Reproductive Characteristics and Pregnancy Outcomes in Hidden Celiac Disease Autoimmunity.

INTRODUCTION: Untreated symptomatic celiac disease (CD) adversely affects female reproduction; however, the effect of hidden CD autoimmunity is uncertain. METHODS: We identified women who were not previously diagnosed with CD and tested positive for tissue transglutaminase and endomysial antibodies between 2006 and 2011 in a community-based retrospective cohort study. We evaluated (i) the rate of adverse pregnancy outcomes and medical complications of pregnancy in successful singleton deliveries and (ii) reproductive characteristics in seropositive women without a clinical diagnosis of CD and age-matched seronegative women. RESULTS: Among 17,888 women whose serum samples were tested for CD autoimmunity, 215 seropositive and 415 seronegative women were included. We reviewed 231 and 509 live singleton deliveries of 117 seropositive and 250 seronegative mothers, respectively. Menarche and menopausal age, gravidity, parity, and age at first child were similar in seropositive and seronegative women. CD seropositivity was not associated with an increased risk of maternal pregnancy complications. Maternal seropositivity was associated with small for gestational age in boys (OR 3.77, 95% CI: 1.47-9.71; P = 0.006), but not in girls (OR 0.57, 95% CI: 0.15-2.17; P = 0.41). CD serum positivity was not associated with prematurity, small for gestational age (birth weight <10th percentile), or 5-minute Apgar score of less than 7. DISCUSSION: Although underpowered, the present study did not show any difference in reproductive characteristics or rates of adverse pregnancy outcomes in women with and without CD autoimmunity, except for birth weight in male offspring. Larger studies are needed to determine the effects of CD autoimmunity on female reproduction.

The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage.

BACKGROUND: Peripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study. METHODS: In total, n = 575 RM patients (n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined by flow cytometry and uterine CD56+ NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)). RESULTS: Patients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /µl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044). CONCLUSIONS: The demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.

Increased HLA-G Expression in Term Placenta of Women with a History of Recurrent Miscarriage Despite Their Genetic Predisposition to Decreased HLA-G Levels.

Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3'UTR) of the HLA-G gene can affect the level of HLA-G expression, which may be altered in women with recurrent miscarriages (RM). This case-control study included 23 women with a medical history of three or more consecutive miscarriages who delivered a child after uncomplicated pregnancy, and 46 controls with uncomplicated pregnancy. Genomic DNA was isolated to sequence the 3'UTR of HLA-G. Tissue from term placentas was processed to quantify the HLA-G protein and mRNA levels. The women with a history of RM had a lower frequency of the HLA-G 3'UTR 14-bp del/del genotype as compared to controls (Odds ratio (OR) 0.28; p = 0.039), which has previously been related to higher soluble HLA-G levels. Yet, HLA-G protein (OR 6.67; p = 0.006) and mRNA (OR 6.33; p = 0.010) expression was increased in term placentas of women with a history of RM as compared to controls. In conclusion, during a successful pregnancy, HLA-G expression is elevated in term placentas from women with a history of RM as compared to controls, despite a genetic predisposition that is associated with decreased HLA-G levels. These findings suggest that HLA-G upregulation could be a compensatory mechanism in the occurrence of RM to achieve an ongoing pregnancy.

Comparison of hepatitis B viral loads and viral antigen levels in child-bearing age women with and without pregnancy.

