INTRODUCTION:Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss.MATERIAL AND METHODS:We searched MEDLINE, Embase and the Cochrane Library, and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low-molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with three or more consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors.RESULTS:No significant difference in live birth rate was found when acetylsalicylic acid was compared with low-molecular-weight heparin or with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate [risk ratio (RR) 1.47, 95% CI 0.83-2.61]. Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate (RR 1.18, 95% CI 1.09-1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo (RR 1.07, 95% CI 0.91-1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome (RR 1.8, 95% CI 1.34-2.41), although the studies were small and at high risk of bias.CONCLUSION:The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone starting from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial.

Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss. We searched MEDLINE, Embase and the Cochrane Library, and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low-molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with three or more consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors. No significant difference in live birth rate was found when acetylsalicylic acid was compared with low-molecular-weight heparin or with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate [risk ratio (RR) 1.47, 95% CI 0.83–2.61]. Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate (RR 1.18, 95% CI 1.09–1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo (RR 1.07, 95% CI 0.91–1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome (RR 1.8, 95% CI 1.34–2.41), although the studies were small and at high risk of bias. The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone starting from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial.

The aim of this study was to estimate the incidence of recurrent pregnancy loss (RPL). The prevalence of RPL defined as three or more consecutive miscarriages before gestation week 22, is often stated to be 1%. To our knowledge no study has estimated the incidence of RPL, which might be more informative and clinically relevant than the prevalence.

Background: The immunological environment during pregnancy may differ between allergic and non-allergic women. This study investigates the effect of maternal allergy on the allergen-induced cytokine and chemokine levels and whether pregnancy modulates these immune responses differently in allergic and non-allergic women. Methods: The birch-, cat-, phytohemagglutinin- and tetanus toxoid-induced interferon-gamma(IFN-gamma), interleukin (IL)-4, IL-5, IL-10, IL-13, the T-helper 1 (Th1)-associated chemokine CXCL10 and the Th2-associated chemokine CCL17 levels were quantified in 20 women with allergic symptoms (sensitized, n=13) and 36 women without allergic symptoms (non-sensitized, n=30) at gestational weeks 10-12, 15-16, 25, 35 and 2 and 12months post-partum. Results: Birch-, but not cat-induced, IL-5, IL-13 and CCL17 levels were increased during pregnancy as compared to post-partum in the sensitized women with allergic symptoms. In contrast, cat-, but not birch-induced, IL-5 and IL-13 levels were increased during pregnancy as compared to post-partum in the non-sensitized women without allergic symptoms. Furthermore, IFN-gamma secretion was increased in the first and decreased in the second and third trimesters in response to birch and decreased in the third trimester in response to cat as compared to post-partum in the non-sensitized women without allergic symptoms. Increased allergen-induced IL-4, IL-5 and IL-13 levels were associated with allergic symptoms and sensitization. Conclusions: Pregnancy had a clear effect on the allergen-induced IL-5, IL-13, CCL17, IFN-gamma and CXCL10 production, with distinct enhanced Th2-responses to birch in the allergic group and to cat in the non-allergic group.

The aim of this study was to estimate the incidence of recurrent pregnancy loss (RPL). The prevalence of RPL defined as three or more consecutive miscarriages before gestation week 22, is often stated to be 1%. To our knowledge no study has estimated the incidence of RPL, which might be more informative and clinically relevant than the prevalence. This retrospective register-based study was conducted from 2003 until 2012 in Sweden with data provided by the Swedish National Board of Health and Welfare. In all, 6852 women were registered with the diagnoses of RPL in the National Patient Register. The incidence of RPL is the number of new women receiving the RPL diagnosis per year in the numerator and population at risk in the denominator. For each year, from 2003 to 2012, the incidence was calculated in two different risk populations: [1] all women aged 18–42 years, and [2] all women registered as being pregnant (deliveries or miscarriages). The average incidence in the study period was 53 per 100 000 (0.05%) in women aged 18–42 years and 650 per 100 000 (0.65%) in women who had achieved pregnancy in the period. The incidence of RPL in the two risk populations increased by 74 and 58%, respectively, during the study period. This study suggests that the incidence of RPL increased during the 10-year period studied. Causes can only be speculated upon in this study design, but might be associated with environmental changes, as the increase was fairly rapid.

Sjögren’s syndrome (SS) is an autoimmune disease characterized by lymphoplasmacytoid focal adenitis leading to mucosal dryness, with 9:1 female dominance and peak incidence at menopause. Due to autoimmune adenitis it can be speculated that the normal epithelial cell renewal has failed, possibly as a result of local intracrine failure to process dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). Local intracrine/-cellular DHT deficiency seems to predispose to SS if estrogens are low, in menopausal women and in men. This intracrine failure could be the initial noxious stimulus, factor X, initiating the development of SS. Abnormal release and presentation of exocrine gland-derived antigens (Ag-epitopes), in a complex with major histocompatibility complex class II (MHC II), by migratory dendritic cells (DC) activates T-cells in the regional lymph nodes. B-cells with the same specificity capture and present self-Ag to Th-cells which provide T-cell help. B-cells transform to plasma cells and start to produce autoantibodies (Ab) against these T-cell-dependent Ag. Ab against SS-A/Ro and SS-B/La ribonucleoproteins occur only in HLA-DQw2.1/DQw6 heterozygous individuals, but hY-RNA and RNA polymerase III transcripts in these Ag may in all SS patients stimulate toll-like receptors (TLR) 7 and 9 of the plasmacytoid DCs, because IFN-α and IFN-signature are produced. CD8 + αEβ7 + cytotoxic T-cells activated via cross-presentation recirculate to attack intracrine-deficient, apoptotic epithelial cells expressing self-Ag on their surface. Exocrine glands fall into the sphere of mucosal/gut-associated lymphatic tissue. This together with immune complexes spreads the immunological memory/aggression to extra-glandular sites explaining the systemic nature of the syndrome. Secondary SS could be explained by disturbed lymphocyte recirculation. There is no conclusive evidence that SS in those few men affected is more severe than in women, suggesting that sex steroid endo-/intracrinology has its major impact on the target tissue, not on immune modulation.This article is part of a Special Issue entitled ‘Essential role of DHEA’.

