Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function.

During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1-5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1-5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8(+), and gammadelta T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.

Experiences of working with induced abortion: focus group discussions with gynaecologists and midwives/nurses.

BACKGROUND: While there exists an extensive amount of research regarding the medical aspects of abortion, there is a great lack of studies investigating staff's views and experiences of working in abortion services. AIMS: To elucidate gynaecologists' and midwives'/nurses' experiences, perceptions and interactions working in abortion services, their experiences of medical abortions and abortions performed at the woman's home. An additional aim was to illustrate gynaecologists', midwives' and nurses' visions of their future professional roles within the abortion services. METHOD: Three focus group discussions within each profession were carried out in 1-hour sessions with a total of 25 gynaecologists and 15 midwives/nurses from three different hospitals. RESULTS: The content analysis reflected that gynaecologists and midwives/nurses had no doubts about participating in abortions despite the fact that they had experienced complex and difficult situations, such as repeat and late-term abortions. They experienced their work as paradoxical and frustrating but also as challenging and rewarding. However, they were rarely offered ongoing guidance and continuously professional development education. For gynaecologists, as well as midwives/nurses, their experiences and perceptions were strongly linked to the concurrent development of abortion methods. The interaction between the professions was found to be based on great trust in each other's skills. CONCLUSIONS: In order to promote women's health, gynaecologists' and midwives'/nurses' need for a forum for reflection and ongoing guidance should be acted on. With a higher number of abortions done medically and a higher proportion of home abortions, midwives/nurses will get increased, responsibilities in the abortion services in the future.

IGF-I during primiparous pregnancy and maternal risk of breast cancer.

Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer.

Maternal hormones during early pregnancy: a cross-sectional study.

BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

Adolescent pregnancies and girls' sexual and reproductive rights in the amazon basin of Ecuador: an analysis of providers' and policy makers' discourses.

BACKGROUND: Adolescent pregnancies are a common phenomenon that can have both positive and negative consequences. The rights framework allows us to explore adolescent pregnancies not just as isolated events, but in relation to girls' sexual and reproductive freedom and their entitlement to a system of health protection that includes both health services and the so called social determinants of health. The aim of this study was to explore policy makers' and service providers' discourses concerning adolescent pregnancies, and discuss the consequences that those discourses have for the exercise of girls' sexual and reproductive rights' in the province of Orellana, located in the amazon basin of Ecuador. METHODS: We held six focus-group discussions and eleven in-depth interviews with 41 Orellana's service providers and policy makers. Interviews were transcribed and analyzed using discourse analysis, specifically looking for interpretative repertoires. RESULTS: Four interpretative repertoires emerged from the interviews. The first repertoire identified was "sex is not for fun" and reflected a moralistic construction of girls' sexual and reproductive health that emphasized abstinence, and sent contradictory messages regarding contraceptive use. The second repertoire -"gendered sexuality and parenthood"-constructed women as sexually uninterested and responsible mothers, while men were constructed as sexually driven and unreliable. The third repertoire was "professionalizing adolescent pregnancies" and lead to patronizing attitudes towards adolescents and disregard of the importance of non-medical expertise. The final repertoire -"idealization of traditional family"-constructed family as the proper space for the raising of adolescents while at the same time acknowledging that sexual abuse and violence within families was common. CONCLUSIONS: Providers' and policy makers' repertoires determined the areas that the array of sexual and reproductive health services should include, leaving out the ones more prone to cause conflict and opposition, such as gender equality, abortion provision and welfare services for pregnant adolescents. Moralistic attitudes and sexism were present - even if divergences were also found-, limiting services' capability to promote girls' sexual and reproductive health and rights.

Home abortion - experiences of male involvement.

OBJECTIVE: To gain knowledge about the male partner's experience of being present during an induced home abortion. METHODS: Twenty-three couples, whose male partner had been present when the woman aborted at home, were interviewed one to two weeks post-abortion. RESULTS: Each of the men supported his partner in her decision to have a home abortion, as this gave him the possibility of being near and of caring for her needs on the expulsion day. All the men were present and all their partners confirmed that they had been supportive. Half the men had been anxious prior to the expulsion, but most considered that their experiences during the expulsion had been 'easier than expected' and their dominant feeling was one of relief. CONCLUSIONS: Abortion is an important life event. When taking place at home, it increases the possibility for the couple to share the experience. Sharing an abortion may have a positive impact on those men who lack a sense of responsibility regarding reproductive issues, such as contraceptive use. This could facilitate society's efforts to involve men as a target group in this field. Designing an abortion policy that caters for the needs of both partners is a challenge.