BACKGROUND: Pregnancy is a unique physiological condition with the cellular immune functions compromised at some extents to allow the mature of growing fetus. Whether pregnancy may influence the replication of hepatitis B virus (HBV) is less studied. The present study aimed to investigate the influence of pregnancy on the replication of HBV and expression of viral antigens by comparing the levels of HBV DNA and viral antigens in pregnant and non-pregnant women. METHODS: A total of 727 HBsAg-positive serum samples, collected from 214 pregnant women and 513 non-pregnant women of childbearing age, were included. Based on the pregnancy status, subjects were divided into four groups: nulliparous (n = 158), pregnant (n = 214), 7-12 months postpartum (n = 170), and 2-5 years postpartum (n = 185). The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were quantitatively measured with microparticle enzyme immunoassay. HBV DNA levels were detected by fluorescent real-time PCR. RESULTS: The median ages of four groups were 25.0, 25.3, 26.2 and 29.3 years, respectively (p < 0.01). HBeAg-positive proportions were 34.2, 33.6, 35.3 and 29.2%, respectively (p = 0.624). HBV DNA levels in HBeAg-positive women were higher than those in HBeAg-negative women (7.88 vs 2.62 log IU/ml, p < 0.001). HBV DNA levels in the four groups with positive HBeAg were 7.8, 7.7, 8.0 and 8.0 log IU/ml, respectively (p = 0.057), while HBsAg titers were 4.4, 4.5, 4.6 and 4.8 log IU/ml (p = 0.086) and HBeAg titers were 3.1, 3.0, 3.1 and 3.0 log S/CO (p = 0.198). In the four groups with negative HBeAg, HBV DNA levels were 2.3, 2.6, 2.5 and 2.8 log IU/ml, respectively (p = 0.085), while HBsAg titers were 3.1, 3.3, 3.3 and 3.0 log IU/ml (p = 0.06). CONCLUSIONS: Serum levels of HBV DNA and viral antigens showed no significant changes in nulliparous, pregnant, and postpartum women, regardless of the HBeAg status. The results indicate that pregnancy has little influence on the replication of HBV and the expression of viral antigens.

Monitoring mRNA transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells of pregnant pigs with different parity.

The reproductive success of mammals is largely dependent on the interaction between maternal and foetal interfaces during early pregnancy. Particularly, immune cells which reside at the maternal endometrium can modulate the conception and placental vascularization. In this study, we analysed the transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells (PBMCs) of pregnant pigs with different parity. Briefly, three groups of female pigs were divided based on parity (0, 2 and 5) and each group was artificially inseminated. Within 30 days of gestation, the total RNA was isolated from the endometrium and PBMCs of sacrificed experimental pigs and the expression patterns of genes involved in early pregnancy were monitored by quantitative real-time RT-PCR. Results indicated absence of correlation between increased parity and the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) mRNA in endometrium among the groups of pigs analysed. Yet, the mRNA levels of Fas, Fas ligand (FasL) and tumour necrosis factor-α (TNF-α) in the endometrium of parity 5 sows were much higher than those of pregnant gilts (parity 0), and the mRNA ratios of both TNF-α:interleukin-4 (IL-4) and IFN-γ (interferon-γ):interleukin-10 (IL-10) in PBMCs of pregnant pigs were augmented with increasing parity. Furthermore, the mRNA levels of TNF-α and IFN-γ in PBMCs of pregnant pigs were inversely correlated with litter size. These combined results may demonstrate that increased parity of pregnant pigs leads to enhance Th1-prone immunity within the maternal-foetal interface during early pregnancy.

Effects of Pregnancy-associated Malaria on T Cell Cytokines in Cameroonian Women.

Although Th17 cells subsets improve immunity against extra and intracellular pathogens, and in modulating Th1 and other immune responses, its role on pregnancy-associated malaria (PAM) is unknown. This study aims to investigate the effects of PAM on Th1 (IFN-γ, TNF-α), IL-10 family (IL-10, IL-19, IL-22), Th17 (IL-17A, IL-23) cytokines and on CXCL-10 chemokine profiles in pregnant women. Between 2010 and 2011, venous blood specimens from 107 volunteer pregnant Cameroonian women was used to determine parasitaemia microscopically and haemoglobin levels using HemoCue analyzer. Plasma levels of the biomarkers were determined by ELISA. Parasitaemia was higher in women with low haemoglobin levels, parity and mother's age. IL-10 and CXCL-10 plasma levels were higher in the malaria infected and in anaemic women while IFN-γ and IL-17A levels were higher in malaria non-infected and in non-anaemic women. Parasitaemia correlated positively with IL-10 and CXCL-10 levels but inversely with IFN-γ and IL-17A. Haemoglobin levels were higher in women with low IL-10 and CXCL-10 levels, and in group with high IFN-γ, IL-17A and IL-23 levels. Only IL-10 levels associated negatively with parity. Positive correlations were observed between Th17 (IL-17A) and Th1 (IFN-γ, TNF-α), IL-10 family (IL-19 and IL-22) and Th17 (IL-23) cytokines. Multivariate analysis showed association between: mother's age and IFN-γ levels, parasitaemia and IL-10 and CXCL-10 levels and haemoglobin levels, gestational age and IL-17A levels. In conclusion, during PAM, CXCL-10 and IL-10 responses are implicated in the pathogenesis while Th17 and Th1 immune responses, via IL-17A and IFN-γ might play protective roles.

