Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma

Genetic, biochemical, and animal model studies strongly suggest a central role for α-synuclein in the pathogenesis of Parkinson's disease. α-synuclein lacks a signal peptide sequence and has thus been considered a cytosolic protein. Recent data has suggested that the protein may be released from cells via a non-classical secretory pathway and may therefore exert paracrine effects in the extracellular environment. However, proof that α-synuclein is actually secreted into the brain extracellular space in vivo has not been obtained. We developed a novel highly sensitive ELISA in conjugation with an in vivo microdialysis technique to measure α-synuclein in brain interstitial fluid. We show for the first time that α-synuclein is readily detected in the interstitial fluid of both α-synuclein transgenic mice and human patients with traumatic brain injury. Our data suggest that α-synuclein is physiologically secreted by neurons in vivo. This interstitial fluid pool of the protein may have a role in the propagation of synuclein pathology and progression of Parkinson's disease

Genetic and epidemiological aspects of implantation defects : Studies on recurrent miscarriage, preeclampsia and oocyte donation

Implantation requires complex molecular and cellular events involving coagulation, angiogenesis and immunological processes that need to be well regulated for a pregnancy to establish and progress normally.  The overall aim of this thesis was to study different models associated with atypical angiogenesis, impaired implantation and/or placentation, such as recurrent miscarriage (RM), oocyte donation (OD) and preeclampsia. Histidine-rich glycoprotein (HRG), a serum protein with angiogenic potential has been previously shown to have an impact on implantation and fertility.  In two retrospective case-control studies, women suffering from RM (Study I) and gestational hypertensive disorders (GHD) (Study IV) have been compared to healthy control women, regarding carriership of HRG genotypes (HRG A1042G and C633T SNP, respectively).  According to the findings of this thesis, heterozygous carriers of the HRG A1042G SNP suffer from RM more seldom than homozygous carriers (Study I).  Additionally, the presence of the HRG 633T allele was associated with increased odds of GHD (GHD IV).  Studies II and III comprised a national cohort of relatively young women with optimal health status conceiving singletons with donated oocytes versus autologous oocytes (spontaneously or via IVF).  We explored differences in various obstetric (Study II) and neonatal (Study III) outcomes from the Swedish Medical Birth Register.  Women conceiving with donated oocytes had a higher risk of GHD, induction of labor and cesarean section, as well as postpartum hemorrhage and retained placenta, when compared to autologously conceiving women.  OD infants had higher odds of prematurity and lower birthweight and length when born preterm, compared to neonates from autologous oocytes.  With regard to the indication of OD treatment, higher intervention but neverthelss favourable neonatal outcomes were observed in women with diminished ovarian reserve; the risk of GHD did not differ among OD recipients after adjustment. In conclusion, HRG genetic variation appears to contribute to placental dysfunction disorders.  HRG is potential biomarker that may contribute in the prediction of the individual susceptibility for RM and GHD.  Regarding OD in Sweden, the recipients-despite being of optimal age and health status- need careful preconceptional counselling and closer prenatal monitoring, mainly due to increased prevalence of hypertensive disorders and prematurity

Mode of conception in relation to nausea and vomiting of pregnancy : a nested matched cohort study in Sweden

Nausea and vomiting of pregnancy (NVP) is a common condition reported however inconclusively among pregnancies after assisted conception. The study objective was thus to explore whether NVP is associated to mode of conception or other in vitro fertilization (IVF)-related variables. This nested matched cohort study, originating from the BASIC-project, was conducted at the Uppsala University Hospital in Sweden between 2010 and 2016. IVF pregnancies (n=210) and age and parity-matched women with spontaneous pregnancies (n=420) comprised the study sample. The study outcome was self-reported NVP at gestational week 17. IVF treatment and pregnancy data were obtained after scrutinization of the medical records. NVP with or without medications was not associated with mode of conception (chi-square test, p=0.889), even after adjusting for potential confounders. In a subgroup analysis among IVF pregnancies, NVP without medication was more frequently seen in the group who received cleavage stage embryos vs blastocysts (chi-square test, p=0.019), exhibiting a marginally significant but strongly increased effect even after adjustment [crude RRR 3.82 (95% CI 1.23-11.92) and adjusted RRR 3.42 (95% CI 0.96-12.11)]. No difference in the rate of NVP with or without medication between women that underwent fresh and frozen/thawed embryo transfers as well as IVF or ICSI was observed. Conception through IVF is not associated with NVP. Transfer of a blastocyst may decrease the risk of developing NVP and further, large-scale prospective studies are required to validate this finding