C-reactive protein and ovarian cancer: a prospective study nested in three cohorts (Sweden, USA, Italy).

OBJECTIVES: Inflammatory processes may influence the risk of epithelial ovarian cancer, but available epidemiological evidence is limited and indirect. Circulating C-reactive protein (CRP), a sensitive marker of inflammation, may serve as a direct biological marker of an underlying association. METHODS: The association between ovarian cancer risk and pre-diagnostic circulating CRP was tested in a case-control study nested within three prospective cohorts from Sweden, USA, and Italy. The study included 237 cases and 427 individually matched controls. CRP was measured in stored blood samples by high-sensitivity immunoturbidimetric assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression. RESULTS: Overall, CRP was not related to risk of ovarian cancer. However, a marked increase in risk was observed for CRP concentrations >10 mg/l: OR (95% CI) 4.4 (1.8-10.9), which remained significant after limiting analyses to cases diagnosed more than two or five years after blood donation (OR 3.0 (1.2-8.0) and 3.6 (1.0-13.2), respectively). Risk of mucinous tumors increased with high CRP, but the number of cases in this analysis was small. CONCLUSION: Study results offer additional support to the concept that chronic inflammation plays a role in epithelial ovarian cancer.

Home abortion implies radical changes for women.

OBJECTIVE: To gain knowledge about women's experiences, views and reactions regarding having a home abortion (medical abortion with the use of misoprostol at home). METHODS: One hundred women were interviewed one week post-abortion; this yielded both quantitative and qualitative data. RESULTS: The overwhelming majority of the women experienced wellbeing and were satisfied with their choice of abortion method. They appreciated the privacy and the comfort of being at home which also allowed the presence of a partner. The intake of mifepristone at the clinic was described by many in existential terms as an emotionally charged act, experienced by some as more difficult than expulsion at home. However, relief was the predominant emotional feeling during the expulsion day. Most women did not find it especially dramatic to see and handle the products of conception although some felt uncomfortable at the sight. CONCLUSION: Given that they choose this method themselves and are well informed, women are able to handle the abortion process by themselves outside a clinical setting. The option to choose home abortion implies a radical change in empowerment for women. Also allowing them the possibility to take mifepristone at home would increase their privacy and personal integrity even more.

Human chorionic gonadotropin and alpha-fetoprotein concentrations in pregnancy and maternal risk of breast cancer: a nested case-control study.

Pregnancy hormones are believed to be involved in the protection against breast cancer conferred by pregnancy. The authors explored the association of maternal breast cancer with human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP). In 2001, a case-control study was nested within the Northern Sweden Maternity Cohort, an ongoing study in which blood samples have been collected from first-trimester pregnant women since 1975. Cases (n = 210) and controls (n = 357) were matched for age, parity, and date of blood donation. Concentrations of hCG and AFP were measured by immunoassay. No overall significant association of breast cancer with either hCG or AFP was observed. However, women with hCG levels in the top tertile tended to be at lower risk of breast cancer than women with hCG levels in the lowest tertile in the whole study population and in subgroups of age at sampling, parity, and age at cancer diagnosis. A borderline-significant decrease in risk with high hCG levels was observed in women who developed breast cancer after the median lag time to cancer diagnosis (> or =14 years; odds ratio = 0.53, 95% confidence interval: 0.27, 1.03; P = 0.06). These findings, though very preliminary, are consistent with a possible long-term protective association of breast cancer risk with elevated levels of circulating hCG in the early stages of pregnancy.

Cesarean by choice? Empirical study of public attitudes.