Phenotypic and genetic relationships of bovine natural antibodies binding keyhole limpet hemocyanin in plasma and milk.

To improve the health status (resilience) of dairy cows, levels of natural antibodies (NAb) might be useful. The objective of the present study was to compare levels and to estimate genetic parameters for NAb measured in milk and plasma samples. Titers of NAb IgM and IgG isotype-binding keyhole limpet hemocyanin of 2,919 cows, in both plasma and milk, were measured using ELISA. Analysis revealed that NAb levels in milk significantly increased with parity, whereas they remained constant in plasma. Moderate positive phenotypic correlations were found between NAb levels in milk and in plasma: 0.18 for IgG and 0.40 for IgM. This indicates that NAb from milk and plasma might reflect different aspects of dairy cow health status. However, high genetic correlations were found for NAb in milk and plasma: 0.81 for IgG and 0.79 for IgM. Heritabilities (SE in parentheses) for NAb measured in plasma [0.15 (0.05) for IgG and 0.25 (0.06) for IgM] were higher than heritabilities of NAb measured in milk [0.08 (0.03) for IgG and 0.23 (0.05) for IgM]. Our results indicate that NAb measured in milk and plasma are heritable and likely have a common genetic background, suggesting that NAb levels measured in milk might be useful for genetic improvement of disease resistance.

Parity and the risk of developing rheumatoid arthritis: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study.

OBJECTIVE: To study the impact of parity history on the risk of antibodies to citrullinated peptide antigens (ACPA) positive and ACPA-negative rheumatoid arthritis (RA), in different age-groups. METHOD: Data from a population-based case-control study of female incident RA cases were analysed (2035 cases and 2911 controls, aged 18-70 years ). Parity history was assessed through a questionnaire. Parous women were compared with nulliparous, by calculating odds ratios (ORs) with 95% confidence interval (CI). RESULTS: Parity was associated with an increased risk of ACPA-negative RA in women aged 18-44 years (OR=2.1, 95% CI 1.4 to 3.2), but not in those aged 45-70 years (OR=0.9, 95% CI 0.7 to 1.3). Among young women, an increased risk of ACPA-negative RA was found in those who gave birth during the year of symptom onset (OR=2.6, 95% CI 1.4 to 4.8) and who were at a young age at first birth (<23) (OR=2.5, 95% CI 1.5 to 4.1). Parity and the postpartum period were not associated with ACPA-positive RA, but older age at first birth was weakly associated with a decreased risk. CONCLUSIONS: The increased risk of ACPA-negative RA in parous women of reproductive age seemed to be associated with an increased postpartum risk and with young age at first birth. Further research is needed to explore the biological mechanisms behind our findings.

Antenatal rubella immunity in Ireland.

The objective of the study was to identify those women attending for antenatal care who would have benefited from prepregnancy rubella vaccination. It was a population-based observational study of women who delivered a baby weighing < or = 500 g in 2009 in the Republic of Ireland. The woman's age, parity, nationality and rubella immunity status were analysed using data collected by the National Perinatal Reporting System. Of the 74,810 women delivered, the rubella status was known in 96.7% (n = 72,333). Of these, 6.4% (n = 4,665) women were not immune. Rubella seronegativity was 8.0% (n = 2425) in primiparous women compared with 5.2% (n = 2239) in multiparous women (p < 0.001), 14.7% (n = 10653) in women < 25 years old compared with 5.0% (n = 3083) in women < or = 25 years old (p < 0.001), and 11.4% (n = 780) in women born outside the 27 European Union (EU27) countries compared with 5.9% (n = 3886) in women born inside the EU27 countries (p < 0.001). Based on our findings we recommend that to prevent Congenital Rubella Syndrome, the health services in Ireland should focus on women who are young, nulliparous and born outside the EU.

Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host?

Small amounts of genetically foreign cells (microchimerism, Mc) traffic between a mother and fetus during pregnancy. Commonly, these grafts durably persist. For women, multiple naturally acquired Mc grafts can accrue, as they harbor Mc from their own mothers (maternal Mc, MMc) and subsequently acquire fetal Mc (FMc) through pregnancy. The nature of interactions between these naturally acquired grafts may inform, and be informed by, observations in transplantation, including the effect of noninherited maternal HLA antigens (NIMA) and double-unit cord blood transplantation (CBT). We asked whether FMc and MMc are impacted by the addition of new grafts as evaluated by increasing parity. Mc was identified by quantitative PCR for a nonshared polymorphism unique to the Mc source. Despite increasing sources of Mc, FMc did not increase with increasing parity. MMc concentration was significantly lower with increasing parity. The odds ratio for detection of MMc for 2 or more births compared with 1 birth was .11 (95% CI 0.03-0.42, P = .001). These observations suggest that interactions occur among naturally acquired grafts and are of interest in light of recent observations of graft-graft interaction resulting in predominance of 1 unit in double-unit CBT and the correlation of MMc with the NIMA effect.

Impact of a transfusion-related acute lung injury reduction strategy on apheresis platelet collections.

BACKGROUND: Most blood centers in the US have implemented transfusion-related acute lung injury (TRALI) mitigation strategies for apheresis platelet (AP) donations based on theoretical impact of donor loss. The aim of this study is to determine the actual impact of a TRALI mitigation strategy in a US blood center. STUDY DESIGN AND METHODS: Daily collection events and resulting products were retrospectively obtained before and after implementation of a TRALI reduction strategy (HLA antibody testing female AP donors four or more pregnancies) for comparison. The retention rate of reassigned donors was determined by reviewing whole blood (WB) and/or apheresis red blood cell (AR) donations post reassignment. Data were obtained to compare donor frequency and split rate from reassigned (historical data) and new AP donors. RESULTS: Mean daily collections (27.7 vs. 30.0) and total products (12,211 vs. 12,957) were significantly higher after implementation, but the number of products/collection event was lower (1.49 vs. 1.40). Mean collections/donor/year (4.0 vs. 1.8) and split rate (36% vs. 27%) were historically higher for reassigned (n = 45) versus new AP donors (n = 1,090). Seventy-three of 112 donors (65%) testing positive for HLA antibodies returned for WB or AR donations, 31 of 45 (69%) active AP donors returned. CONCLUSIONS: Donor loss may not be adequate to estimate impact on AP inventory, as donation characteristics may differ between new donors and those reassigned. We show successful implementation of a TRALI mitigation strategy by increasing collection goals and AP donor recruitment efforts beyond donor loss. Retaining the majority of reassigned donors is feasible.

Allogeneic disparities in immunoglobulin-like transcript 5 induce potent antibody responses in hematopoietic stem cell transplant recipients.

In hematopoietic stem cell transplant (HSCT) recipients, the recognition of polymorphic antigens by the donor-derived immune system is an important mechanism underlying both graft-versus-host disease and graft-versus-leukemia (GVL) effect. Here we show that a subset of HSCT recipients (13.9%, n = 108) have antibodies directed to surface molecules of dendritic cells. We have used one such serum in conjunction with retroviral expression cloning to identify the highly polymorphic surface molecule immunoglobulin-like transcript 5 (ILT5) as one of the targets of dendritic cell-reactive antibodies. ILT5 reactive antibodies were found in 5.4% of HSCT patients but not in solid organ transplantation recipients, patients with collagen diseases, multiparous women, or polytransfused or healthy persons. We show that ILT5-specific antibodies can mediate killing of ILT5-bearing cells and furthermore demonstrate ILT5 expression in some leukemic cells, indicating that it might be a target for GVL effects. Thus, our results represent the first description of potent allogeneic antibody responses to a non-major histocompatibility complex cell surface molecule in hematopoietic stem cell transplanted patients and warrant further studies to elucidate the role of antibodies to polymorphic cell surface molecules in GVL and graft-versus-host responses.

