Naisesta ja miehestä johtuvat tekijät toistuvassa keskenmenossa

Recurrent pregnancy loss (RPL) has several known underlying causes and risk factors, including maternal age, chromosomal and uterine abnormalities, thrombophilia, and endocrinological disorders. In Finland, couples undergo RPL investigations mainly after their third clinical pregnancy loss. However, we do not know how often these investigations find an explanatory factor for pregnancy losses. In addition, even after thorough examinations, RPL often remains unexplained, indicating that there still are gaps in our understanding of the etiological factors. Thus, we aimed to investigate the etiology of miscarriages from several new approaches, focusing on both maternal and paternal factors. This thesis includes two register-based and two case-control studies conducted at the University of Helsinki, Helsinki University Hospital, Helsinki, Finland, and Hyvinkää Hospital, Hyvinkää, Finland. We linked the clinical data of 334 couples investigated for three or more consecutive pregnancy losses between 2007 and 2016 to national health and population registers. The investigations revealed one or more abnormal test results in 42.8% of couples. In 53.3%, RPL remained unexplained. 70.4% of couples achieved one or several live births after RPL investigations. Maternal age <35 years and unexplained RPL were associated with a good prognosis. In contrast, maternal smoking, paternal obesity, and a long duration of pregnancy attempts for four years or over before investigations were negatively associated with the prognosis. High sperm DNA fragmentation level lacked an association. Serum anti-Müllerian hormone (AMH) level reflects the size of the maternal ovarian follicle pool. Data on 1383 women undergoing their first in vitro fertilization or intracytoplasmic sperm injection treatment between 2012 and 2016 were collected from hospitals' medical databases. The women underwent 2733 embryo transfer cycles leading to 1123 pregnancies, of which 38% ended in early pregnancy loss. Women with low serum AMH levels (<2.0 micrograms per liter) became pregnant less likely than women with normal serum AMH (≥2.0 micrograms per liter), but low AMH level was not associated with a risk of early pregnancy loss. The Toive study recruited 50 couples with RPL and 50 control couples without a history of pregnancy loss between 2018 and 2021. The endometrial and vaginal microbiota compositions were analyzed using 16s ribosomal RNA gene amplicon sequencing. Endometrial Lactobacillus crispatus was less abundant in women with RPL than in control women. Gardnerella vaginalis was more abundant in women with RPL than controls in both endometrium and vagina. These results suggest dysbiotic female reproductive tract microbiota is associated with RPL. We analyzed human leukocyte antigens (HLA)-G and HLA-DRB1 in the peripheral blood samples collected from women and men participating in the Toive study. Results were compared between RPL and control women and men and with Finnish population controls. The polymorphisms of the 3’ untranslated region of the HLA-G gene were not associated with RPL in women or men. However, the maternal HLA-DRB1*04:04 allele was more frequent in women with RPL than in the Finnish population. In addition, the HLA-DRB1*01:01 allele was less frequent in men of couples with RPL than in the Finnish population and associated with successful later pregnancy in women. In conclusion, our results suggest that both maternal and paternal factors are involved in RPL. Patients with several losses are often worried and need counseling on their future chance of having a living baby. Our results show that maternal age <35 years and unexplained RPL are associated with a favorable prognosis, while maternal smoking and a couple’s prolonged pregnancy attempts are associated with reduced chances of later live birth. Paternal obesity may worsen the prognosis, but sperm DNA damage seems not to be associated with it. The comforting news is also that low maternal serum AMH level seems not to be associated with pregnancy loss in assisted reproduction. Dysbiotic maternal reproductive tract microbiota is associated with RPL, potentially opening new treatment options in the future. HLA-DRB1 alleles may be associated with RPL, but the polymorphisms of the 3’ untranslated region of the HLA-G gene are not associated with RPL in the Finnish population. We suggest that both women and men be included in RPL examinations, counseling, and care.Joka kuudes raskaus päättyy keskenmenoon ja 1-3% pareista kokee useita peräkkäisiä keskenmenoja. Suomessa tutkimukset toistuvien keskenmenojen kartoittamiseksi aloitetaan yleensä kolmen keskenmenon jälkeen. Kattavista tutkimuksista huolimatta keskenmenot jäävät usein selittämättömiksi, jolloin hoitomahdollisuudet ovat vähäiset. Toivotun raskauden menetys aiheuttaa vanhemmissa usein voimakasta surua ja sillä voi olla kauaskantoisia vaikutuksia heidän mielenterveyteensä ja hyvinvointiinsa. Uutta tietoa keskenmenoista tarvitaan sekä hoidon optimoimiseksi että neuvonnan tueksi. Tämä väitöstutkimus selvitti toistuvan keskenmenon taustasyitä ja pariskuntien myöhempää ennustetta. Tutkimukseen rekrytoitiin potilaita Helsingin yliopistollisesta sairaalasta ja Hyvinkään sairaalasta; lisäksi käytettiin rekisteriaineistoja. Noin puolella (53%) toistuvan keskenmenon takia tutkituista pariskunnista keskenmenojen syy jäi tuntemattomaksi. Ennuste oli kuitenkin kaiken kaikkiaan verraten hyvä, sillä miltei 70% pareista sai vähintään yhden elävän lapsen keskenmenojen jälkeen. Voimakkaimmin ennusteeseen vaikutti naisen ikä. Ennustetta heikensivät myös naisen tupakointi ja – hieman yllättäen – miehen lihavuus. Lisäksi havaitsimme, että selittämättömän toistuvan keskenmenon jälkeen todennäköisyys elävän lapsen syntymään oli suurempi kuin taustasyyn löytyessä. Tulostemme perusteella on oleellista jakaa tietoa iän ja elintapojen vaikutuksesta hedelmällisyyteen ja kannustaa hedelmällisessä iässä olevia naisia ja miehiä terveellisiin valintoihin. Naisen iän lisääntyessä munasolujen määrä vähenee ja niiden laatu huononee, jolloin raskaaksi tuleminen vaikeutuu ja keskenmenon riski kasvaa. Munasarjoissa jäljellä olevien munasolujen määrää kuvastavan seerumin anti-Müllerhormonin pitoisuus oli matala (