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Few, mostly small, studies have investigated the distribution of HLA class II antigens among women with unexplained recurrent miscarriage. Although some studies have reported statistically significant associations between this syndrome and certain HLA-DR antigens--especially the -DR1 and -DR3 antigens--other studies have been unable to demonstrate such associations. For the present meta-analysis, 18 cross-sectional or case-control studies (published or unpublished) reporting on frequencies of HLA-DR1 and -DR3 antigens among Caucasian women with unexplained repeated miscarriage were identified by searching literature databases (MEDLINE and EMBASE), reading the references of identified studies, and by contacting researchers within the field. The studies comprised a total of 1508 patients. The methodological quality of most of the studies was low, especially because of small numbers of patients and because patients with only two miscarriages were included in many studies; this is defined as repeated miscarriage. The odds ratios of repeated miscarriage for the HLA-DR1 and -DR3 antigens were calculated for the individual studies and subsequently the pooled odds ratios for the studies were calculated. The combined odds ratio for HLA-DR1 was 1.29 [95% confidence interval (CI) = 1.05-1.58] (17 studies) which is statistically significant (P <0.05). The combined odds ratio for HLA-DR3 was 1.00 (95% CI 0.80-1.24) (18 studies), which is not significant. The results of the meta-analysis suggest that the HLA-DR antigen DR1 is associated with an increased susceptibility to unexplained repeated miscarriage.

A possible relationship between recurrent spontaneous abortions and autoimmune abnormalities was studied. Eight serological autoimmune or autoimmune-correlated parameters were investigated in 91 women with unexplained recurrent abortions (greater than or equal to 3 consecutive, spontaneous abortions) and 89 fertile control women. Five parameters were seen significantly more frequently in 19 women with at least one second trimester miscarriage which had been associated with severe intrauterine growth regardation (IUGR), than in controls. Seventeen of these 19 patients (89%) had at least one positive autoimmune parameter, compared to 15 of 72 patients (21%) with no second trimester abortions with IUGR (P less than 0.0001) and 14 (16%) of the controls (P less than 0.0001). No single autoantibody characterized patients who exhibited a significant accumulation of autoimmune parameters. These findings may suggest that women with recurrent abortions, in whom autoimmunity is thought to play a role, cannot be identified merely by one laboratory assay, such as that for cardiolipin antibodies, but must be defined by positivity of several criteria. Using our own test panel, preliminary clinical and serological criteria have been set up for the definition of an autoimmune-associated recurrent abortion condition. Twenty-three per cent of the patients in our material fulfilled these criteria, and seven out of nine of these women (78%) have to date been treated successfully with heparin/aspirin during pregnancy.

Eleven women who had previously experienced four to eight unexplained fetal losses (median 6.0 fetal losses/woman) were treated in their next pregnancy with individualized doses of pooled intravenous immunoglobulins. Nine women (82%) delivered healthy infants subsequent to the treatment. Prior to treatment, the pregnant patients had a significantly (P less than 0.05) increased median level of complement C3 neodeterminants in the blood compared with a group of 33 normal first trimester pregnant women. This may be a sign of increased turnover of complement in these women.

In a previous case-control study of women with unexplained recurrent miscarriages we reported that the frequency of women positive for each of the two histocompatibility (HLA) types HLA-DR1, Br and HLA-DR3 was increased in a subset of patients with a history of four or more miscarriages. In the present study we examined whether the increased frequency of the two HLA types in this subset of patients indicated that they would result in a poor pregnancy prognosis. We related pregnancy outcomes to the mothers' HLA-DR type in a prospective study of a well-defined, closely supervised group of 94 women with unexplained recurrent miscarriages who had achieved intra-uterine pregnancy in the course of one of two prospective placebo-controlled trials concerning the efficacy of immunotherapy. Of the patients who were HLA-DR1, Br and/or HLA-DR3 positive 62% miscarried their next pregnancy compared with 29% of the patients negative for the two HLA types [relative risk of miscarriage in the former group = 2.2 (P < 0.002) unadjusted, and 1.8 (P = 0.025) when adjusted for the number of previous miscarriages]. The results suggest that Danish women with unexplained recurrent miscarriages who are positive for HLA-DR1, Br and/or -DR3 display a poorer pregnancy outcome than patients negative for these types.

