Massive Intravenous Immunoglobulin Treatment in Women with Four or More Recurrent Spontaneous Abortions of Unexplained Etiology: Down-Regulation of NK Cell Activity and Subsets

PROBLEM: The aims of this study were to investigate the efficacy of massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology, and to investigate changes in peripheral natural killer (NK) cell activity and subsets. METHOD OF STUDY: MIVIg treatment was performed in 18 pregnancies from 15 women with 4 or more consecutive RSA of unexplained etiology. NK cell activity and subsets were assessed in 8 of the pregnancies. RESULTS: 14 pregnancies resulted in live births and 4 resulted in abortions with chromosome abnormality. The pre-infusion NK cell activity (mean + SD. 40.9 + 17.0%) at 4.4 +/- 0.5 weeks of gestation (GW) decreased to 15.0 +/- 7.90% at post-infusion status (5.4 +/- 0.5 GW). Pre-infusion percentages of CD56+ CD16- cells (3.5 +/- 2.1%) and CD56+ CD16- cells (16.8 +/- 8.8%) decreased to 3.0 +/- 2.2% and 11.1 +/- 6.9%, respectively, after MIVIg treatment. CONCLUSIONS: MIVIg treatment was effective in all 14 pregnancies from RSA women of unexplained etiology, excluding 4 abortions with chromosome abnormality. Peripheral NK cell activity and subsets were suppressed by MIVIg treatment.     

Pre-conceptional natural killer cell activity and percentage as predictors of biochemical pregnancy and spontaneous abortion with normal chromosome karyotype

PROBLEM: The aim of the present study was to determine whether pre-conceptional natural killer (NK) cell activity and percentage are predictive of subsequent spontaneous abortion in women with recurrent spontaneous abortion (RSA). METHOD OF STUDY: Pre-conceptional NK cell activity and percentage in peripheral blood of women who had a history of two or more RSA was prospectively assessed. The 51Cr release assay and flow cytometric analysis were performed. A total of 113 RSA women were recruited, and 85 conceived later. RESULTS: Pre-conceptional NK cell activity/percentage values in women whose next pregnancies ended in biochemical pregnancy and spontaneous abortion with normal fetal karyotype (n = 17, median 47%/17.1%), but spontaneous abortion with abnormal karyotype (n = 9, 27%/15.7%), were higher than those in live births (n = 59, 33%/13.1%). High values of pre-conceptional NK cell activity (> 46%; relative risk 3.6, 95%CI 1.6-8.0) and percentage (> 16.4%; 4.9, 1.7-13.8) were found to predict biochemical pregnancy and spontaneous abortion with normal karyotype in the next pregnancy. CONCLUSION: Pre-conceptional NK cell abnormalities were predictive of spontaneous abortion with normal fetal karyotype.     

复发性自然流产患者外周血自然杀伤细胞免疫表型检测

目的 检测复发性自然流产(RSA)患者外周血自然杀伤(NK)细胞的免疫表型。方法 应用流式细胞术检测27例RSA妊娠患者、41例RSA非妊娠患者、32例正常妊娠者和25例正常非妊娠者外周血CD56dimCD 16+、CD56brightCD16+/-、CD69+、HLA-DR+ NK细胞表达并进行比较。结果RSA妊娠组、RSA非妊娠组、正常妊娠组和正常非妊娠组外周血CD56dimCD16+ NK细胞占总NK细胞的比例分别为(88.69.±5.86)％、(79.25±9.31)％、(79.24±10.09)％、(75.49±11.96)％;CD56brightCD16+/- NK细胞的比例分别为(8.18±5.54)％、( 12.20±6.49)％、( 13.13±8.65)％、( 11.53±6.23)％;CD69+ NK细胞的比例分别为(3.42±2.13)％、(2.36±1.72)％、(2.68±1.81)％、(2.08±1.73)％;HLA-DR+ NK细胞的比例分别为(15.26±9.32)％、(9.96±7.18)％、( 10.57±8.05)％、(9.64±6.12)％。与RSA非妊娠组、正常妊娠组及正常非妊娠组比较,RSA妊娠组CD56dimCD16+、CD69+、HLA-DR+ NK细胞显著升高（均P＜0.05）。与RSA非妊娠组及正常妊娠组比较,RSA妊娠组CD56brightCD16+/- NK细胞明显降低（均P＜0.05）。结论 RSA妊娠患者外周血中NK细胞CD56dimCD16+、CD69+和HLA-DR+表达增高,而CD56brightCD16+/-表达下降,可能在RSA的发生发展中起着一定的作用。     

