Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses.

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.

Pregnancy modulates the allergen-induced cytokine production differently in allergic and non-allergic women.

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-γ (IFN-γ), 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 12 months 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-γ 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-γ and CXCL10 production, with distinct enhanced Th2-responses to birch in the allergic group and to cat in the non-allergic group.

Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden.

INTRODUCTION: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia.

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.

The placental immune milieu is characterized by a Th2- and anti-inflammatory transcription profile, regardless of maternal allergy, and associates with neonatal immunity.

PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear. METHOD OF STUDY: Expression 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. RESULTS: Placental 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. CONCLUSIONS: Gene 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.

Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy.

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.

Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women.

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.

Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia.

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.

Multiple pregnancy failures: an immunological paradigm.

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.

High cord blood levels of the T-helper 2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of life.

Exposure to a strong T-helper 2 (Th2)-like environment during fetal development may promote allergy development. Increased cord blood (CB) levels of the Th2-associated chemokine CCL22 were associated with allergy development during the first 2 y of life. The aim of the present study was to determine whether CB Th1- and Th2-associated chemokine levels are associated with allergy development during the first 6 y of life, allowing assessment of respiratory allergic symptoms usually developing in this period. The CB levels of cytokines, chemokines, and total IgE were determined in 56 children of 20 women with allergic symptoms and 36 women without allergic symptoms. Total IgE and allergen-specific IgE antibody levels were quantified at 6, 12, 24 mo, and 6 y of age. Increased CB CCL22 levels were associated with development of allergic sensitization and asthma and increased CCL17 levels with development of allergic symptoms, including asthma. Sensitized children with allergic symptoms showed higher CB CCL17 and CCL22 levels and higher ratios between these Th2-associated chemokines and the Th1-associated chemokine CXCL10 than nonsensitized children without allergic symptoms. A pronounced Th2 deviation at birth, reflected by increased CB CCL17 and CCL22 levels, and increased CCL22/CXCL10 and CCL17/CXCL10 ratios might promote allergy development later in life.

Association between 5 min Apgar scores and planned mode of delivery in diabetic pregnancies.

OBJECTIVE: Due to the high incidence of neonatal complications in diabetic pregnancies, the aim of our study was to investigate whether elective cesarean section could prevent adverse neonatal outcome. DESIGN: Population-based study. SETTING: Data were extracted from the Swedish Medical Birth Registry. POPULATION: All women (n=13 491) with diabetic pregnancies during the period 1990-2007. METHODS: Neonatal outcome in diabetic pregnancies was compared after elective cesarean section at 38 completed gestational weeks with planned vaginal delivery at 39 completed weeks of gestation or later. Odds ratios with 95% confidence intervals for Apgar scores <7 at 5 min after birth were calculated using multiple logistic regression. MAIN OUTCOME MEASURES: Apgar score <7 at 5 min after birth. RESULTS: A significantly decreased risk of Apgar score <7 at 5 min after birth in the group who underwent an elective cesarean section at 38 completed gestational weeks was found compared with those who continued pregnancy to 39 completed weeks of gestation or more, irrespective of final mode of delivery. CONCLUSIONS: Our results indicate a protective effect of planned cesarean section on the risk of low Apgar scores in diabetic pregnancies.

Sera from preeclampsia patients elicit symptoms of human disease in mice and provide a basis for an in vitro predictive assay.

Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10-/- mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fms-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

Haplotype-dependent differential activation of the human IL-10 gene promoter in macrophages and trophoblasts: implications for placental IL-10 deficiency and pregnancy complications.

PROBLEM: polymorphic changes in the IL-10 gene promoter have been identified that lead to altered IL-10 production. We hypothesized that because of these genotypic changes, the IL-10 promoter might be expressed in a cell type-specific manner and may respond differentially to inflammatory triggers. METHOD OF STUDY: we created reporter gene promoter constructs containing GCC, ACC, and ATA haplotypes using DNA from patients harboring polymorphic changes at -1082 (G→A), -819 (C→T), and -592 (C→A) sites in the IL-10 promoter. These individual luciferase reporter constructs were transiently transfected into either primary term trophoblasts or THP1 monocytic cells. DNA-binding studies were performed to implicate the role of the Sp1 transcription factor in response to differential promoter activity. RESULTS: our results suggest that the GCC promoter construct was activated in trophoblast cells in response to lipopolysaccharide (LPS), as demonstrated by reporter gene expression, but not in monocytic cells. The ACC construct showed weaker activation in both cell types. Importantly, while the ATA promoter was constitutively activated in both cell types, its expression was selectively repressed in response to LPS, but only in trophoblasts. DNA-nuclear protein binding assays with nuclear extracts from LPS treated or untreated cells suggested a functional relevance for Sp1 binding differences at the -592 position. CONCLUSIONS: these results demonstrate cell type-specific effects of the genotypic changes in the IL-10 gene promoter. These responses may be further modulated by bacterial infections or other inflammatory conditions to suppress IL-10 production in human trophoblasts.

Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol.

CD4(+)CD25(high) regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17beta-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4(dim)CD25(high) Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4(+) population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17beta-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4(dim)CD25(high)Foxp3(+) cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4(+)CD25(-) responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-alpha, and IFN-gamma secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

Total and allergen-specific IgE levels during and after pregnancy in relation to maternal allergy.

Type 2 T-helper cell (Th2)-skewed immunity is associated with successful pregnancy and the ability to easily direct immune responses to a Th2-polarised profile may be an evolutionary benefit. The Th2-like immunity associated with allergic disease might generate favourable effects for the maintenance of pregnancy, but could also promote development of Th2-like immune responses and allergic disease in the offspring. The aim of this study was to explore, by using IgE as a stable proxy for Th2, the Th1/Th2 balance in allergic and non-allergic women by measuring allergen-specific and total IgE antibody levels in plasma during pregnancy and after delivery. Specific and total IgE antibody levels were determined by ImmunoCAP technology at five occasions during pregnancy (gestational weeks 10-12, 15-16, 25, 35 and 39), as well as at 2 and 12 months after delivery. Thirty-six women without and 20 women with allergic symptoms were included, of whom 13 were sensitised with allergic symptoms and 30 were non-sensitised without allergic symptoms. The levels of total IgE, but not allergen-specific IgE, were increased during early pregnancy when compared to 12 months after delivery in the sensitised women with allergic symptoms, but not in the non-sensitised women without allergic symptoms (p<0.01). This increase in total IgE levels during early pregnancy only in the sensitised women with allergic symptoms indicates that allergy is associated with an enhanced Th2 deviation during pregnancy.

Cord blood cytokines and chemokines and development of allergic disease.

Exposure to ubiquitous allergens early in life, even before birth, may influence the incidence of allergic diseases later in life. During pregnancy, the fetomaternal interface is surrounded by high levels of T-helper (Th)2-like cytokines, possibly favouring the development of Th2-like immune responses in the offspring. The aim of this study was to evaluate the relation between cord blood (CB) IgE antibodies, Th1- and Th2-like cytokines and chemokines, maternal allergy and development of allergic disease during the first 2 yr of life in the offspring. The CB cytokine and chemokine levels from children of 20 allergic and 36 non-allergic women were determined by a multiplexed Luminex assay and ELISA. Total CB and maternal IgE antibody concentrations were quantified using ImmunoCAP technology. The maternal IgE levels during and after pregnancy correlated with CB IgE and Th2-associated macrophage-derived chemokine [MDC (CCL22)] levels. Development of allergic disease and sensitization was associated with increased CB IgE and MDC (CCL22) levels, as well as high ratios of MDC (CCL22) to Th1-associated interferon-gamma inducible protein 10 [IP-10 (CXCL10)] and interferon-gamma inducible T-cell alpha-chemoattractant [I-TAC (CXCL11) (n = 7 allergic vs. n = 25 non-allergic)]. The correlations between maternal IgE and CB IgE and MDC (CCL22) levels possibly indicate that the maternal immunity can affect the Th1/Th2 profile in the neonate. Development of allergic disease is associated with a more marked Th2-like deviation already at birth, shown as increased levels of CB IgE and MDC (CCL22) and higher ratios of MDC (CCL22) to IP-10 (CXCL10) and I-TAC (CXCL11).

Increased circulating paternal antigen-specific IFN-gamma- and IL-4-secreting cells during pregnancy in allergic and non-allergic women.