The aim of this trial was to investigate whether infusions of i.v. immunoglobulins (Ig) to women with secondary recurrent spontaneous abortions and recurrent second trimester spontaneous abortions can increase the rate of successful pregnancy. In a prospective, double-blind, placebo-controlled trial, infusions of i.v. Ig (Nordimmun) or placebo were given during pregnancy to 34 women with a history of either unexplained recurrent spontaneous abortion subsequent to a birth or including at least one second trimester miscarriage. The success rate was 52.9% in the i.v. Ig group compared with 29.4% in the placebo group (not significantly different, therapeutic gain 23.5%, 95% confidence interval -8.6 to 55.7%). No changes in autoantibody concentrations or major lymphocyte subsets were induced by i.v. Ig treatment. In conclusion, an expected 55% therapeutic gain of i.v. Ig in recurrent spontaneous abortion could not be confirmed using the treatment regimen tested. However, to determine whether the trend of therapeutic gain of i.v. Ig in these women may be statistically significant, a larger trial is in progress.

The release of certain cytokines, e.g. tumour necrosis factor (TNF)-alpha, in the amniotic fluid has been suggested to be a cause of preterm birth. The predisposition to excessive liberation of cytokines from peripheral leukocytes has been shown to depend partly on the individual's HLA-DR genotype. The HLA-DR1 and -DR3 alleles have previously been reported as being associated with a TNF-alpha high responder status and have also been associated with unexplained recurrent spontaneous abortions. In the present study, HLA-DR typing was performed in 10 women who had experienced recurrent very early preterm births resulting in perinatal death, or late spontaneous abortions under a clinical picture resembling that traditionally attributed to cervical incompetence. All patients had had at least one mid-trimester miscarriage in spite of the insertion of a cervical cerclage. Nine out of 10 (90%) patients had the HLA-DR phenotypes DR1 and/or DR3 compared with 37% in the background population (P < 0.005). The results suggest that HLA-DR-associated immunological factors might play a part in recurrent late spontaneous abortions and extremely preterm births under a cervical incompetence-like picture, at least in the subset of cases not treatable by cervical cerclage.

The scientific basis for many traditionally accepted causes of recurrent miscarriage (RM) is weak. A significant proportion of RM cases with relatively few miscarriages can presumably be attributed to the random occurrence of consecutive chromosomally abnormal conceptions. New insights in the immunological interactions taking place at the feto-maternal interface provide us with the opportunity to propose detailed pathophysiological models for immunologically mediated RM. Scientific support for the theory that RM is a consequence of graft rejection-like alloimmune reactions against paternal human leukocyte antigens on the fetus is sparse. Conversely, there is considerable evidence that decidual natural killer cells play a role in the implantation and early invasion of the trophoblast and in the pathogenesis of RM. T helper (Th) cells from women with RM react against trophoblast antigens in vitro with the secretion of mainly interleukin-2 and interferon-gamma (a so-called Th1 response), which are known to inhibit trophoblast growth. The predisposition to a Th1 response against a given antigen may be determined by an individual's class II histocompatibility genes. In accordance with this, case-control, prospective and family studies indicate that maternal histocompatibility haplotypes comprising DR1 and DR3 alleles confer susceptibility to RM. The frequent occurrence of autoantibodies in women with RM is compatible with the theory of a Th1 response against trophoblast as a cause of the syndrome, but the autoantibodies themselves probably do not cause RM.