Increased natural killer cell cytotoxicity and IL-2 production in recurrent spontaneous abortion

PROBLEM: To determine whether natural killer (NK) cells cytotoxicity in peripheral blood is altered in patients with a history of recurrent spontaneous abortion (RSA); also, if there is any correlation between cytokine production and NK cytotoxicity. METHOD OF STUDY: In this case-control study, 21 patients with RSA within 24 hr of the last abortion (group I), and 32 pregnants with no history of abortion (group II) were surveyed. NK cell cytotoxicity was evaluated by flow cytometry, and IL-2, IL-10, transforming growth factor beta1 were measured in cell culture supernatant by ELISA method. RESULTS: Group I showed higher NK cytotoxicity than group II at all of effector to target (E:T) ratios (P < or = 0.045).The correlation between production of IL-2 and NK cytotoxicity was positively significant (R = 0.350, P = 0.001). Group I had significantly higher levels of IL-2 than group II (P = 0.001). In group II, the production of IL-10 by peripheral blood mononuclear cells was higher than group I (P = 0.002). CONCLUSION: Increased NK cell cytotoxicity and high level of IL-2 may be considered as a risk factor for RSA.     

Decrease in a specific killer cell immunoglobulin-like receptor on peripheral natural killer cells in women with recurrent spontaneous abortion of unexplained etiology

PROBLEM: The aim of this study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in women with recurrent spontaneous abortion (RSA) of unexplained etiology. METHOD OF STUDY: Peripheral blood cells were obtained from 20 RSA women and 15 fertile controls. The expression of perforin, CD94, CD161, CD158a, CD158b, and CD244 on CD3- CD56+ NK cells was analyzed by flow cytometry. RESULTS: A significant decrease in CD158a expression was demonstrated in RSA women (mean +/- SD, 22.9 +/- 8.7%) as compared with that in controls (33.6 +/- 15.7%) (P < 0.05). The percentage of NK cells showing dual expression of CD94 and CD161 was relatively higher in RSA women (55.1 +/- 10.2%) than in the controls (47.1 +/- 19.0%), but without statistically significant (P = 0.096). The expression of perforin, CD158b, or CD244 in RSA women did not differ from that in the controls. CONCLUSIONS: A divergence of the specific NK cell repertoire might be related to the etiology of RSA.     

Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility

PROBLEM: Preconception high peripheral natural killer (NK) cell activity in women with recurrent spontaneous abortion can predict subsequent miscarriages. We have examined prospectively, for the first time, the pregnancy rate in patients with unexplained infertility by measuring the peripheral NK activity. METHOD OF STUDY: We tested the peripheral NK activity of 94 infertile women who despite treatment were unable to conceive for 6 or more months (mean; 2.4 years). Peripheral NK activity was measured by a chromium-51 release cytotoxicity assay. Women were followed for 2 years and assessed. RESULTS: In 77 patients who were followed for 2 years, 28 had conceived but 49 did not. The peripheral NK activity of the group that became pregnant (mean +/- S.D.; 34.5 +/- 13.8%) was significantly lower than that of non-conception group (42.3 +/- 13.3%, P = 0.017). CONCLUSIONS: Our finding suggests that elevated peripheral NK activity in patients with unexplained infertility is a risk factor for attaining pregnancy success.     

High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins

PROBLEM: To determine the levels of peripheral blood natural killer (NK) cells in healthy women and recurrent aborters, and the effect of intravenous immunoglobulins (IVIGs) on these levels. METHOD OF STUDY: A total of 659 women were evaluated for NK cells by means of flow cytofluorimetry: 42 non-pregnant healthy women, 394 non-pregnant recurrent spontaneous abortion (RSA) women, 36 pregnant healthy women and 187 pregnant RSA women. Fifty-four of the pregnant RSA women were treated with IVIG; in 18 of them NK cells were measured immediately before and after the very first IVIG infusion (0.5 g/kg body weight). RESULTS: Blood NK cell results were increased in RSA pregnant/non-pregnant women, and significantly reduced by IVIG, even after the very first infusion. In RSA pregnant women treated by means of IVIG therapy, 92.3% success rate was observed. CONCLUSIONS: High levels of NK cells are detected in women affected by RSA. IVIGs are capable of decreasing them with a short- and long-term efficacy, allowing having a very high success rate of pregnancies in RSA women.     

