Growth of singletons born after frozen embryo transfer until early adulthood: a Finnish register study.

STUDY QUESTION: Are there growth differences between singleton children born after frozen embryo transfer (FET), fresh embryo transfer (ET), and natural conception (NC)? SUMMARY ANSWER: Adolescent boys born after FET have a higher mean proportion and increased odds of overweight compared to those born after fresh ET. WHAT IS KNOWN ALREADY: Children born after FET have higher mean birthweights and an increased risk of large-for-gestational-age compared to those born after fresh ET and even NC. This raises questions about possible growth differences later in childhood. Previous studies on child growth after FET report partly conflicting results and lack long-term data until adolescence. STUDY DESIGN, SIZE, DURATION: This was a cohort study based on national population-based registers, the Finnish Medical Birth Register and the Register of Primary Health Care visits, including singletons born after FET (n = 1825), fresh ET (n = 2933), and NC (n = 31 136) in Finland between the years 1995 and 2006. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proportions of overweight (i.e. age- and sex-adjusted ISO-BMI for children ≥ 25) were compared between the groups. Odds ratios (ORs) and adjusted odds ratios (aORs) of overweight were calculated. Adjustments were made for birth year, preterm birth, maternal age, parity, and socioeconomic status. Mean heights, weights, and BMIs were compared between the groups each year between the ages of 7 and 18. MAIN RESULTS AND THE ROLE OF CHANCE: FET boys had a higher mean proportion of overweight (28%) compared to fresh ET (22%, P < 0.001) and NC (26%, P = 0.014) boys. For all ages combined, the aOR of overweight was increased (1.14, 95% CI 1.02-1.27) for FET boys compared to fresh ET boys. For girls, the mean proportions of overweight were 18%, 19%, and 22% for those born after FET, fresh ET, and NC, respectively (P = 0.169 for FET vs fresh ET, P < 0.001 for FET vs NC). For all ages combined, FET girls had a decreased aOR of overweight (0.89, 95% CI 0.80-0.99) compared to NC girls. Growth measurements were available for 6.9% to 30.6% of FET boys and for 4.7% to 29.4% of FET girls at different ages. LIMITATIONS, REASONS FOR CAUTION: Unfortunately, we were not able to adjust for parental anthropometric characteristics. The growth data were not available for the whole cohort, and the proportion of children with available measurements was limited at the start and end of the follow-up. During the study period, mainly cleavage stage embryos were transferred, and slow freezing was used for ART. WIDER IMPLICATIONS OF THE FINDINGS: The risk of overweight among FET boys warrants further research. Future studies should aim to investigate the mechanisms that explain this sex-specific finding and combine growth data with long-term health data to explore the possible risks of overweight and cardiometabolic disease in adulthood. STUDY FUNDING/COMPETING INTEREST(S): Funding was obtained from the Päivikki and Sakari Sohlberg Foundation, the Alma and K.A. Snellman Foundation (personal grants to A.M.T.), and the Finnish Government Research Funding. The funding sources were not involved in the planning or execution of the study. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Health of singletons born after frozen embryo transfer until early adulthood: a Finnish register study.

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, METHODS: 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 significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34). LIMITATIONS, REASONS FOR CAUTION: Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer. WIDER IMPLICATIONS OF THE FINDINGS: For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S): Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and 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.

Physical health of singleton children born after frozen embryo transfer using slow freezing: a 3-year follow-up study.

