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 Paivikki 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.Peer reviewe

Mortality of midlife women with surgically verified endometriosis-a cohort study including 2.5 million person-years of observation

STUDY QUESTION Is all-cause and cause-specific mortality increased among women with surgically verified endometriosis? SUMMARY ANSWER The all-cause and cause-specific mortality in midlife was lower throughout the follow-up among women with surgically verified endometriosis compared to the reference cohort. WHAT IS KNOWN ALREADY Endometriosis has been associated with an increased risk of comorbidities such as certain cancers and cardiovascular diseases. These diseases are also common causes of death; however, little is known about the mortality of women with endometriosis. STUDY DESIGN, SIZE, DURATION A nationwide retrospective cohort study of women with surgically verified diagnosis of endometriosis was compared to the reference cohort in Finland (1987-2012). Follow-up ended at death or 31 December 2014. During the median follow-up of 17years, 2.5 million person-years accumulated. PARTICIPANTS/MATERIALS, SETTING, METHODS Forty-nine thousand nine hundred and fifty-six women with at least one record of surgically verified diagnosis of endometriosis in the Finnish Hospital Discharge Register between 1987 and 2012 were compared to a reference cohort of 98824 age- and municipality-matched women. The age (meanstandard deviation) of the endometriosis cohort was 36.49.0 and 53.612.1years at the beginning and at the end of the follow-up, respectively. By using the Poisson regression models the crude and adjusted all-cause and cause-specific mortality rate ratios (MRR) and 95% confidence intervals (CI) were assessed. Calendar time, age, time since the start of follow-up, educational level, and parity adjusted were considered in the multivariate analyses. MAIN RESULTS AND THE ROLE OF CHANCE A total of 1656 and 4291 deaths occurred in the endometriosis and reference cohorts, respectively. A lower all-cause mortality was observed for the endometriosis cohort (adjusted MRR, 0.73 [95% CI 0.69 to 0.77])-there were four deaths less per 1000 women over 10years. A lower cause-specific mortality contributed to this: the adjusted MRR was 0.88 (95% CI 0.81 to 0.96) for any cancer and 0.55 (95% CI 0.47 to 0.65) for cardiovascular diseases, including 0.52 (95% CI 0.42 to 0.64) for ischemic heart disease and 0.60 (95% CI 0.47 to 0.76) for cerebrovascular disease. Mortality due to alcohol, accidents and violence, respiratory, and digestive disease-related causes was also decreased. LIMITATIONS, REASONS FOR CAUSATION These results are limited to women with endometriosis diagnosed by surgery. In addition, the study does not extend into the oldest age groups. The results might be explained by the characteristics and factors related to women's lifestyle, and/or increased medical attention and care received, rather than the disease itself. WIDER IMPLICATIONS OF THE FINDINGS These reassuring data are valuable to women with endometriosis and to their health care providers. Nonetheless, more studies are needed to address the causality. STUDY FUNDING/COMPETING INTEREST This research was funded by the Hospital District of Helsinki and Uusimaa and The Finnish Medical Foundation. None of the authors report any competing interest in relation to the present work; all the authors have completed the disclosure form.Peer reviewe

Low anti-Müllerian hormone level is not a risk factor for early pregnancy loss in IVF/ICSI treatment

STUDY QUESTION: Is a low ( SUMMARY ANSWER: A low or moderately low serum AMH level does not associate with miscarriage, non-visualized pregnancy loss or overall early pregnancy loss rate in the IVF/ICSI treatment. WHAT IS KNOWN ALREADY: Low AMH predicts poor ovarian response and small oocyte yield in IVF/ICSI treatment, but its value in the evaluation of live birth rate (LBR) is modest Little is known about the risk of early pregnancy loss in ART among women with low AMH. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study on 1383 women undergoing their first oocyte retrieval for IVF/ICSI in Helsinki University Hospital in Helsinki, Finland, between 2012 and 2016, with all associated fresh (n = 1315) and frozen-thawed (n = 1418) ET cycles finished by August 2018. AMH was measured within 12 months before the IVF/ICSI stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of all the women, 235 (17.0%) had low (= 2.0 mu g/L) AMH. The primary outcomes were miscarriage, non-visualized pregnancy loss and early pregnancy loss (miscarriage and non-visualized pregnancy loss combined) after fresh or frozen-thawed ET. The impact of AMH on these outcomes was calculated in three populations: among all women who became pregnant, among women with AMH MAIN RESULTS AND THE ROLE OF CHANCE: Of 1123 pregnancies, 285 (25.4%) ended in non-visualized pregnancy loss and 143 (12.7%) in miscarriage. The LBR was 24.6% per ET (673/2733). Low or moderately low AMH, compared with normal AMH, did not associate with miscarriage or non-visualized pregnancy loss in analyses among all women who became pregnant (adjusted relative risk (RR) for miscarriage vs live birth, 0.70 and 95% CI 0.42-1.17 in low AMH and adjusted RR, 1.00 and 95% CI, 0.68-1.49 in moderately low AMH; adjusted RR for non-visualized pregnancy loss vs live birth, 0.90 and 95% CI, 0.65-1.23 in low AMH and adjusted RR, 1.09 and 95% CI 0.85-1.41 in moderately low AMH), nor did low or moderately low AMH associate with the overall early pregnancy loss rate (adjusted RR for early pregnancy loss vs live birth, 0.86 and 95% CI, 0.68-1.10 in low AMH and adjusted RR, 1.01 and 95% CI, 0.86-1.27 in moderately low AMH). Results remained similar after restricting the analysis to women with AMH LIMITATIONS, REASONS FOR CAUTION: The number of miscarriages in women with low AMH was moderately small, limiting the power of the study. The real-world clinical setting of the study restricted the ability to control for all factors causing selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The cLBR was higher among women with normal AMH than among women with low or moderately low AMH in their first IVF/ICSI treatment because these women had more oocytes and embryos. Women with low or moderately low AMH did not have an increased risk for early pregnancy loss. This information is reassuring for couples and useful in counseling. These results are also valuable when assessing the overall effectiveness of IVF/ICSI treatment.Peer reviewe