PROBLEM:A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia.OBJECTIVE:Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia.METHOD OF STUDY:Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls.RESULTS:No differences were found in major Treg populations including CD127(low) CD25(+) /CD127(ow) FOXP3(+) , resting (FOXP3(dim) CD45RA(+) ), and activated (FOXP3(bright) CD45RA(-) ) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations.CONCLUSIONS:Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.

BACKGROUND:The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children.METHODS:The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2-associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10-12, 15-16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 years of age. Total IgE levels were measured using ImmunoCAP Technology.RESULTS:The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pregnancy (irrespectively of maternal allergy status) as compared to post-partum. In the whole group, the Th1-like chemokine levels were higher at gw 39 than during the first and second trimester and post-partum. Maternal CXCL11, CCL18 and CCL22 levels during and after pregnancy correlated with the corresponding chemokines in the offspring during childhood. Increased CCL22 and decreased CXCL10 levels in the children were associated with sensitisation and increased CCL17 levels with allergic symptoms during childhood. Maternal chemokine levels were not associated with maternal allergic disease.CONCLUSIONS:Allergic symptoms and sensitisation were associated with decreased Th1- and increased Th2-associated chemokine levels during childhood, indicating a Th2 shift in the allergic children, possibly influenced by the maternal immunity during pregnancy.

Background: The influence of maternal allergy on the development of immune responses and allergy in the offspring is not understood.Objective: To investigate (i) if maternal allergy influences the ...

ProblemHow maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.Method of studyExpression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non‐allergic women and their offspring.ResultsPlacental gene expression was dominated by a Th2‐/anti‐inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = −0.88, P < 0.001) and IL‐5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2‐associated CCL22 in CBMC preceded allergy development.ConclusionsGene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

American Journal of Reproductive ImmunologyVolume 68, Issue 3 p. 187-188 Letter to the Editor Reply to Do dose-related mechanisms exist for the angiogenic behaviours of heparin derivatives?, Yavuc C, Karahan O. In Am J Reprod Immunol 2012 Leif Matthiesen, Corresponding Author Leif Matthiesen University of Linkoping, Linkoping, Sweden Correspondence Leif Matthiesen Department Obstetrics and Gynecology, Helsingborg Hospital, 251 87 Helsingborg E-mail: leif.matthiesen@skane.seSearch for more papers by this author Leif Matthiesen, Corresponding Author Leif Matthiesen University of Linkoping, Linkoping, Sweden Correspondence Leif Matthiesen Department Obstetrics and Gynecology, Helsingborg Hospital, 251 87 Helsingborg E-mail: leif.matthiesen@skane.seSearch for more papers by this author First published: 22 June 2012 https://doi.org/10.1111/j.1600-0897.2012.01168.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume68, Issue3September 2012Pages 187-188 RelatedInformation

Tumor-associated M2 macrophages (TAMs) produce chemokines that affect the formation of cutaneous T-cell lymphoma (CTCL) by stromal factors. Since IFNs are an effective treatment for advanced-stage mycosis fungoides (MF), we hypothesized that IFNs might modulate M2 macrophages.To prove our hypothesis, we stimulated monocyte-derived M2 macrophages with IFN-α2a or IFN-γ and examined the mRNA expression of chemokines.By using a microarray, we selected a series of chemokines and MMPs that were strongly connected with the IL-4 stimulation. Then, we investigated the effects of IFN-α2a and IFN-γ on these chemokines.IFN-α2a and IFN-γ decreased the expression and production of CCL17 and CCL18 and increased those of CXCL10 and CXCL11. Moreover, the subcutaneous administration of IFN-α2a increased the CXCL11-producing cells in the lesional skin of patients with advanced MF.Our data suggest one possible mechanism of the therapeutic effects of IFNs through TAMs for the treatment of advanced-stage MF.

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.

Recurrent spontaneous abortion ( RSA ), three or more pregnancy losses prior to 20 weeks, occurs in about 1% of all pregnancies, 50% of RSA cases remain unexplained and unresolved. Recently, immune pathways have been implicated in the pathophysiology of RSA . Immune tolerance of the fetal–placental unit and placental angiogenesis are mandatory for a successful pregnancy outcome. Unscheduled dysregulation of the placental vasculature is thought to be the pathophysiologic mechanisms underlying an array of pregnancy complications like infertility, miscarriage, pre‐eclampsia, and fetal growth restriction and death. Investigations on mechanisms and management of RSA are mired by substandard design and lack of optimal randomized clinical trials and have resulted in disagreement on guidelines for evaluation and treatments for patients with multiple pregnancy losses of unknown etiology. The present review focuses on evidence‐based research discussion with immunologic causes, and immune‐regulatory therapies recommended for helping patients with a history of RSA . We highlight data that might support revalidation of low molecular weight heparin as a protective therapy in RSA . Newly launched growth factors, GM ‐ CSF , and potentially novel agents to suppress inflammatory rejection, including regulatory T cells, human chorionic gonadotropin, and M‐ CSF / IL ‐10, may work in concert with tender‐loving‐care therapy and give hope to couples with multiple pregnancy losses.

PROBLEM:Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown.METHOD OF STUDY:About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed.RESULTS:Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results.CONCLUSIONS:Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.