STUDY QUESTION: Are there differences in the physical health of singleton children born after frozen embryo transfer (FET) compared with children born after fresh embryo transfer (fresh ET)? SUMMARY ANSWER: Register-based health indicators were similar among FET and fresh ET singletons during a 3-year follow-up. WHAT IS KNOWN ALREADY: Large cohort studies have shown that perinatal outcomes are similar or even better in FET than fresh ET children. The early childhood morbidity among FET and fresh ET children has been shown to be quite similar, but so far these studies have been small. The short-term health outcomes of assisted reproductive technology (ART) children have been shown to be slightly worse compared with spontaneously conceived children. STUDY DESIGN, SIZE, DURATION: This register-based study includes women who had undergone ART treatments leading to singleton live births (n = 4758 children) in 1995-2006. A 10% random sample of women with spontaneous pregnancies from the Finnish Medical Birth Register (FMBR) served as the reference group (n = 31 137 children). The children were identified through the FMBR by using the mother's personal identification (ID) number. Children's ID numbers were linked with two nationwide registries; the Finnish Hospital Discharge Register and the Cause-of-Death Register at Statistics Finland. Information on all visits was received until 2009 using ICD-10 codes. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study includes 1825 children born after FET, 2933 children born after fresh ET and 31 137 children born after spontaneous pregnancies. The risk estimates for diseases were adjusted for the child's year of birth and maternal age, parity, socio-economic status and prematurity. The study focused on the differences between FET and fresh ET children. MAIN RESULTS AND THE ROLE OF CHANCE: Most health indicators were similar among FET and fresh ET children during the 3-year follow-up. The most common discharge diagnoses, including gastroenteritis and colitis, otitis, upper and lower respiratory diseases, asthma and allergies were similar between the ART groups. A large proportion of FET children (70.1%) and fresh ET children (69.9%) had visited a hospital at least once (P = 0.877). The risk of hospital admission did not differ between the two groups after adjusting for premature births [adjusted odds ratio (aOR) 1.01; 0.88-1.17]. Comparing with children born after spontaneously conceived pregnancies, the risk of hospital admission was slightly increased in the ART group, even after adjusting for premature births (aOR 1.10; 1.02-1.19). LIMITATIONS, REASONS FOR CAUTION: Due to the study design, we were not able to control for some parental background factors, such as the cause and length of infertility. Furthermore, the health registries do not include data on the growth of the children. Our findings are generalizable only to the slow-freezing method. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides further evidence of the safety of embryo cryopreservation. The early physical health of FET children is similar to that of children born after fresh ET. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the University Hospital of Oulu and Helsinki, Finland. The National Institute for Health and Welfare (THL) covered the data linkages and the work of Mika Gissler. There are no competing interests to be reported.

Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006.

STUDY QUESTION: Is there a different risk for major congenital anomalies (CAs) in children born after frozen-thawed embryo transfer (FET) compared with children born after fresh embryo transfer (ET)? SUMMARY ANSWER: Children born after FET have a similar risk of developing major CAs as children born after fresh ET. WHAT IS KNOWN ALREADY: The perinatal outcome in children born after FET is as good as that after fresh ET. Children born as a result of assisted reproductive technology (ART) have an increased risk for CAs when compared with spontaneously conceived children, but the knowledge on the risk for CAs in specific organ systems of children born after FET is limited. STUDY DESIGN, SIZE, DURATION: This register-based cohort study includes women who have undergone ART treatments with ET leading to singleton births (n = 4772) between the years 1995 and 2006. The women were identified from the registers of the infertility clinics, and the corresponding births were matched with data from the Finnish Medical Birth Register (FMBR). The 10% random sample of women with spontaneous pregnancies from the FMBR served as the reference group (n = 31,243). The study data were linked with the Register of Congenital Malformations using the mothers' and children's personal identification numbers to get information on CAs. Furthermore, the personal identification numbers of the ART women were linked with the Register of Induced Abortions to find their selective terminations of pregnancy for severe foetal anomalies. PARTICIPANTS, SETTING, METHODS: The study was focused on singleton births and included 1830 children born after FET, 2942 children born after fresh ET and 31 243 children born after spontaneous pregnancies. Only major CAs were analysed in keeping with European Concerted Action on Congenital Anomalies and Twins. The risk estimates for CAs were adjusted for the children's year of birth and maternal age, parity and socioeconomic status. The total prevalence of major CAs was counted, including both births and selective terminations of pregnancy for major fetal anomalies (n = 33). MAIN RESULTS AND THE ROLE OF CHANCE: Among singletons at least one major CA was reported in 77 cases (4.2%) in the FET group, 132 cases (4.5%) in the fresh ET group and 994 cases (3.2%) in the reference group. The risk for at least one major CA of the children born after FET was not increased compared with the children born after fresh ET [adjusted odd ratio (aOR) 0.95; 0.71-1.27]. Furthermore, no increased risks according to the organ system affected were found between these two ART groups. When comparing the children born after ART (FET and fresh ET) with the reference group children, the risk of having at least one major CA was moderately increased in the ART group (aOR 1.24; 1.05-1.47). LIMITATIONS, REASONS FOR CAUTION: Because of the study design we were neither able to examine the aetiology of infertility nor could we compare the data with a group of subfertile women to account for the effect of infertility per se on CAs. WIDER IMPLICATIONS OF THE FINDINGS: Perinatal outcomes of FET children, including the risks for CAs, are good and comparable with outcomes of other ART children indicating that slow freezing is a safe method to use during ART treatments. STUDY FUNDING/COMPETING INTEREST(S): University Hospital of Oulu and Helsinki, Finland. THL covered the data linkages and the work of Annukka Ritvanen and Mika Gissler. There are no competing interests to be reported.