Mortality in individuals with intellectual disabilities in Finland

Objectives: This study aimed at ascertaining the standardized mortality ratios (SMR) for those with an intellectual disability (ID) in Finland. Materials and Methods: We used the statistical database of the national insurance institution of Finland and Statistics Finland&#39;s mean population figures. We determined the number of individuals who received benefits (disability allowance, disability pension, or care allowance for pensioners) due to an ID diagnosis and the number of those whose benefit had been terminated due to death during the years 1996-2011. Results: SMR for females with a mild ID (IQ 50-69) was 2.8 (95% CI: 2.60-3.01) and for males 2.0 (95% CI: 1.88-2.14), and for females with a severe ID (IQ &lt; 50) 5.2 (95% CI: 4.99-5.50) and for males 2.6 (95% CI: 2.48-2.72). Conclusion: This significant difference in the SMR figures between males and females with ID warrants further research.</p

The risk of psychiatric disorders among Finnish ART and spontaneously conceived children: Finnish population-based register study

Evidence regarding the psychiatric morbidity of children born after Assisted Reproductive Techniques (ART) is inconsistent and limited. While normal mental well-being for ART children is usually reported, concerns are still being raised. Previous studies examine only some psychiatric disorders, but not all of them, ignore the impact of multiplicity, and limit the follow-up time to childhood. We examined all psychiatric diagnoses for singletons until their young adulthood. The aim was to study whether the risk of psychiatric disorders differs between ART and spontaneously conceived (SC) singletons until young adulthood. This retrospective Finnish population-based register study includes all ART and SC live-born children born in Finland during 1990-2013 and their hospital care in 1990-2014 (n = 1,425,975 of which 1,385,956, 97.2% were singletons). After excluding multiples, the final population included 17,610 ART and 1,368,346 SC singletons in 1990-2013 from the Finnish Medical Birth Registry. These data were linked to the Finnish Hospital Discharge Registry with the child's and mother's encrypted IDs. ART singletons had fewer psychiatric diagnoses (ART 10.2%, n = 1796, SC 12.0%, n = 164,408), but they received their diagnoses earlier (mean 8.3 years old, SD 5.0) than SC singletons (mean 10.5 years old, SD 5.7). After adjusting for confounding factors, ART singletons had an increased likelihood of getting a psychiatric diagnosis until young adulthood and the results were similar for boys (adjusted hazard ratios [aHR] = 1.16, 95% confidence interval (CI) 1.10-1.24) and girls (aHR = 1.25, 95% CI 1.16-1.35). We conclude that ART children receive their psychiatric diagnoses earlier than SC children, in particular during childhood and early adolescence. After adjusting for confounding factors ART children a slightly increased likelihood of any psychiatric diagnosis compared to SC controls

Predictive Values of Serum Chlamydia trachomatis TroA and HtrA IgG Antibodies as Markers of Persistent Infection in the Detection of Pelvic Adhesions and Tubal Occlusion

