Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden.

BACKGROUND: It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT). METHODS: This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated. RESULTS: Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes. CONCLUSIONS: Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations. TRIAL REGISTRATION DETAILS: Not applicable.

Polycystic ovary syndrome and risk of pre-eclampsia: A national register-based cohort study.

OBJECTIVE: To explore whether the association between polycystic ovary syndrome (PCOS) and pre-eclampsia depends on treated clinical hyperandrogenism and whether PCOS is associated with different subtypes of pre-eclampsia. DESIGN: Nationwide register-based cohort study. SETTING: Sweden. POPULATION: Nulliparous women with PCOS (n = 22 947) and non-PCOS controls (n = 115 272) giving singleton birth at ≥22 gestational weeks during 1997-2015. Treated clinical hyperandrogenism was defined as filled prescriptions of anti-androgenic drugs during 2005-2017 (n = 2301 among PCOS women). METHODS: The risk of pre-eclampsia was estimated with conditional logistic regression, expressed as adjusted odds ratio (OR) with 95% confidence interval (CI). Adjustments were performed individually for confounders and predictors. MAIN OUTCOME MEASURES: Overall pre-eclampsia. Early/late (delivery <34/≥34 weeks) pre-eclampsia. Pre-eclampsia with or without a small-for-gestational-age (SGA) infant. RESULTS: Compared with controls, women with PCOS had a 29% increased risk of pre-eclampsia (predictor adjusted OR 1.29, 95% CI 1.20-1.39), with similar risk estimates for PCOS women with and without treated clinical hyperandrogenism. The association between PCOS and early pre-eclampsia seemed stronger than its association with late pre-eclampsia (predictor adjusted OR 1.64 (95% CI 1.33-2.02) and 1.26 (95% CI 1.17-1.37). Additionally, the association seemed slightly stronger between PCOS and pre-eclampsia in women with an SGA infant than without. CONCLUSIONS: Women with PCOS face an increased risk for pre-eclampsia, especially early pre-eclampsia and pre-eclampsia with an SGA infant. We were unable to determine on the basis of available data, whether hyperandrogenism is associated with pre-eclampsia.

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.

Hyperandrogenic Symptoms Are a Persistent Suffering in Midlife Women with PCOS; a Prospective Cohort Study in Sweden.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women, and the majority suffers from hyperandrogenism. Hyperandrogenism causes psychological morbidity and impaired quality of life in women with PCOS during the reproductive years, but data on prevalence and impact during midlife are lacking. Thus, this study aimed to address whether hyperandrogenism persists into midlife and, if so, what impact it has on quality of life. In order to answer this question, we performed a multicenter prospective cohort study, where we included women already diagnosed with PCOS who had reached the age of 45 years or more and age-matched controls. All participants underwent a physical exam, structured medical interview, biochemical testing and filled out self-assessment questionnaires. More than 40% of the women with PCOS and 82% of those who presented with the hyperandrogenic phenotype at the diagnostic work-up still suffered from hirsutism. Circulating testosterone levels were similar between women with PCOS and controls while free androgen index was higher in women with PCOS, independent of weight. Women with hyperandrogenic PCOS expressed persisting concerns regarding hirsutism at the follow-up assessment. In conclusion, women with PCOS who present with hyperandrogenic symptoms at the time they are diagnosed with PCOS have a higher risk of persistent androgenic symptoms and impaired quality of life in midlife.

Higher risk of type 2 diabetes in women with hyperandrogenic polycystic ovary syndrome.

OBJECTIVE: To assess the risk of type 2 diabetes (T2D) in women with polycystic ovary syndrome (PCOS) in relation to body mass index (BMI) and the hyperandrogenic (HA) PCOS phenotype. DESIGN: Population-based cohort study. SETTING: Data from six Swedish national registers, with participants being followed for a maximum of 19 years. PATIENT(S): All women with an International Statistical Classification of Diseases and Related Health Problems, version 10, diagnosis of PCOS, androgen excess, or anovulatory infertility born between 1950 and 1999 (n = 52,535) were identified in the Patient Register. The HA PCOS phenotype was defined by two filled prescriptions for anti-androgenic drugs. For each woman with PCOS, five control women (n = 254,624) were randomly chosen from the Total Population Register, matched for age and geographic area. INTERVENTION(S): No interventions were performed. MAIN OUTCOME MEASURE(S): International Statistical Classification of Diseases and Related Health Problems, version 10, diagnosis of T2D or prescription of antidiabetic treatment other than metformin. RESULT(S): The cumulative incidence rates of T2D were 1.3%, 4.4%, and 14.2% in controls (non-PCOS women) and women with normoandrogenic (NA) and HA PCOS, respectively. After adjustment for BMI, women with PCOS had a twofold higher rate of T2D than non-PCOS women (adjusted hazard ratio, 2.52 [95% confidence interval, 2.15-2.96]). Women with HA PCOS had a higher rate of T2D than those with NA PCOS (adjusted hazard ratio, 3.86 [95% confidence interval, 3.16-4.72]). CONCLUSION(S): Polycystic ovary syndrome is an independent risk factor for T2D, even after adjustment for BMI. Women with the HA PCOS phenotype face an even higher risk of T2D than those with the NA PCOS phenotype.