Serum sex hormone-binding globulin and testosterone in relation to cardiovascular disease risk factors in young men: a population-based study.

OBJECTIVE: Reduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men. DESIGN: Observational, cross-sectional study. SETTING: General community. PARTICIPANTS: The study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples. OUTCOME VARIABLES: Blood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers. RESULTS: SHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (all P<0.05). These linearly graded associations persisted with additional adjustment for TT. SHBG was significantly associated with total cholesterol only with adjustment for covariates and TT (P<0.05). The direction and magnitude of associations between TT and risk factors were variable, but further adjustment for insulin, adiposity and SHBG showed positive associations between TT and BP, total and LDL-cholesterol and triglycerides and an inverse association with CRP (all P<0.05), but its relation with HDL-cholesterol was no longer significant. CONCLUSIONS: In this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.

Elective single-embryo transfer in women aged 40-44 years.

STUDY QUESTION: Is an elective single-embryo transfer (eSET) policy feasible for women aged 40 or older? SUMMARY ANSWER: For older women (aged 40-44 years) with a good prognosis, an eSET policy can be applied with acceptable cumulative clinical pregnancy rates and live birth rates. WHAT IS KNOWN ALREADY: Various studies have shown the effectiveness of eSET in women aged <35 years with high cumulative pregnancy rates and low rates of multiple births. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 628 women treated between 2000 and 2009. PARTICIPANTS, SETTING, METHODS: Women aged 40-44 years underwent a fresh cycle of IVF or ICSI treatment with eSET (n = 264) or double-embryo transfer (DET) (n = 364). In the subsequent frozen-thawed embryo transfer cycles, SET/DET was performed in both groups according to the number of embryos available and the opinion of the couple. The study was performed at the Family Federation of Finland Helsinki Fertility Clinic. MAIN RESULTS AND THE ROLE OF CHANCE: In the fresh cycles, the clinical pregnancy rates were 23.5 and 19.5% in the eSET and DET groups, respectively, and live birth rates were 13.6 and 11.0%, respectively. In the fresh cycles with eSET, there were no twin pregnancies, but in the DET group, there were three sets of twins (7.5%). The cumulative clinical pregnancy rates per oocyte retrieval were 37.1 and 24.2% in the eSET and DET groups, respectively (P < 0.001), and the cumulative live birth rates were 22.7 and 13.2%, respectively (P = 0.002). Cumulative twin rates were 6.7% (n = 4) in the eSET group and 8.3% (n = 4) in the DET group (P = 0.726). All of the twin pregnancies in the eSET group resulted from frozen and thawed DET embryo transfer cycles. LIMITATIONS: The characteristics of the two patients groups are not comparable because the suitability of eSET was individually assessed by a clinician based on both clinical prognostic factors and the outcome of IVF or ICSI, i.e. the number and quality of embryos. WIDER IMPLICATIONS OF THE FINDINGS: This study may be generalized to IVF units having experience in eSET and cryopreservation.

Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study.

STUDY QUESTION: Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence? SUMMARY ANSWER: Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity. Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence. STUDY DESIGN: This population-based, cross-sectional study used postal questionnaires to targeting 15-16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567). PARTICIPANTS AND SETTING: There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: 'Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?' The girls who answered 'yes' to this question were considered to be suffering from menstrual disorders and were classified as 'symptomatic'. The girls who answered 'no' were defined as 'non-symptomatic'. MAIN RESULTS AND THE ROLE OF CHANCE: There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile. IMPLICATIONS: Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage. BIAS, LIMITATIONS, GENERALIZABILITY: The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.