INTRODUCTION: Allergic women have been reported to give birth to more children than non-allergic women, speculatively explained by the former's predisposition for Th2 polarization, possibly favoring pregnancy. AIM: The aim of this study was to test the hypothesis that allergy is associated with more Th2-deviated responses to paternal antigens throughout pregnancy. METHODS: Blood samples were collected on six occasions during pregnancy and two occasions postpartum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Eleven women fulfilled the strict criteria for allergy (allergic symptoms and circulating IgE antibodies to inhalant allergens) and 23 were strictly non-allergic (non-sensitized without symptoms). The numbers of blood mononuclear cells secreting IFN-gamma and IL-4, spontaneously and in response to paternal alloantigens, were compared between the groups. RESULTS: The numbers of spontaneously as well as paternal antigen-induced IFN-gamma- and IL-4-secreting cells were similar in allergic and non-allergic pregnant women on all occasions. A similar increase in the numbers of both IFN-gamma- and IL-4-secreting cells were found in allergic and non-allergic women during pregnancy, both regarding spontaneous and paternal antigen-induced secretion. CONCLUSIONS: This study does not support the hypothesis of a more pronounced Th2-deviation to paternal antigens in allergic pregnant women compared with non-allergic pregnant women, as measured by number of cytokine-secreting cells. The observed increase of both IFN-gamma- and IL-4-secreting cells during normal pregnancy may be interpreted as a Th2-situation, since the effects of IL-4 predominate over the effects of IFN-gamma.

Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype.

BACKGROUND: Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known. METHODOLOGY/PRINCIPAL FINDINGS: Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM)-2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications. CONCLUSIONS/SIGNIFICANCE: The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells.

A case of severe Rh (D) alloimmunization treated by intensive plasma exchange and high-dose intravenous immunoglobulin.

BACKGROUND: In extremely severe Rh (D) alloimmunization, during pregnancy, early diagnosis and treatment is essential to avoid hydrops fetalis. Intrauterine transfusion (IUT) is of utmost importance in the prevention of fetal anemia but it is usually feasible only after 20 weeks of pregnancy. Therefore, additional treatment options in early pregnancy are needed. STUDY DESIGN AND METHODS: A 27-year-old severely D+C immunized woman was admitted at 8 weeks of gestation in her fifth pregnancy with an extremely high concentration of anti-D. Her first pregnancy was uneventful but resulted in D+C alloimmunization. The next two pregnancies were unsuccessful, because of hydrops fetalis resulting in fetal death in pregnancy week 20 and 24, respectively, despite treatment with high-dose intravenous immunoglobulin (IVIG) and IUT treatment. A fourth pregnancy was terminated with legal abortion. The patient was eager and persistent to accomplish a successful pregnancy. Therefore, a combination of treatments consisting of plasma exchange (PE) three times/week and IVIG 100g/week was started in pregnancy week 12. PE was performed 53 times and totally 159L of plasma was exchanged. RESULTS: The anti-D concentration was 12mug/mL (IAT titer 2000) before start of treatment by PE and IVIG in pregnancy week 12. The concentration of anti-D was gradually reduced to approximately 3mug/mL after only two weeks of treatment and was maintained at that level until pregnancy week 22. In pregnancy week 26 and 27, signs of hydrops were detected by ultrasonography and IUT were performed at each occasion. Sectio was inevitable at pregnancy week 28+1 and a male baby was born: Hb 58g/L (cord sample) and 68g/L (venous sample); weight 1385g; Apgar score=4-5-7; Bilirubin 56-150mmol/L (4h). Exchange transfusion was performed on day two and day five. Phototherapy was also implemented for eight days. The newborn's recovery thereafter was uneventful and complete. CONCLUSION: A combination of PE and IVIG may be an efficient treatment possible to start in early pregnancy in patients with extremely severe Rh (D) alloimmunization, with a history of hydrops fetalis in previous pregnancies.

Cytokine mapping of sera from women with preeclampsia and normal pregnancies.

INTRODUCTION: Preeclampsia is a pregnancy-specific syndrome. The immune system in preeclampsia is changed with an increased innate activity and there is a hypothesis of a shift towards Th1-type immunity. The aim of this study was to determine a spectrum of soluble immunological factors denoting different aspects of immune activation in third trimester sera from women with preeclampsia (N=15) and compare with levels in sera from normal pregnant women (N=15). MATERIAL AND METHODS: IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFN-alpha, IFN-gamma, TNF-alpha, GM-CSF, MIP-lalpha, MIP-1beta, MCP-1, eotaxin and RANTES were measured in serum using multiplex bead arrays. The levels of soluble CD14 and soluble IL-4 receptor were measured by enzyme-linked immunoassay (ELISA). RESULTS: Preeclamptic women had significantly increased levels of circulating IL-6 (p=0.002), IL-8 (p=0.003) and soluble IL-4R (p=0.037), compared to women with normal pregnancies. CONCLUSION: This study supports the hypothesis of increased inflammatory responses in preeclampsia, illustrated by the increased levels of IL-6 and IL-8. The finding of increased levels of soluble IL-4 receptor is an intriguing finding with several interpretations, which may partly support the hypothesis of a Th1 shift in preeclampsia.