Natural killer cell activity and cytokine production after in vitro immunoglobulin treatment of lymphocytes derived from pregnant women with or without risk for spontaneous abortion

OBJECTIVE: To investigate the possible mechanism of action effective in immunoglobulin G (IgG) treatment of recurrent spontaneous abortion (RSA). The effect in vitro of a commercially available intravenous immunoglobulin (IvIg) on the rate of interleukin (IL)-10 and IL-12 positive cells (Th1/Th2 balance) and on natural killer (NK) cell activity in populations of peripheral lymphocytes of healthy pregnant women and women at risk for premature pregnancy termination was studied. Primary habitual aborters as well as women showing clinical symptoms (bleeding or regular uterine contractions) of threatened premature pregnancy termination were included. METHODS: Lymphocytes of 20 pregnant women were tested. Five different batches of an IvIg with reported immunomodulatory potential were used at a concentration of 10 mg/mL. Cytokine profiles of the lymphocytes were determined by immunocytochemistry. For testing of NK cell activity, the 4 hr single cell cytotoxicity assay was used. RESULTS: Incubation with IgG of lymphocytes from recurrent spontaneous aborters concomitantly and significantly decreased the rate of IL-12 positive cells (P < 0.01) and increased the rate of IL-10 positive cells (P < 0.01), whereas such treatment had no significant effect on lymphocytes of pregnant women not at risk of abortion. Dialysis or heat treatment (56 degrees C, 30 min) of the IgG preparations did not modify the effect. Elevated NK cell activity of women at risk for premature pregnancy termination significantly decreased after IgG incubation of cells in all cases, whereas NK cell activity of normal pregnancy lymphocytes was not altered. CONCLUSION: This study suggests that incubation of peripheral lymphocytes from RSA patients with polyclonal polyspecific IgG alters cytokine profiles and NK activity while the same treatment does not affect lymphocytes of healthy pregnant women. These data might add to the understanding of mechanisms of action of IvIg in prevention of recurrent pregnancy loss.     

Psychosocial factors regulating natural-killer cell activity in recurrent spontaneous abortions

PROBLEM: The preconceptional natural-killer cell (NK) activity predicts subsequent miscarriage among women with unexplained recurrent spontaneous abortion (RSA). Psycho-neuro-immuno-endocrine network has recently been proposed as a mechanism for abortions. We therefore examined which psychosocial factors influenced the NK activity among women with RSA. METHOD OF STUDY: We measured the preconceptional NK activity of 61 women with a history two consecutive unexplained first-trimester miscarriages and no live births. We also administered semi-structured interviews and a battery of self-report questionnaires to assess their social support, personality, self-esteem and psychiatric symptoms. RESULTS: The preconceptional NK activity was negatively correlated with the women's neuroticism personality trait (r= -0.32, P = 0.01) and current depressive symptoms (r = -0.26, P= 0.05), and positively correlated with their self-esteem (r = 0.34, P = 0.01). CONCLUSIONS: In addition to several substances such as transforming-growth-factor beta and granulocyte-macrophase colony-stimulating factor, we found that low neuroticism, low depression scale score and high self-esteem contributed to high NK activity among women with RSA.     

Decidual natural killer cells in recurrent spontaneous abortion with normal chromosomal content.

PROBLEM: The maternal local immune responses in unexplained recurrent spontaneous abortion (RSA) are not yet well known. Maternal peripheral and decidual natural killer (NK) cells were evaluated in RSA with normal chromosomal content. METHOD OF STUDY: Maternal peripheral blood, villous trophoblast, and decidua were taken from 15 normal pregnancies and 9 RSA patients with normal chromosomes. The NK cells in decidual lymphocytes were evaluated by flow cytometry using monoclonal antibodies for CD56, CD16, and CD3. RESULTS: The percentages of CD56+ CD16- CD3- cells in decidual lymphocytes in RSA were lower than in normal pregnancies (P < 0.002). The CD56+CD16+/CD56+CD16- cells ratio in RSA was higher than in normal pregnancies (P < 0.02). CONCLUSION: The lower percentages of CD56+CD16-CD3- cells in RSA cases may show an inappropriate accumulation of NK cells in the decidua, and this finding may be a factor involved in RSA.     