Pregnancy outcome in women with polycystic ovary syndrome in relation to second-trimester testosterone levels.

RESEARCH QUESTION: Do women with polycystic ovary syndrome (PCOS) have higher testosterone levels during pregnancy and what role does high testosterone play in the development of obstetric complications? DESIGN: Retrospective cohort study from Uppsala University Hospital, Sweden. The study population consisted of women with PCOS (n = 159) and a comparison group of women without PCOS matched for body mass index (n = 320). Plasma testosterone levels were measured in the early second trimester by liquid chromatography with tandem mass spectrometry, and women with PCOS were grouped into tertiles according to their testosterone levels. Possible associations with obstetric complications, maternal metabolic factors and offspring birth weight were explored by multivariable logistic and linear regression models. RESULTS: Compared with women who do not have PCOS, women with PCOS had higher total testosterone (median 1.94, interquartile range [IQR] 1.21-2.64 versus 1.41, IQR 0.89-1.97; P < 0.001), and free androgen index (median 0.25, IQR 0.15-0.36 versus 0.18, IQR 0.11-0.28; P < 0.001). Women with PCOS who had the highest levels of testosterone had increased risk for preeclampsia, even when adjusted for age, parity, country of birth and smoking (adjusted OR 6.16, 95% CI 1.82 to 20.91). No association was found between high testosterone in women with PCOS and other obstetric complications. CONCLUSIONS: Women with PCOS have higher levels of total testosterone and free androgen index during pregnancy than women without PCOS matched for body mass index. Preliminary evidence shows that women with PCOS and the highest maternal testosterone levels in early second trimester had the highest risk of developing preeclampsia. This finding, however, is driven by a limited number of cases and should be interpreted with caution.

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.

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.

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.

Investigating the effect of lifestyle risk factors upon number of aspirated and mature oocytes in in vitro fertilization cycles: Interaction with antral follicle count.

INTRODUCTION: There is evidence demonstrating that certain lifestyle factors have a detrimental effect on fertility. Since such factors often coexist, possible synergistic effects merit further investigation. Thus we aimed to examine the cumulative impact of lifestyle factors on in vitro fertilization (IVF) early reproductive treatment outcomes and their interaction with measures of ovarian reserve. MATERIALS AND METHODS: By following women who were starting their first fresh IVF cycle in 2 cohorts, the "Lifestyle study cohort" (hypothesis generating cohort, n = 242) and the "UppSTART study" (validation cohort, n = 432) in Sweden, we identified two significant risk factors acting independently, smoking and BMI, and then further assessed their cumulative effects. RESULTS: Women with both these risk factors had an Incidence Rate Ratio (IRR) of 0.75 [(95% CI 0.61-0.94)] regarding the number of aspirated oocytes compared to women without these risk factors. Concerning the proportion of mature oocytes in relation to the total number of aspirated oocytes, the interaction between BMI and Antral Follicle Count (AFC) was significant (p-value 0.045): the lower the value of AFC, the more harmful the effect of BMI with the outcome. CONCLUSIONS: Data shows that there is an individual as well as a cumulative effect of smoking and BMI on the number of aspirated and mature oocytes in fresh IVF treatment cycles. AFC might modify associations between BMI and the proportion of mature oocytes in relation to the total number of aspirated oocytes. These results highlight the importance of lifestyle factors on IVF early reproductive outcomes and provide additional evidence for the importance of preconception guidance for the optimization of IVF cycle outcome.

Pregnancy and neonatal complications in women with polycystic ovary syndrome in relation to second-trimester anti-Müllerian hormone levels.