Accelerated fetal growth in early pregnancy and risk of preterm birth : a prospective cohort study

Background Preterm birth (occurring before 37 completed weeks of gestation) affects 15 million infants annually, 7.5% of which die due to related complications. The detection and early diagnosis are therefore paramount in order to prevent the development of prematurity and its consequences. So far, focus has been laid on the association between reduced intrauterine fetal growth during late gestation and prematurity. The aim of the current study was to investigate the association between accelerated fetal growth in early pregnancy and the risk of preterm birth. Methods This prospective cohort study included 69,617 singleton pregnancies without congenital malformations and with available biometric measurements during the first and second trimester. Estimation of fetal growth was based on measurements of biparietal diameter (BPD) at first and second trimester scan. We investigated the association between accelerated fetal growth and preterm birth prior to 37 weeks of gestation. The outcome was further stratified into very preterm birth (before 32 weeks of gestation) or moderate preterm birth (between 32 and 37 weeks of gestation) and medically induced or spontaneous preterm birth and was further explored. Results The odds of prematurity were increased among fetuses with accelerated BPD growth (> 90th centile) estimated between first and second ultrasound scan, even after adjustment for possible confounders (aOR 1.36; 95% CI 1.20–1.54). The findings remained significant what regards moderate preterm births but not very preterm births. Regarding medically induced preterm birth, the odds were found to be elevated in the group of fetuses with accelerated growth in early pregnancy (aOR 1.34; 95% CI 1.11–1.63). On the contrary, fetuses with delayed fetal growth exhibited lower odds for both overall and spontaneous preterm birth. Conclusions Fetuses with accelerated BPD growth in early pregnancy, detected by ultrasound examination during the second trimester, exhibited increased odds of being born preterm. The findings of the current study suggest that fetal growth in early pregnancy should be taken into account when assessing the risk for preterm birth

Early initiation of anti-androgen treatment is associated with increased probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome : a population-based multiregistry cohort study in Sweden

STUDY QUESTION: Is anti-androgen treatment during adolescence associated with an improved probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Early initiation of anti-androgen treatment is associated with an increased probability of childbirth after spontaneous conception among women with PCOS. WHAT IS KNOWN ALREADY: PCOS is the most common endocrinopathy affecting women of reproductive age. Hyperandrogenism and menstrual irregularities associated with PCOS typically emerge in early adolescence. Previous work indicates that diagnosis at an earlier age (<25 years) is associated with higher fecundity compared to a later diagnosis. STUDY DESIGN, SIZE, DURATION: This population-based study utilized five linked Swedish national registries. A total of 15 106 women with PCOS and 73 786 control women were included. Women were followed from when they turned 18 years of age until the end of 2015, leading to a maximum follow-up of 10 years. First childbirth after spontaneous conception was the main outcome, as identified from the Medical Birth Registry. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included all women born between 1987 and 1996 with a diagnosis of PCOS in the Swedish Patient Registry and randomly selected non-PCOS controls (ratio 1:5). Information on anti-androgenic treatment was retrieved from the Swedish Prescribed Drug Registry with the use of Anatomic Therapeutic Chemical (ATC) codes. Women with PCOS who were not treated with any anti-androgenic medication were regarded as normo-androgenic, while those treated were regarded as hyperandrogenic. Women were further classified as being mildly hyperandrogenic if they received anti-androgenic combined oral contraceptive (aaCOC) monotherapy, or severely hyperandrogenic if they received other anti-androgens with or without aaCOCs. Early and late users comprised women with PCOS who started anti-androgenic treatment initiated either during adolescence (<= 18 years of age) or after adolescence (>18 years), respectively. The probability of first childbirth after spontaneous conception was analyzed with the use of Kaplan-Meier hazard curve. The fecundity rate (FR) and 95% confidence interval for the time to first childbirth that were conceived spontaneously were calculated using Cox proportional hazards regression models, with adjustment for obesity, birth year, country of birth and education level. MAIN RESULTS AND THE ROLE OF CHANCE: The probability of childbirth after spontaneous conception in the PCOS group compared to non-PCOS controls was 11% lower among normo-androgenic (adjusted FR 0.68 (95% CI 0.64-0.72)), and 40% lower among hyperandrogenic women with PCOS (adjusted FR 0.53 (95% CI 0.50-0.57)). FR was lowest among severely hyperandrogenic women with PCOS compared to normo-androgenic women with PCOS (adjusted FR 0.60 (95% CI 0.52-0.69)), followed by mildly hyperandrogenic women with PCOS (adjusted FR 0.84 (95% CI 0.77-0.93)). Compared to early anti-androgenic treatment users, late users exhibited a lower probability of childbirth after spontaneous conception (adjusted FR 0.79 (95% CI 0.68-0.92)). LIMITATIONS, REASONS FOR CAUTION: We lacked direct information on the intention to conceive and the androgenic biochemical status of the PCOS participants, applying instead the use of anti-androgenic medications as a proxy of hyperandrogenism. The duration of anti-androgenic treatment utilized is not known, only the age at prescription. Results are not adjusted for BMI, but for obesity diagnosis. The period of follow-up ( 10 years) was restricted by the need to include only those women for whom data were available on the dispensing of medications during adolescence (born between 1987 and 1996). Women with PCOS who did not seek medical assistance might have been incorrectly classified as not having the disease. Such misclassification would lead to an underestimation of the true association between PCOS and outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Early initiation of anti-androgen treatment is associated with better spontaneous fertility rate. These findings support the need for future interventional randomized prospective studies investigating critical windows of anti-androgen treatment