Chlamydia trachomatis IgG antibody testing (CAT) has been used as a screening test for tubal factor infertility (TFI), but as the CAT is only a marker of a past exposure to C. trachomatis and not of late sequelae, the positive predictive value (PPV) of the test is low. The persistence of C. trachomatis in the upper genital tract has been suggested as one of the key mechanisms in the development of TFI. Serum antibodies against C. trachomatis TroA and HtrA, proteins expressed specifically during persistent infection, have been suggested as novel biomarkers for TFI diagnostics. We studied serum IgG antibody responses against C. trachomatis TroA, HtrA and MOMP in 79 subfertile women, of whom 28 had laparoscopically proven TFI. We confirmed that the accuracy of CAT in diagnosing TFI is low, whereas TroA IgG and HtrA IgG are more accurate tests in detecting tubal occlusion and pelvic adhesions. However, the sensitivity and negative predictive value (NPV) of TroA IgG and HtrA IgG are still too low to justify their use as a screening test in clinical practice. Individual immunogenetic profiles combined with TroA and HtrA antibody responses might identify women with the highest risk for developing late complications after C. trachomatis infection

Predictive Values of Serum Chlamydia trachomatis TroA and HtrA IgG Antibodies as Markers of Persistent Infection in the Detection of Pelvic Adhesions and Tubal Occlusion

Chlamydia trachomatis IgG antibody testing (CAT) has been used as a screening test for tubal factor infertility (TFI), but as the CAT is only a marker of a past exposure to C. trachomatis and not of late sequelae, the positive predictive value (PPV) of the test is low. The persistence of C. trachomatis in the upper genital tract has been suggested as one of the key mechanisms in the development of TFI. Serum antibodies against C. trachomatis TroA and HtrA, proteins expressed specifically during persistent infection, have been suggested as novel biomarkers for TFI diagnostics. We studied serum IgG antibody responses against C. trachomatis TroA, HtrA and MOMP in 79 subfertile women, of whom 28 had laparoscopically proven TFI. We confirmed that the accuracy of CAT in diagnosing TFI is low, whereas TroA IgG and HtrA IgG are more accurate tests in detecting tubal occlusion and pelvic adhesions. However, the sensitivity and negative predictive value (NPV) of TroA IgG and HtrA IgG are still too low to justify their use as a screening test in clinical practice. Individual immunogenetic profiles combined with TroA and HtrA antibody responses might identify women with the highest risk for developing late complications after C. trachomatis infection

Adolescent attachment to parents and peers in singletons and twins born with assisted and natural conception

STUDY QUESTION Does adolescent attachment to parents and peers differ between singletons and twins born with ART or natural conception (NC)? SUMMARY ANSWER Adolescent attachment anxiety with the father was higher among NC singletons than among ART and NC twins, whereas attachment avoidance with the father was higher in ART singletons than in NC singletons and NC twins. No differences were found in attachment to the mother, best friend or romantic partner. WHAT IS KNOWN ALREADY Most studies have not found differences between ART and NC singletons in parent-adolescent relationships, but twin relationships may be more at risk. No previous study has examined all four groups in the same study, or specifically looked at attachment relationships. STUDY DESIGN, SIZE, DURATION This was an 18-year, prospective and controlled longitudinal study with families of 496 ART singletons, 101 ART twin pairs, 476 NC singletons and 22 NC twin pairs. Families were recruited during the second trimester of pregnancy; the ART group was recruited from five infertility clinics in Finland and the control group was recruited from a hospital outpatient clinic during a routine visit. PARTICIPANTS/MATERIALS, SETTING, METHODS Mothers and fathers gave background information for this study during pregnancy, and during the child's first year and early school age (7-8 years). For the ART group, infertility characteristics and prenatal medical information was also obtained from the patient registry of the infertility clinics. Children (originally 50% girls) filled in electronic questionnaires related to their attachment to mother, father, best friend and romantic partner (Experiences in Close Relationships-Relationship Structures) at 17-19 years of age. MAIN RESULTS AND THE ROLE OF CHANCE Adolescent attachment anxiety to father was higher in NC singletons than in ART twins, P = 0.004 and marginally higher than in NC twins, P = 0.06. Adolescent attachment avoidance to father was higher in ART singletons than in NC singletons, P = 0.006 and marginally higher than in NC twins, P = 0.055. LIMITATIONS, REASONS FOR CAUTION The sample size was small especially in the NC twin group and there was drop-out over the 18-year time period, especially among boys and families with lower parental education level. The study only included native Finnish-speaking families. The results could differ in a more diverse population. ART singletons were younger and had fewer siblings than ART twins and NC children, and ART and NC twins had more newborn health risks than ART and NC singletons. WIDER IMPLICATIONS OF THE FINDINGS The study adds to a growing body of evidence that neither ART treatments nor being a twin places mother-child relationships or peer relationships at long-term risk. However, in our study, which was the first to examine both ART and twinhood simultaneously, we found that there may be more problems in father-adolescent relationships, but only in ART singletons and only related to attachment avoidance. Our findings suggest that men, as well as women, should receive enough support in pre- and peri-natal health care during and after infertility treatments. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Academy of Finland (grant number 2501308988), the Juho Vainio Foundation and the Finnish Cultural Foundation. The authors report no conflict of interest.Peer reviewe