Bone and cellular immune system of multiparous sows are insensitive to ovariectomy and nutritive calcium shortage.

Research in osteoporosis, which is a complex systemic disease, demands suitable large animal models. In pigs, most research has been done in growing minipigs, which probably are not ideal models for postmenopausal osteoporosis. Therefore, our aim was to analyze the effects of ovariectomy (OVX) and nutritive calcium shortage on multiparous Large White sows. 32 animals were randomly assigned to 4 groups in a cross design with OVX vs. sham and physiological calcium supplementation (0.75% calcium) vs. dietary calcium shortage (0.3% calcium). The observation period was 10 months with blood sampling every 2 months for hematological, immunological, and biochemical bone marker measurements. At the termination of the experiment, animals were sacrificed. Samples of trabecular bone of distal radius, proximal tibia, and sixth lumbar vertebra were subjected to micro-computed tomography imaging and ashed afterwards. Dual X-ray absorptiometry scans of the proximal femora were performed with prepared bones being placed in a water bath for mimicking soft tissue. Analyses of bone marker and cytokine profile kinetics, distribution of leukocyte subpopulations, and morphometrical and densitometrical analyses showed no evidence of any impact of OVX or calcium shortage. In conclusion, the skeleton of adult sows of a conventional breed is seemingly protected from effects of OVX and calcium shortage.

Does pregnancy provide vaccine-like protection against rheumatoid arthritis?

OBJECTIVE: Previous studies have evaluated the correlation between rheumatoid arthritis (RA) risk and pregnancy history, with conflicting results. Fetal cells acquired during pregnancy provide a potential explanation for modulation of RA risk by pregnancy. The present study was undertaken to examine the effect of parity on RA risk. METHODS: We examined parity and RA risk using results from a population-based prospective study in Seattle, Washington and the surrounding area and compared women who were recently diagnosed as having RA (n = 310) with controls (n = 1,418). We also evaluated the distribution of parity in cases according to HLA genotype. RESULTS: We found a significant reduction of RA risk associated with parity (relative risk [RR] 0.61 [95% confidence interval 0.43-0.86], P = 0.005). RA risk reduction in parous women was strongest among those who were younger. Most striking was that RA risk reduction correlated with the time that had elapsed since the last time a woman had given birth. RA risk was lowest among women whose last birth occurred 1-5 years previously (RR 0.29), with risk reduction lessening progressively as the time since the last birth increased (for those 5-15 years since last birth, RR 0.51; for those >15 years, RR 0.76), compared with nulliparous women (P for trend = 0.007). No correlation was observed between RA risk and either age at the time a woman first gave birth or a woman's total number of births. Among cases with the highest genetic risk of RA (i.e., those with 2 copies of RA-associated HLA alleles), a significant underrepresentation of parous women versus nulliparous women was observed (P = 0.02). CONCLUSION: In the present study, there was a significantly lower risk of RA in parous women that was strongly correlated with the time elapsed since a woman had last given birth. While the explanation for our findings is not known, HLA-disparate fetal microchimerism can persist many years after a birth and could confer temporary protection against RA.

Mid-trimester amniotic fluid concentrations of the proinflammatory cytokines IL-6, IL-8, TNF-α, and lipopolysaccharide binding protein in normal pregnancies: a prospective evaluation according to parity, gestational age, and fetal gender.