Neonatal outcomes in pregnancies resulting from oocyte donation: a cohort study in Sweden

Background: Pregnancies resulting through oocyte donation have been associated with increased risk for adverse outcomes for the mother, such as gestational hypertensive disorders. However, little is known about possible neonatal complications of such pregnancies. The purpose of this study was to evaluate the neonatal health outcomes among singleton pregnancies in a population of relatively young and healthy oocyte recipients in Sweden, taking into account the medical indication leading to treatment. Methods: This cohort study involved 76 women conceiving with donated oocytes, 149 age-matched nulliparous women conceiving spontaneously and 63 women conceiving after non-donor IVF. Participants were recruited during 2005-2008 and followed up until delivery. Data on neonatal outcomes were retrieved from the National Birth Medical Register and the medical records of oocyte recipients from seven Swedish University Hospitals with IVF clinics. Logistic regression analyses were performed to examine the association of mode of conception and neonatal outcomes, adjusted for maternal age and BMI, gestational age and delivery by cesarean section. Results: Infants conceived through oocyte donation had higher odds for premature delivery [OR 2.36, 95 % CI (1.02-5.45)], for being small for gestational age [OR 4.23, 95 % CI (1.03-17.42)] and having Apgar score below 7 at 5 min [OR 10.57, 95 % CI (1.21-92.20)] compared to spontaneously conceived infants. Similar trends were observed when comparing infants conceived through oocyte donation to those conceived by traditional IVF. Furthermore, donor oocyte infants had a lower mean birthweight and length compared to autologous oocyte neonates (p = 0.013); however no differences were noted among infants born at term. Neonatal outcomes were more favorable among women with diminished ovarian reserve compared to those with other indications for oocyte donation. Conclusions: Infants conceived after oocyte donation in Sweden have higher odds of being born prematurely and having lower mean birthweight in comparison to non-donor infants. It seems that these unfavorable neonatal outcomes are present despite the age, weight and health restrictions applied to recipients before oocyte donation treatment in Sweden.Funding Agencies|Merck Serono; Family Planning Fond in Uppsala; Swedish Research Council for Health, Working Life and Welfare</p

Access to infertility evaluation and treatment in two public fertility clinics and the reasons for withholding it : a prospective survey cohort study of healthcare professionals

