Search

Assisted reproductive technology (ART) is the most efficient way of helping couples suffering from infertility. In the past years, the use of frozen embryo transfer (FET) has been on the rise, and even freeze all cycles have been advocated. FET enables fertility sparing and allows time for preimplantation genetic testing. Most importantly, embryo freezing enables the use of elective single embryo transfer, which reduces the prevalence of multiple gestations, thus improving the perinatal health of ART offspring. The risks of preterm birth, low birth weight and small-for-gestational-age are reduced for FET singletons compared to fresh embryo transfer (ET). However, FET singletons have a higher mean birth weight and an increased risk of large-for-gestational-age (LGA) compared to fresh ET and natural conception (NC). The aim of these studies was to examine the growth and health of FET singletons until early adulthood. In the study based on a large Nordic population-based cohort, the birth weights of FET compared to fresh ET were significantly higher starting from gestational week 33 for boys and 34 for girls. The risk of LGA was almost twofold for FET compared to fresh ET and 1.3-fold for FET compared to NC. In the regional Finnish cohort, no growth differences were found until 5 years of age between term-born FET, fresh ET, and NC singletons. In the Finnish register-based cohort, no significant differences were found between FET girls, fresh ET and NC concerning height, weight, or BMI nor between FET boys and fresh ET concerning height between ages 7 and 18. However, boys born after FET were taller compared to NC and heavier with a higher BMI and an increased risk of overweight compared to fresh ET and NC in the teen years. Compared to NC, FET was associated with slightly or moderately increased risks of diagnoses in several main diagnosis chapters, as well as a slightly, but significantly increased need for hospital care. However, no differences in morbidity, Tiivistelmä Koeputkihedelmöityshoito on tehokkain tapa auttaa lapsettomuudesta kärsiviä pareja. Viime vuosina pakastetun alkion siirtojen (PAS) määrä on lisääntynyt voimakkaasti. PAS mahdollistaa hedelmällisyyden säilyttämisen ja antaa aikaa alkiodiagnostiikan käyttöön. Ennen kaikkea PAS mahdollistaa elektiiviset yhden alkion siirrot, mikä vähentää monisikiöisiä raskauksia ja parantaa näin lasten syntymäterveyttä. Yksisikiöisistä PAS-raskauksista syntyneillä lapsilla on alentunut riski ennenaikaisuuteen, pieneen syntymäpainoon ja raskauden kestoon suhteutettuun pienikokoisuuteen verrattuna tuorealkionsiirrosta syntyneisiin lapsiin. Heillä on kuitenkin suurempi keskimääräinen syntymäpaino ja kohonnut riski raskauden kestoon suhteutettuun suurikokoisuuteen. Tämän väitöskirjan tavoitteena oli tutkia PAS-lasten kasvua ja terveyttä aikuisikään saakka. Pohjoismaisessa väestötason kohortissa todettiin, että PAS-poikien syntymäpainot olivat merkitsevästi korkeammat raskausviikosta 33 alkaen ja PAS-tyttöjen viikosta 34 alkaen verrattuna tuorealkionsiirtolapsiin. PAS-lasten riski raskauden kestoon suhteutettuun suurikokoisuuteen oli lähes kaksinkertainen verrattuna tuorealkionsiirtolapsiin ja 1,3-kertainen verrattuna luonnollisesti alkunsa saaneisiin lapsiin. Alueellisessa kohortissa kasvueroja ei todettu viiteen ikävuoteen mennessä täysiaikaisina syntyneiden PAS-, tuorealkionsiirto- ja luonnollisesti alkunsa saaneiden lasten välillä. Suomalaisiin rekistereihin pohjautuvissa tutkimuksissa tyttöjen osalta kasvueroja ei todettu painossa, pituudessa tai painoindeksissä 7 ja 18 ikävuoden välillä. PAS- ja tuorealkionsiirtopoikien pituudessa ei todettu eroja, mutta PAS-pojat olivat pidempiä verrattuna luonnollisesti alkunsa saaneisiin poikiin, ja he olivat painavampia sekä heidän riskinsä ylipainoon oli koholla murrosiässä verrattuna tuorealkionsiirrosta syntyneisiin ja luonnollisesti alkunsa saaneisiin poikiin. Verrattuna luonnollisesti alkunsa saaneisiin lapsiin, PAS-lapsilla tod