OBJECTIVE: To assess mid-trimester amniotic fluid concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and lipopolysaccharide binding protein (LBP) in pregnancies with normal outcome and correlate them with gestational week (GW), parity, and fetal gender. METHODS: Cytokine concentrations were measured within a week of amniocentesis during GW 15+0 to 20+6 and correlated with GW at birth, parity, and fetal gender. RESULTS: After exclusion of women with an adverse pregnancy outcome or those lost to follow-up, 273 consecutive patients were evaluated (median parity: 1; range: 0-5). Ranges for IL-6, IL-8, TNF-α, and LBP were 4.9-2620 pg/mL, 36.2-5843 pg/mL, 8.0-28.2 pg/mL, and 0.06-1.9 µg/mL, respectively. IL-6, IL-8, and LBP values did not respectively differ among time points, but TNF-α values did between the 15(th) and 16(th) and the 15(th) and 18(th) weeks of gestation (P<0.05). No significant correlations between cytokine levels and parity or fetal gender were identified. CONCLUSIONS: Cytokine concentrations in amniotic fluid during the mid-trimester did not differ with parity or fetal gender. IL-6, IL-8, and LBP levels appeared stable with GW, whereas GW significantly influenced TNF-α concentrations. Further analyses are warranted to establish the role of cytokines in predicting adverse pregnancy outcomes.

Alloantibodies to glycoprotein La/LLa (anti-HPA-5a and -5b) and IIb/IIIa (anti-HPA1a, -3a and -4a) in Nigerian parous women.

Human platelet antibodies are often implicated in conditions such as neonatal alloimmune thrombocytopenia (NAIT), idiopathic thrombocytopenic purpura (ITP) and platelet refractoriness; however, the frequency of such alloantibodies has not been reported in Nigeria and West Africa. A cross section of apparently healthy adult female staff at a tertiary health facility in the Niger Delta, Nigeria, was screened for alloantibodies to human platelet antigens (HPA) using the GTI PakPlus qualitative solid-phase enzyme-linked immunosorbent assay (ELISA) method. Among the 100 women screened, no anti-glycoprotein IIb/IIIa (anti-HPA-Ia,-3a and -4a) antibodies were detected; however, prevalence of anti-glycoprotein Ia/IIa (anti-HPA-5b) was 30% and pf anti-glycoprotein Ia/IIa (anti-HPA-5a) was 18%. Parity had a significant influence on the development to HPA antibodies (Fisher's Exact test: 11.683, P < 0.05; 13.577, P < 0.01). Platelet count did not have an influence on the development of antibodies (P > 0.05). Clearly, there is need to initiate platelet serology in this setting and also a need to educate women about the risk associated with frequent pregnancies. Furthermore, caution should be exercised when recruiting parous women as blood donors

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory.

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy - and how the fundamental immunological principle of memory may promote this adaptive response.

The 3'-untranslated region of the HLA-G gene in relation to pre-eclampsia: revisited.

Abnormal human leukocyte antigen G (HLA-G) expression may be involved in pre-eclampsia. A 14 bp insertion/deletion polymorphism exists in exon 8 of the HLA-G gene. Fetal +14/+14 bp HLA-G genotype may predispose to pre-eclampsia in the mother. Other polymorphisms, besides the 14 bp polymorphism (rs66554220), in the 3'-untranslated region (3'-UTR) (exon 8) of the HLA-G gene might be associated with severe pre-eclampsia, especially in primiparas. By haplotype-specific polymerase chain reaction amplification and DNA sequence analysis in the offspring from 50 pre-eclamptic cases and 85 controls (35 and 58 primiparas), 4 single nucleotide polymorphisms (SNPs) were detected in exon 8 of the HLA-G gene [SNP2995 (rs1710), SNP3127 (rs1063320), SNP3172 (rs9380142), and SNP3181 (rs1610696)]. Complete linkage disequilibrium between the +14 bp allele and three of the SNPs (SNP2995, SNP3127, and SNP3172) were observed. Two of the polymorphisms (SNP3172 and SNP3181) were located right before and after an AUUUA-pentamer sequence; AU-rich sequences seem to be involved in mRNA stability. However, only the genotypes of the earlier showed 14 bp polymorphism and the SNP3127 (with a C to G substitution; P = 0.008, P(C) = 0.04) were significantly associated with severe pre-eclampsia in primiparas. In conclusion, this study indicates that the +14 bp HLA-G allele defines a nearly unique exon 8 haplotype, and fetuses homozygous for this haplotype [SNP 2995(C)/SNP 3127(G)/SNP 3172(A)/SNP 3181(G)/+14 bp] are associated with severe pre-eclampsia in primiparas.