OBJECTIVE: This study examines public attitudes towards maternal requests for cesarean delivery and its association with health care and birth experiences. In addition, this study attempts to ascertain whether gender, age and residence influence these attitudes. DESIGN: Cross-sectional population survey with a postal questionnaire. SETTING: The counties of Stockholm and Vasterbotten in Sweden. POPULATION: Equal numbers of women and men between 20 and 80 years of age (n=2,000) by population size and gender distribution. METHODS: Descriptive statistics and content analysis. RESULTS: Of the 1,066 women (53%) who responded, two-thirds stated that a cesarean should be decided on for medical reasons and by a doctor. One-third considered that a woman, without persuasion, should decide herself about mode of delivery and should be free to choose a cesarean. These respondents used arguments such as women's rights, bodily integrity and childbirth fear. The results were associated with low trust in health care, women being young or middle aged, urban living and having no children. Low trust in health care was associated with experiences of insecurity, vulnerability and perceived maltreatment. CONCLUSION: Public norms towards women's own decision making on mode of delivery are associated with younger age, lower trust in health care and urban living. Antenatal care will encounter more parents asking for a cesarean and demanding that health professionals provide an ethically appropriate informed consent process. Considering the risk of violating young women's trust if not respecting her wish, it seems reasonable that making decisions whether or not to perform a cesarean is part of shared decision making.

Women's reproductive rights in the Amazon basin of Ecuador: challenges for transforming policy into practice.

Despite advances made by Ecuador in developing policies on reproductive and sexual rights, implementation, and oversight remain a challenge, affecting in particular those living in the Amazon basin. This paper reports on an evaluation of sexual and reproductive health and rights (SRHR) in Orellana, Ecuador, the basis of which was the Health Rights of Women Assessment Instrument, which was altered to focus on government obligations, the reality of access and utilization of services, and the inequities and implementation challenges between the two. A community-based cross-sectional survey conducted in 2006 served to document the current status of SRHR Local female field workers interviewed 2025 women on three areas of womens reproductive health: delivery care, family planning, and pregnancy among adolescent girls age 10-19. The results suggest a reality more dismal than that of the official information for the area. Skilled delivery care, modern contraceptive use, and wanted pregnancies were conspicuously lower among indigenous women living in rural areas. Access to reproductive health services varied between rural and urban women. These significant differences in care--amongst others documented--raise concerns over the utility of national-level data for addressing inequities. The gaps evident in the validity of available information for monitoring policies and programs, and between national policy and action reveal that much still needs to be done to realize SRHR for women in the Amazon basin, and that current accountability mechanisms are inadequate.

Midwives' experiences of encountering women seeking an abortion.

In order to gain knowledge about midwives' clinical and emotional experiences of working with termination of pregnancy (TOP) and their perception of women's motives for having an abortion questionnaires were mailed to a representative sample of Swedish midwives (n = 258), and 84% responded. Responses to 17 statements were studied and interpreted. It was found that every third midwife had not at all worked with TOP, and every fifth had not done so in the preceding two years. Among those who had experienced this work, few midwives had considered changing their job or had had misgivings or feelings of inadequacy caused by encountering women seeking an abortion. Both working currently with TOP and for a longer period of time were found to evoke positive experiences in every other midwife. Midwives' perception of motives for abortion corresponded very well to motives provided by women themselves. Half the midwives had had misgivings concerning late abortions and somewhat fewer regarding surgical abortions. In general, religious belief did not influence midwives' views of TOP. Those midwives who had themselves had an abortion reported fewer misgivings about late abortions than those without personal experience of TOP.

Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial.

CONTEXT: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. DESIGN: This was an explorative randomized, double-blind, placebo-controlled study. SETTING: Swedish multicentre study with 10 centers. PARTICIPANTS: Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott's algorithm. INTERVENTION: Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. OUTCOME MEASURES: The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). RESULTS: 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. CONCLUSIONS: This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.

Insulin-like growth factor I in pregnancy and maternal risk of breast cancer.