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Study question: Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood? Summary answer: The health of singletons born after FET does not differ from that of singletons born after fresh ET. What is known already: The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce. Study design, size, duration: This retrospective register-based cohort study compares singletons born after FET (n = 1825) between the years 1995 and 2006 to those born after fresh ET (n = 2933) and natural conception (NC, n = 31 136) with a mean follow-up time of 18–20 years. Participants/materials, setting, mehods: Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother’s occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student’s T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person. Main results and the role of chance: No si

Introduction: The incidence of ectopic pregnancy is up to four times higher after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) than in spontaneous pregnancies, and the risk of ectopic pregnancy is increased by tubal factor infertility and the transfer of multiple embryos. However, the effect of embryo quality on the probability of ectopic pregnancy has not been investigated until now and it is not clear whether ovarian stimulation parameters affect the incidence of ectopic pregnancy. Material and Methods: An historical cohort study of 15 006 clinical pregnancies (diagnosed by ultrasound at 6–8 gestational weeks) after non-donor IVF/ICSI with fresh embryo transfer (n = 8952) or frozen–thawed embryo transfer (n = 6054). Treatments were performed during 2000–2017 in Finland. A total of 9207 (61.4%) single and 5799 (38.6%) double embryo transfers of no more than one top-quality embryo were evaluated. We analyzed the effects of multiple factors on ectopic pregnancy by logistic regression, including type of cycle (fresh vs frozen embryo transfer), female age, number and quality of embryos transferred, tubal factor infertility and factors of ovarian response to gonadotropin stimulation. Results: Ectopic pregnancy was observed in 2.3% of cycles. There was no significant difference in ectopic pregnancy rate after fresh embryo transfer and frozen embryo transfer (2.2% vs 2.4%, p = 0.3). The ectopic pregnancy rate was lower in cycles with top-quality embryo transfer (1.9%) than of those where only non-top quality embryos were transferred (2.7%, p < 0.0001). Tubal factor infertility was diagnosed more often in ectopic pregnancy than in intrauterine pregnancies (21.2% vs 11.0%, p < 0.0001). Logistic regression revealed lower odds for ectopic pregnancy after a top-quality embryo transfer than after transfer of a non-top quality embryo (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.56–0.92, p = 0.007). Transfer of two vs one embryo (OR 1

Research question: Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? Design: Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. Results: Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. Conclusions: Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

In this paper we present the results announced in the recent work by the first, second, and fourth authors of the current paper concerning Rubio de Francia extrapolation for the so-called multilinear Muckenhoupt classes. Here we consider the situations where some of the exponents of the Lebesgue spaces appearing in the hypotheses and/or in the conclusion can be possibly infinity. The scheme we follow is similar, but, in doing so, we need to develop a one-variable end-point off-diagonal extrapolation result. This complements the corresponding "finite"case obtained by Duoandikoetxea, which was one of the main tools in the aforementioned paper. The second goal of this paper is to present some applications. For example, we obtain the full range of mixed-norm estimates for tensor products of bilinear Caldeŕon-Zygmund operators with a proof based on extrapolation and on some estimates with weights in some mixed-norm classes. The same occurs with the multilinear Caldeŕon-Zygmund operators, the bilinear Hilbert transform, and the corresponding commutators with BMO functions. Extrapolation along with the already established weighted norm inequalities easily give scalar and vectorvalued inequalities with multilinear weights and these include the end-point cases.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