Influence of the mother's preceding pregnancies on fetal development and postnatal survival of the neonate, in normal pregnancy. An immunological phenomenon?

OBJECTIVES: The objective of this study is to test for an association between the sex of conceptuses of the mother's preceding pregnancies and fetal development and early neonatal survival in normal pregnancy. METHODS: A population of 27,243 neonates, including a subsample of 7,773 "newborn/mother/placenta units" were divided into cohorts according to the sex of the neonate and the sex and number of conceptuses of the mother's preceding pregnancies. The average birth weight, placenta weight and early neonatal mortality rate were measured for each cohort and compared. The "dose effect" of preceding pregnancy was tested by linear and quadratic regression analysis, and by chi-square trend test for linearity of proportions. RESULTS: The results have shown an association between these three variables and the preceding pregnancies of the mother. Fetal development and early survival of the neonate are positively associated with the mother's preceding pregnancies of same sex as the neonate, and negatively associated with the preceding pregnancies of opposite sex to the neonate. The strength of the phenomenon increases with parity, at least for the first three parities. The association is statistically significant. CONCLUSIONS: The association between fetal development and neonatal survival and preceding pregnancies of the mother would be compatible with the action of male and female specific antigens capable of affecting selective implantation of blastocysts, which commands subsequent fetal development as well as early neonatal survival.

Risk factors for the presence of non-rhesus D red blood cell antibodies in pregnancy.

OBJECTIVE: To identify risk factors for the presence of non-rhesus D (RhD) red blood cell (RBC) antibodies in pregnancy. To generate evidence for subgroup RBC antibody screening and for primary prevention by extended matching of transfusions in women <45 years. DESIGN: Case-control study. SETTING: Nationwide evaluation of screening programme for non-RhD RBC antibodies. CASES: consecutive pregnancies (n=900) with non-RhD immunisation identified from 1 September 2002 to 1 June 2003 and 1 October 2003 to 1 July 2004; controls (n=968): matched for obstetric caregiver and gestational age. METHODS: Data collection from the medical records and/or from the respondents by a structured phone interview. MAIN OUTCOME MEASURES: Significant risk factors for non-RhD immunisation in multivariate analysis. RESULTS: Significant independent risk factors: history of RBC transfusion (OR 16.7; 95% CI: 11.4-24.6), parity (para-1 versus para-0: OR 1.3; 95% CI: 1.0-1.7; para-2 versus para-0: OR 1.4; 95% CI: 1.0-2.0; para >2 versus para-0: OR 3.2; 95% CI: 1.8-5.8), haematological disease (OR 2.1; 95% CI: 1.0-4.2), history of major surgery (OR 1.4; 95% CI: 1.1-1.8). For the clinically most important antibodies, anti-K, anti-c and other Rh-nonD-antibodies RBC transfusion was the most important risk factor, especially for anti-K (OR 96.4; 95%-CI: 56.6-164.1); 83% of the K-sensitised women had a history of RBC transfusion. Pregnancy-related risk factors were a prior male child (OR 1.7; 95% CI: 1.2-2.3) and caesarean section (OR 1.7; 95% CI: 1.1-2.7). CONCLUSIONS: RBC transfusion is by far the most important independent risk factor for non-RhD immunisation in pregnancy, followed by parity, major surgery and haematological disease. Pregnancy-related risk factors are a prior male child and caesarean section. Subgroup screening for RBC antibodies, with exclusion of RhD-positive para-0 without clinical risk factors, is to be considered. This approach will be equally sensitive in detecting severe Haemolytic Disease of the Fetus and Newborn compared with the present RBC antibody screening programme without preselection. Primary prevention by extending preventive matching of transfusions in women younger than 45 will prevent more than 50% of pregnancy immunisations.