Results of mineral exploration of the first major gold deposit discovered in far southwestern Greenland are presented. An 800-m-long quartz Main Vein, containing abundant visible gold, was discovered in August 1992 and sampled at 20-m intervals. Geologic mapping and geophysical surveys were under way in 1993 to locate the sources of the deposit, to explore along the trend of the Main Vein (where mineralized extensions are expected to exist), and to determine the pattern of a nearby high-angle fault. Gold is distributed irregularly in discrete domains of the Main Vein and in smaller veins within its hanging wall. The main gold occurrences are found in granulated crush zones, with fine-grained irregular quartz grains within a much coarser-grained matrix. Other than gold there are very few minerals, the most important being lollingite.Microscopic examination of gravity concentrations during metallurgical testing revealed that free gold varies in size from 5-380 microns. Good recovery appears probable through a combination of gravity and cyanidization methods. A concluding section outlines favorable prospects for the discovery of additional Au-mineralized zones in the Nanortalik area and outlines factors supporting a favorable prognosis for development of an operating mine at the site. It also outlines the program of exploratory drilling conducted in 1993.

Autoantibody production is commonly associated with particular HLA class II phenotypes. The aim of the present study was to investigate whether the presence of antiphospholipid (APL) antibodies and other autoantibodies in women with unexplained recurrent miscarriage was associated with particular human leukocyte antigen (HLA)-DR or -DQ alleles or linked epitopes which have previously been reported as being associated with the recurrent miscarriage syndrome or the presence of APL. In a total of 123 Danish and Czech women with recurrent miscarriage, serum was investigated for six different APL antibodies including anticardiolipin (ACL) antibody. Antinuclear antibodies (ANA), anti-zona pellucida antibodies and anti-sperm antibodies were also investigated. The women were HLA-DR and -DQ typed by DNA-based methods. The frequency of HLA-DR phenotypes did not differ significantly between APL antibody positive recurrent miscarriage patients and APL antibody negative recurrent miscarriage patients or healthy controls. Among ACL antibody positive recurrent miscarriage patients, significantly more were positive for the HLA-DR3 phenotype and negative for the HLA-DR2 phenotypes compared with healthy controls (P < 0.05). Among ANA positive recurrent miscarriage women, 55% carried the HLA-DR3 phenotype compared with 28% of ANA negative patients (P < 0.05) and 21% of healthy controls (P < 0.002). In conclusion, among recurrent miscarriage women, the HLA-DR3 phenotypes seem to predispose to formation of ACL antibodies and ANA. The association between APL antibodies and particular HLA alleles and HLA-linked epitopes reported in studies of patients with lupus erythematosus (e.g. HLA-DR7 and -DR4) could not be confirmed in patients with recurrent miscarriage.

Sharing of major histocompatibility antigens between spouses has been claimed to play an aetiological role in couples with unexplained, habitual spontaneous abortions. On the other hand there is evidence that a subset of habitually aborting women exists, in whom autoimmune aberrations seem to be of importance. In the present study, 56 couples with unexplained habitual abortions were histocompatibility typed for HLA-A, -B and -DR specificities, as were a group of 33 fertile control couples with two or more children and no spontaneous abortions. The DR-typing was done partly by use of the restriction fragment length polymorphism (RFLP). There was no significant difference in the distribution of histocompatibility antigens between the habitually aborting women and the control women. No increased HLA-antigen sharing could be demonstrated between spouses in aborting couples compared with controls, neither in each single locus nor in the combination of all loci (all P-values greater than 0.2). Neither could any increased HLA-antigen sharing in sub-groups of aborting couples with and without autoimmunity be demonstrated. It can be concluded from these data that compatibility between spouses for HLA-A, -B and DR-antigens per se only plays a minor role in the aetiology of habitual abortion.

The electrical, mechanical, and hermeticity properties of low-temperature, plasma activated direct silicon bonds were investigated. On individual dies with a bonding area ranging from 1–4 mm2, the bonded interface was found to have a capacitance ranging from 2.62 pF/mm2–2.89 pF/mm2at 1 kHz. Linear I-V curves showed ohmic behavior without hysteresis. A resistance around 2.2 Ω and a current density of 1.1 × 104A/m2was measured at DC. We speculate that the capacitive and resistive responses are related to traps that are formed during the plasma activation process. The applied bonding process resulted in hermetic sealing with 100% yield on 2 × 481 dies. The maximum leak rate of the seals was 2.4 × 10−11mbar⋅l⋅s−1, but could be significantly lower. No gross leaks were observed following a steady-state life test, a thermal shock test, and a moisture resistance test applied on 100 dies.