The main goal of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment is a healthy mother and a healthy child. The most important complication following IVF/ICSI arises from the increased risk of multiple pregnancies. An elective single embryo transfer (eSET) with the freezing of spare embryos and subsequent treatment with frozen embryo transfer (FET) is the only way to avoid this complication. For this reason, the number of children born after FET is steadily rising. The aim of this study was to provide more detailed evidence on the safety of FET, particularly focusing on serum hormone profiles during the first trimester weeks of singleton pregnancies after IVF/ICSI fresh embryo transfer (ET), after FET during a natural menstrual cycle, and after spontaneous conception. Another part of this study compared the perinatal outcomes, congenital anomalies (CAs), and morbidity of singletons born after FET and IVF/ICSI fresh ET. The reference group was those born after spontaneously conceived (SC) pregnancies. In the clinical prospective study, the maternal serum estradiol and progesterone levels in pregnancies after fresh ET (n=39) were higher during early pregnancy weeks than in FET (n=30) and SC pregnancies (n=41), while the hormonal profiles after FET did not differ from SC pregnancies. In the large register study, FET children (n=1830) were found to have a reduced risk for adverse perinatal outcomes, such as preterm birth, a low birthweight, and being small for their gestational age compared with children born after fresh ET (n=2942). However, FET children have an increased risk for being large for their gestational age. The major CAs and morbidity until three years of age did not differ between groups. When compared with SC children (n =31 243), the perinatal outcome was worse and the rates of CAs and morbidity were higher in FET children. The FET cycle seemed to provide a better physiological environment for early fetal develop, Tiivistelmä Koeputkihedelmöityshoidon (in vitro fertilization, IVF ja intracytoplasmic sperm injection, ICSI) tavoitteena on terve äiti ja terve lapsi. Monisikiöraskaus on hoidon komplikaatio, koska siihen liittyy selkeästi kohonnut riski äidille ja lapselle. Yhden alkion siirto, jäljelle jääneiden alkioiden pakastus ja myöhemmin tehtävä pakastetun alkion siirto (PAS) ovat lisänneet IVF/ICSI-hoitojen turvallisuutta ja tehokkuutta. Täten PAS:sta syntyneiden lasten määrä kasvaa. Tutkimuksen tavoitteena on lisätä PAS-hoitojen turvallisuutta tarkastelemalla veren steroidihormonien muutoksia alkuraskaudessa naisilta, jotka olivat tulleet raskaiksi IVF/ICSI-tuorealkion siirroista, luonnollisen kuukautiskierron aikana tehdystä PAS:sta ja luonnollisesti. Lisäksi tutkimuksessa verrattiin PAS- ja IVF/ICSI-tuorealkion siirrosta alkunsa saaneiden lasten terveyttä kolmeen ikävuoteen asti. Viiteryhmän muodostivat luonnollisesti alkunsa saaneet lapset. Kliinisessä prospektiivisessa tutkimuksessa havaittiin naisilla, joilla oli tuorealkion siirrosta alkanut raskaus (n=39), merkittävästi koholla olevat seerumin estradioli- ja progesteronipitoisuudet 7–8 raskausviikolle asti verrattuna naisiin, joilla raskaudet olivat alkaneet PAS:sta (n=30) tai luonnollisesti (n=41). Vastaavasti PAS-raskauksissa hormonipitoisuudet eivät eronneet merkittävästi luonnolliseen raskauteen verrattuna. Laajassa rekisteritutkimuksessa havaittiin PAS-lapsilla (n=1830) olevan pienempi riski ennenaikaisuuteen ja pienipainoisuuteen kuin tuorealkiolapsilla (n=2942). Kuitenkin PAS-lapsilla oli lisääntynyt riski syntyä isokokoisina raskausviikkoihin nähden. Synnynnäisten epämuodostumien ja eri sairauksien esiintyvyyksissä ei ollut eroja. Luonnollisesti alkunsa saaneisiin lapsiin (n= 31 243) verrattaessa, PAS-lapsilla oli vastasyntyneisyyskaudelta lähtien enemmän terveyteen liittyviä ongelmia. Tutkimus osoitti PAS-raskaudessa sikiön kehittyvän alkuviikkoina luonnollisemmassa ympäristössä kuin tuorealkion siirtorask