman. I thank you for your excellent collaboration and expertise that made this work feasible. Special thanks for Jaakko Matomäki and Tero Vahlberg, two statisticians at the University of Turku. You not only provided the best possible methods for our studies but also took the trouble to introduce me to the basics of statistics and methods used in this thesis.
Research group. Eija Kortelainen, Tiina Jääskeläinen, Inkeri Lokki, Tea Kaartokallio and Jenni Heikkinen-Eloranta. Thank you for your inspiring enthusiasm towards research and invigorating discussions during our research group meetings. Special thanks for Eija Kortelainen who helped me with many practical issues, especially when I started in the research group. You were always eager to clarify the difficulties that I met as a beginner
in the field. Many thanks for docent Tiina Jääskeläinen for her pleasant company during our unforgettable adventure in California.
Thesis committee. My warm thanks for your support, guidance, and encouragement during the past years. Seija Grénman. Professor (emerita) of Obstetrics and Gynaecology at University of Turku and Turku University Hospital. You carefully read my reports and articles and gave me many valuable practical advices. Eeva Ekholm.
Docent and my boss, who closely followed my advancement and provided the best possible circumstances for combining clinical work and research. I admire your positive and energetic attitude towards everything.
Colleagues and work mates in clinics. I thank my colleagues, midwives, nurses, and hospital auxiliary staff at Turku University Hospital. I am privileged to have the opportunity to work with you all.
Päivi Polo. Professor of Obstetrics and Gynaecology at the University of Turku and Turku University Hospital, who encouraged and supported me with finalising the thesis. Your unselfish and kind guidance and your wise advices were always available when needed.
Kaarin Mäkikallio. Head of the Department of Obstetrics and Gynaecology who made it possible to combine PhD studies and clinical work. I am grateful for your trust and understanding as well as sharing your superior knowledge and skills on foetal ultrasound.
Warm thanks for my nearest colleagues in obstetrics, Susanna Timonen, Kirsi Rinne, Nanneli Pallasmaa, Kristiina Tertti, Kaisa Holmberg, Outi Pellonperä, Mirjami Mattila, Lara Lehtoranta, Minna Siltanen and Tuija Järvenpää. I am grateful for your collegial support in my specialisation to perinatology. With you I can share and discuss about difficult clinical problems and about any other issues on earth. Together we are more than the sum of our individual expertise.
The running club ‘Buns of Steel’ at our clinic. Although the name of our club may have been changed during the past years to a more realistic one. Anyways the group jogging on Fridays helped me to keep on track both mentally and physically.
My former colleagues and workmates at Turunmaa Hospital, Salo Hospital, Lohja Hospital, Central Hospital of Kanta-Häme and Kuopio University Hospital. Special thanks to the former Head of Turunmaa Hospital Reijo Grönfors, Head of Gynaecology at Salo Hospital Tiina Backman, colleagues at Salo Hospital Matti Eriksson and Kaija Suomalainen, Head of the Department of Obstetrics and Gynaecology at Lohja Hospital Raija Räty and former Head of the Department of Obstetrics and Gynaecology at the Central Hospital of Kanta-Häme Merja Vainio. Each of you has contributed to the success of my thesis project.
Alyce Whipp for the skilful language revision.
Friends. My deepest gratitude goes to the group of my coursemates from medical school ‘Happotytöt’, less formally ‘Happikset’. Päivi Peldán, Maria Tengstöm, Kati Kinnunen, Marja Tiihonen, and Sari Kemppainen, you and your families are a vital part
of my life. You are my life-long true friends. We can all trust on the ever-lasting nature of our friendship.
At this moment, my warm thoughts are with Satu and the late Janne Leminen. Our friendship started in upper secondary school, we spent our vivid youth together, and saw our children grow. I am very proud of the guitar band ‘The Leminen Brothers’ as a god mother of your son Into and a great fan of your son Onni. I miss you Janne.
I also want to thank my dear childhood friend Milja ‘Milli’ Vojinovíc. We have known each other since kindergarten. I am grateful for your friendship, which helped me through the difficult times during my teenage years. We shared a similar situation in life and supported each other.
Mirtta-Mari Numminen, Katariina Ruusunen-Nurmio, Niina Stade, Johanna Heino, Arja Virta and Hanna Ansas and their families, my former and present neighbours. We built our homes and raised our kids. Your friendship and support were and are invaluable.
Family. My in-law Anja and the late Pentti, thank you for being great parents-in-law, and grandparents to our children. We have always had your holistic support, on which we were able to lean when needed. We miss you Pentti. My mother Kaarina, a woman with exceptional energy and an excess of love to share with all around her. You are my true hero. My aunt Aila and her husband Ante, my ‘spare parents’, whose love and care have played a crucial role in my life. Our children have been fortunate to have five grandparents. Aunt Eila and her husband Tauno, warm thanks for the great summers with my sister in Ruovesi in our childhood.
My sisters Marikka and Tanja, and their families. With you I would go to a desert island.
I know I could concentrate on reflecting, while you are already acting and getting things done. We complement each other and together we are invincible.
Timo, my love for over 30 years. There are no words to express my love and gratitude for the time we have been together. My life has been very beautiful with you and because of you. Our children Anna, Aino and Severi. You are the masterpieces of our lives. Nothing else truly matters.
This work was financially supported by the University of Helsinki Funds, the Hospital District of Helsinki and Uusimaa (EVO), Svenska Läkaresällskapet, the Finnish Medical Foundation, TYKS-säätiö, Academy of Finland, Signe and Ane Gyllenberg Foundation, Sigrid Juselius Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Jane and Aatos Erkko Foundation, and Päivikki and Sakari Sohlberg Foundation. This work was supported by PerkinElmer Finland Oy (PlGF assays).
I thank the University of Helsinki and its doctoral programme in clinical research for its high-quality educational support to achieve the required knowledge and skills of the doctoral degree. I am grateful to the excellent services of Meilahti Campus Library, especially the Information Specialist Katri Larmo, whose skills and services saved me a lot of time and effort.
I have been fortunate to work at the University of Turku and the Hospital District of Southwest Finland, where we have excellent support for clinicians who do research. I have had easy access to digital library and statistical services.
I thank the doctors and study nurses for their work on the PREDO Project and I am grateful to the women who participated in the study.
Turku, May 2021
Katja Murtoniemi
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