Objectives: Study the proportion of patients affected by involuntary childlessness who are denied fertility treatment and the reasons behind this in a publicly funded healthcare system. Design: Survey study using prospectively collected information by healthcare professionals. Setting: Two university-affiliated fertility clinics in Sweden. Participants: Single women and couples in heterosexual and homosexual relationships seeking fertility evaluation and treatment between November 2017 and April 2018 (943 individual cases). Primary and secondary outcome measures: Number and proportion of individuals who were either denied, delayed or granted fertility treatment directly. Furthermore, the reasons behind delaying or completely withholding treatment. Results: The majority of those seeking evaluation were heterosexual couples (75%), while 14% were single women and 7.5% were same-sex couples. The great majority of those undergoing evaluation were granted treatment either directly (85%) or after in-depth evaluation (7.5%), while 7.5% were denied treatment. Among those who were denied treatment, there were a greater proportion of single women and couples seeking treatment with donated gametes. Among heterosexual couples, gamete origin was not associated with treatment refusal. Although age did not differ between those granted and denied treatment, a higher body mass index (in both recipient and partner, when applicable) was observed among those being refused treatment. Fertility specialists in Sweden focused their assessment on parental factors that may indirectly entail a risk of harm to the future child, such as medical and psychiatric conditions of the individuals involved, their financial constraints and other social reasons, substance abuse and female obesity. Conclusion: Being single or receiving treatment with donated gametes can both be reasons for withholding fertility treatment. Although difficult to operationalise, parenting assessment in Sweden is employed interchangeably in treatments with donated gametes (legally mandated assessment) and even autologous gametes (non-legally mandated assessment)-making evident a need for clear official policy guidelines regulating these assessments and the provision of treatment

Attitudes among paediatric healthcare professionals in Sweden towards sperm donation to single women : a survey study

Background: The number of families conceived through sperm donation to single women is increasing. However, there is limited knowledge about health care professionals' attitudes towards solo-mothers by choice, and there is some indication that professionals' personal opinions influence their care of individuals who use alternate ways to build a family. The primary aim of the study was to investigate attitudes towards, and experiences of, families following sperm donation to single women among healthcare professionals working in primary child healthcare. Methods: Between April and November 2016 a total of 712 physicians, registered nurses and psychologists working within primary healthcare in Sweden were invited to participate in a cross-sectional online survey study. The study-specific questionnaire contained the following four domains: Attitudes towards legalization and financing, Attitudes towards the family and the child's health, Clinical experience and Knowledge about sperm donation to single women. Results: The majority of the participants were positive or neutral towards sperm donation being allowed to single women in Sweden. However, one third believed that children risk worse mental health and social stigma. Half of healthcare professionals had own clinical experience of caring for solo-mothers by choice and their children, and of these one third perceived that these families had more need of support than other parents. One out of four indicated that they did not have sufficient knowledge to be able to provide adequate care to these families. Conclusions: The present results indicate that while there was a relatively large support for sperm donation being allowed to single women in Sweden among health care professionals, many expressed concerns about the child's health, as well as low confidence in their knowledge about the specific needs in this patient group. There is a need for educational interventions targeted to healthcare professionals in primary child healthcare in order to provide adequate care to solo-mothers by choice and their children

Perceived social support in solo women seeking treatment with donor gametes and in women in heterosexual couples seeking IVF-treatment with own gametes

Solo motherhood is a family constellation that is becoming increasingly common in high income countries. The demographic characteristics of solo women entering treatment with donated sperm or embryo have been shown to be different from that of cohabiting women. The general importance of perceived social support is frequently amplified when health and quality of life are concerned, and positively affects mental health status, experienced stress, perceived self-efficacy during the transition to parenthood and during parenthood itself. The objective of the present study was to compare demographic characteristics, social network and perceived social support among solo women and cohabiting women awaiting fertility treatment. This objective was explored with a study-specific demographic and background questionnaire as well as through questions on access to practical support and the Multidimensional Scale of Perceived Social Support (MSPSS) assessing different sources of support. This study is a part of a longitudinal prospective multicenter study of solo women who awaited donation treatment in six Swedish public and private fertility clinics and a comparison group of women who were cohabiting/married to male partner and awaited in vitro fertilization (IVF) treatment with the couple’s own gametes. A total of 670 women were invited and 463 accepted participation (69% response rate); 207 solo women (study group) and 256 cohabiting women (comparison group). The results show significant differences in age, education, and employment between the groups. Solo women were on average 3.6 years older, had a higher level of education, a higher-income profession, and were more frequently working full time. Solo women perceived an equally high degree of social support from their families, significantly higher levels of support from friends and significantly lower support from a significant other compared to cohabiting women. Solo women expected their mother to be the most supportive person in future parenthood, while cohabiting women most often stated their cohabiting partner to fill that role. The study adds to the body of knowledge of solo women as a sociodemographic distinct group going at motherhood alone, stating a high degree of currently perceived and expected social support. The previously studied negative impact that lack of a co-parent might have, may be attenuated by the expected and perceived social support from family and friends