RESEARCH QUESTION: An association has been found between high anti-Müllerian hormone (AMH) levels during pregnancy and the development of polycystic ovary syndrome (PCOS)-like phenotypic traits in mouse offspring. The aim of this study was to determine whether AMH levels are associated with maternal testosterone levels, and whether high AMH concentration influences the risk of developing PCOS-related adverse pregnancy outcomes. DESIGN: Maternal serum AMH, testosterone and sex hormone binding globulin levels were measured in blood samples taken in early second-trimester pregnancies from women with PCOS (n = 159) and healthy controls matched for body mass index (n = 320). Possible associations with preeclampsia, gestational hypertension, gestational diabetes, preterm birth and birthweight was explored by logistic and linear regression models. RESULTS: Women with PCOS had higher AMH, higher total testosterone levels and higher free androgen index than controls (P < 0.001 for all three parameters). Among women with PCOS, high testosterone levels (B = 2.7; ß = 0.26; P = 0.001) and low first trimester body mass index (B = -0.5; ß = -0.17; P = 0.043) remained independently associated with AMH. High AMH levels were associated with decreased risk of gestational hypertension (adjusted OR 0.55; 95% CI 0.34 to 0.87), but no association was found with other adverse pregnancy outcomes or birthweight. CONCLUSIONS: Women with PCOS had higher AMH levels during pregnancy compared with controls, but high AMH was not associated with increased risk of adverse pregnancy outcomes or birthweight.

HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study.

BACKGROUND: Preeclampsia and gestational hypertensive disorders are thought to occur due to endothelial cell dysfunction and abnormal placentation, triggered by angiogenesis-related factors yet undetermined. The aim of this study was to investigate whether a genetic polymorphism (SNP) of Histidine-rich glycoprotein (HRG), HRG C633T SNP, is associated with gestational hypertensive disorders. METHODS: It was performed a nested case-control study from the BASIC Cohort of Uppsala University Hospital comprising 92 women diagnosed with gestational hypertensive disorders without other comorbidities and 200 women with full term uncomplicated pregnancies, all genotyped regarding HRG C633T SNP. RESULTS: The genetic analysis of the study sample showed that C/C genotype was more prevalent among controls. The presence of the T-allele showed a tendency towards an increased risk of gestational hypertensive disorders. After clustering the study participants based on their genotype, it was observed that the odds for gestational hypertensive disorders among heterozygous C/T or homozygous T/T carriers were higher compared to homozygous C/C carriers [OR 1.72, 95% CI (1.04-2.84)]. The association remained significant even after adjustment for maternal age, BMI and parity. CONCLUSIONS: The HRG C633T genotype seems to be associated with gestational hypertensive disorders, and as part of a greater algorithm, might contribute in the future to the prediction of the individual susceptibility to the condition.

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.

Adverse obstetric outcomes in pregnancies resulting from oocyte donation: a retrospective cohort case study in Sweden.

BACKGROUND: Oocyte donation has been associated to gestational diabetes, hypertensive disorders, placental abnormalities, preterm delivery and increased rate of caesarean delivery while simultaneously being characterized by high rates of primiparity, advanced maternal age and multiple gestation constituting the individual risk of mode of conception difficult to assess. This study aims to explore obstetrical outcomes among relatively young women with optimal health status conceiving singletons with donated versus autologous oocytes (via IVF and spontaneously). METHODS: National retrospective cohort case study involving 76 women conceiving with donated oocytes, 150 nulliparous women without infertility conceiving spontaneously and 63 women conceiving after non-donor IVF. Data on obstetric outcomes were retrieved from the National Birth Medical Register and the medical records of oocyte recipients from the treating University Hospitals of Sweden. Demographic and logistic regression analysis were performed to examine the association of mode of conception and obstetric outcomes. RESULTS: Women conceiving with donated oocytes (OD) had a higher risk of hypertensive disorders [adjusted Odds Ratio (aOR) 2.84, 95% CI (1.04-7.81)], oligohydramnios [aOR 12.74, 95% CI (1.24-130.49)], postpartum hemorrhage [aOR 7.11, 95% CI (2.02-24.97)] and retained placenta [aOR 6.71, 95% CI (1.58-28.40)] when compared to women who conceived spontaneously, after adjusting for relevant covariates. Similar trends, though not statistically significant, were noted when comparing OD pregnant women to women who had undergone non-donor IVF. Caesarean delivery [aOR 2.95, 95% CI (1.52-5.71); aOR 5.20, 95% CI (2.21-12.22)] and induction of labor [aOR 3.00, 95% CI (1.39-6.44); aOR 2.80, 95% CI (1.10-7.08)] occurred more frequently in the OD group, compared to the group conceiving spontaneously and through IVF respectively. No differences in gestational length were noted between the groups. With regard to the indication of OD treatment, higher intervention was observed in women with diminished ovarian reserve but the risk for hypertensive disorders did not differ after adjustment. CONCLUSION: The selection process of recipients for medically indicated oocyte donation treatment in Sweden seems to be effective in excluding women with severe comorbidities. Nevertheless, oocyte recipients-despite being relatively young and of optimal health status- need careful counseling preconceptionally and closer monitoring prenatally for the development of hypertensive disorders.