BACKGROUND: The role of insulin-like growth factor (IGF)-I in breast cancer remains controversial, despite numerous reports on the association of the hormone with breast cancer or high-risk mammographic densities. We hypothesized that exposure to elevated IGF-I during early pregnancy, a period characterized by intense cell proliferation in the breasts and in the presence of high concentrations of sex steroids, will be associated with increased maternal risk to develop a breast malignancy. METHODS: The Northern Sweden Maternity Cohort is an ongoing prospective study, collecting blood samples from first-trimester-pregnant women since 1975 as part of screening for infectious diseases. A case-control study (212 cases and 369 controls) was nested among Northern Sweden Maternity Cohort members who delivered singleton babies. RIA was used to measure IGF-I and IGF-II levels. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Breast cancer risk increased with increasing IGF-I (top tertile OR, 1.7; 95% CI, 1.1-2.7). The association was stronger among the primiparous (OR, 2.2; 95% CI, 1.1-4.4) than in the nonprimiparous women (OR, 1.4; 95% CI, 0.7-2.8). Upper-tertile risks seemed to decrease within the <28-, 28 to 33, and >33-year groups of age at sampling, from 2.5 (0.9-7.6) to 2.1 (0.9-5.0) and 1.2 (0.5-2.5), respectively. There was no association of breast cancer with first-trimester-pregnancy IGF-II. CONCLUSIONS: The study offers further evidence that IGF-I is important in breast cancer. Our findings suggest that the adverse effect of IGF-I on the breast may be stronger before the remodeling of the gland induced by a first pregnancy.

Environmental odor intolerance in pregnant women.

Previous findings indicating that pregnant women experience a shift in odor sensitivity and hedonics raise the question of whether these changes evoke adverse reactions to odorous and pungent environmental substances in daily activities, to a larger extent in pregnant than in nonpregnant women. Forty-four women in pregnancy weeks 21-23 and 44 nonpregnant women were therefore compared with respect to affective reactions to and behavioral disruptions by odorous/pungent daily environments by means of the questionnaire-based, 21-item Chemical Sensitivity Scale (CSS). This scale refers to neurasthenic and sensory/somatic symptoms and includes the 11 items of the Chemical Sensitivity Scale for Sensory Hyperreactivity (CSS-SHR). This latter scale refers predominantly to sensory/somatic symptoms. To investigate whether there is a general environmental hypersensitivity during pregnancy, the Noise Sensitivity Scale (NSS) was used that is analogous to the CSS (including 11 NSS items corresponding to those of the CSS-SHR; "NSS-SHR"). Results show that the two groups were similar with respect to scores on both the CSS and NSS, whereas the pregnant women had higher scores than the nonpregnant women on the CSS-SHR, but not on the "NSS-SHR". These results suggest that pregnant women to a larger extent than nonpregnant women manifest an odor intolerance that affects their daily activities, with predominantly sensory/somatic symptoms, which appears not to be due to a general environmental hypersensitivity. This behavior may have embryo- and maternal-protective functions.

Olfactory and chemosomatosensory function in pregnant women assessed with event-related potentials.

The purpose of the study was to better understand past findings of nasal chemosensory hypersensitivity in pregnant women by recording chemosensory event-related potentials (CSERPs) for information about cortical neuronal allocation (amplitudes) and temporal processing (latencies) of three concentrations of pyridine ranging from predominantly olfactory to trigeminal in activation in 15 pregnant and 15 non-pregnant women. CSERP components of primarily sensory (N1 and P2) and cognitive (P3) origin were evaluated. The results displayed no group differences in either N1 or P2 amplitudes or latencies, but tendencies of larger amplitudes and shorter latencies for P3 in pregnant women. This implies that pregnant women's hypersensitivity may more likely be referred to cognitive than sensory processing.

Implications of antenatal depression and anxiety for obstetric outcome.

OBJECTIVE: To investigate the obstetric outcome and health care consumption during pregnancy, delivery, and the early postpartum period in an unselected population-based sample of pregnant women diagnosed with antenatal depressive and/or anxiety disorders, compared with healthy subjects. METHODS: Participants were 1,495 women attending 2 obstetric clinics in Northern Sweden. The Primary Care Evaluation of Mental Disorders was used to evaluate depressive and anxiety disorders in the second trimester of pregnancy. To assess demographic characteristics, obstetric outcome, and complications, the medical records of the included women were reviewed. RESULTS: Significant associations were found between depression and/or anxiety and increased nausea and vomiting, prolonged sick leave during pregnancy and increased number of visits to the obstetrician, specifically, visits related to fear of childbirth and those related to contractions. Planned cesarean delivery and epidural analgesia during labor were also significantly more common in women with antenatal depression and/or anxiety. CONCLUSION: There is an association between antenatal depressive and/or anxiety disorders and increased health care use (including cesarean deliveries) during pregnancy and delivery.

Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer.

Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.