The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study.

BACKGROUND: Histidine-rich glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage. METHODS: The study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP. RESULTS: The results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p<0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p<0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p<0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p<0.05). CONCLUSIONS: Women who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Thyroid function tests at delivery and risk for postpartum depressive symptoms.

Postpartum depression (PPD) is a common childbirth complication, which can have negative effects on both the newly delivered woman and her family. This condition is underdiagnosed and inadequately treated, while a biological diagnostic test is not yet available. Furthermore, postpartum thyroid dysfunction is common among new mothers, and some evidence point to an association between PPD and thyroid function disturbances. The aim of this study was to evaluate the possible association between serum levels of thyroid hormones at the time of delivery, and the later development of depressive symptoms, using data from a population based cohort of Swedish women. Blood samples were collected during delivery from 347 participating women, delivering at Uppsala University Hospital. The participating women filled in at least one of three structured questionnaires, containing the Edinburgh Postnatal Depression Scale (EPDS), at five days, six weeks and six months postpartum. A cut-off of 12 or more was applied on the EPDS, to identify cases of self-reported PPD and controls. Using a binary logistic regression model (adjusting for previous psychiatric contact, smoking during pregnancy, pre-pregnancy body mass index (BMI) and sleep), having a thyroid stimulating hormone (TSH) level over the clinical cut-off level of 4.0 mU/L was associated with increased risk for depressive symptoms at six months postpartum (OR 11.30, 95% CI 1.93-66.11). A ROC analysis revealed that the predictive variable (PV) had significant predictive ability for PPD at 6 months postpartum, given that the AUC was 0.764, and at a PV cut-off value of 6.33, the sensitivity and specificity were 76.2% and 69.4%, respectively. If these findings are replicated in future studies, they can have important clinical implications, since TSH determination is an inexpensive routine blood test, and its inclusion in a biological screening test for PPD involving other parameters would be tempting.

Embryoid bodies from mouse stem cells express oxytocin receptor, Oct-4 and DAZL.

Oxytocin is a nine amino acid peptide involved in a wide spectrum of physiological functions; predominantly those concerning reproduction and differentiation are of interest. Oxytocin receptors are expressed at early developmental stages of mammals, suggesting that oxytocin might be involved in the determination of the germ stem cell line, at the very early stages of mammalian development. In this respect, the proximate aim of the present study was to confirm and further analyze the existence of oxytocin receptors at a very early level of cell commitment, that is, the determination of germ cells derived from embryoid bodies. To achieve our purpose we have cultured mouse embryonic stem cells under conditions inducing formation of embryoid bodies. In this work, ES cells were allowed to aggregate in a novel medium, "Stefanidis medium" from day 0 to day 14 until formed EBs. RNA was isolated from EBs and using RT-PCR we showed that EBs expressed Oct-4, OTR, OT, and DAZL. To demonstrate simultaneous expression immunocytochemistry was preformed, in which EBs showed strong immunoreactivity for both, OTR and DAZL molecular markers. We found that 35% of the cells displayed OTR, using flow cytometry. In addition, this novel medium showed to increase OTR mRNA. We propose, that at least in murine induced embryoid bodies there is simultaneous expression of oxytocin receptors and germ cell markers (DAZL) in many cells (expressing Oct-4). We thus conclude that, the oxytocin might indeed be a molecule playing a leading role in germ cell determination.

Oxytocin receptor- and Oct-4-expressing cells in human amniotic fluid.

BACKGROUND/AIMS: The present clinical and molecular study aimed at investigating the presence of the genes encoding oxytocin receptor (OT-R) and Oct-4 in human amniotic fluid cells. METHODS: Amniotic fluid samples were obtained from amniocentesis. Cells from human amniotic fluid samples were analyzed for mRNA expression of OT-R and Oct-4 via reverse transcription-polymerase chain reaction (RT-PCR). Immunocytochemistry was also performed with OT-R and Oct-4 antibodies. RESULTS: RT-PCR from 10 independent amniocentesis samples demonstrated the expression of OT-R and Oct-4 mRNA. The cells also showed strong immunoreactivity for molecular markers of OT-R and Oct-4. CONCLUSION: OT-R and Oct-4 are expressed in human amniotic fluid cells. The role of oxytocin in the physiology and pathophysiology of amniotic fluid cells remains to be settled.