Peripheral natural killer cytotoxicity and CD56(pos)CD16(pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion

For diagnostic purposes we assessed peripheral natural killer (NK) cell cytotoxicity and NK and T cell numbers to assess their putative predictive value in recurrent spontaneous abortion (RSA). A total of 43 women with subsequent pregnancy, 37 healthy controls and 39 women successfully partaking in an in-vitro fertilization (IVF) procedure, were included in the study. We show that before pregnancy, levels of NK cytotoxicity and numbers of both single CD56(pos) and double CD56(pos)CD16(pos) cells were similar between RSA women and controls. But notably, within the RSA group, NK cell numbers of <12% were strongly associated with a subsequent pregnancy carried to term. Supplementation of folic acid led to an increase of single CD56(pos) cells, but cytotoxic function appeared unaffected. The expression pattern of killer inhibitory receptors on CD56(pos) cells was not different between patients and controls. A longitudinal study revealed that, compared with controls, in RSA women higher numbers of double CD56(pos)CD16(pos) cells were present during early pregnancy, paralleled by an increase in cytotoxic NK cell reactivity. The single CD56(pos) population decreased in number. In conclusion, the analysis of peripheral NK cell characteristics appears a suitable diagnostic tool in RSA. Immunomodulation aimed at NK cell function appears a promising therapeutic measure.     

X-chromosome inactivation patterns in Korean women with idiopathic recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) defines as two or more consecutive losses at < or = 20 weeks of gestation and affects an estimated 1 of every 100 couples wishing to have children. However, it remains a poorly understood phenomenon. Recent reports observed a significant association between highly skewed X chromosome and RSA, supporting that X chromosome inactivation might be an important and previously unknown cause of RSA. X-inactivation pattern, using polymeric X-linked women with idiopathic RSA and 80 control subjects with a single successful pregnancy and no history of spontaneous abortion. The ratio of heterozygotes was 68.2% (45/66) in women with RSA and 67.5% (54/80) in control group. Among 45 informative RSA cases, only 1 (2.2%) woman showed extreme skewed X inactivation (> or = 90%) and 4 (8.9%) had mild skewed inactivation (> or = 85%). In 54 heterozygous control subjects, 5 (9.3%) women showed extreme skewed X inactivation and 7 (13.0%) had mild one. The frequency of skewed X inactivation between RSA patients and control group was not significantly different (p>0.05). This finding suggests that skewed x chromosome be not associated with unexplained RSA patients.     

自然流产患者蜕膜组织NK细胞受体表达分析

目的研究自然流产患者子宫蜕膜组织中NK细胞受体的表达格局。方法采用RT-PCR和免疫组织化学法检测了12例早期自然流产及40例同期正常早孕要求行人工流产者蜕膜组织的NK细胞受体表达水平。结果NK细胞受体中阳性最高的是KIR2DL4,流产组和对照组分别为100%和95%,其次是KIR2DL1,分别为83.3%和75%。ILT2和ILT4的阳性率较低,流产组和对照组分别为25%、30%和8.3%、10%。统计结果显示,KIR2DL4、KIR2DL1、ILT2和ILT4mRNA阳性率在早期自然流产病人组和对照组之间均无显著性差异。与对照组相比,早期自然流产病人的蜕膜组织中KIR2DL4分子的表达水平明显降低,具体表现在KIR2DL4的分布密度上。结论早期流产的发生与NK细胞受体的转录水平可能并无直接关联,但KIR2DL4分子的表达水平高低,可能对早期胚胎的生长、发育起关键作用。     

sHLA-G1 and HLA-G5 levels are decreased in Tunisian women with multiple abortion

Pregnancy is associated with increased levels of soluble (s) human leukocyte antigen (HLA)-G molecules, while during abortion these molecules are decreased. To date, little is known about the role of sHLA-G isoforms during abortion. In this study, we investigated the levels of total sHLA-G and its isoforms: HLA-G1 (membrane shedded isoform) and alternative spliced HLA-G5 in plasma samples obtained from 55 women who had experienced spontaneous abortion, 108 pregnant healthy women and 56 non pregnant healthy women.We found that pregnant women exhibited higher amounts of sHLA-G compared to either non pregnant women or women with abortion. Among women who had experienced spontaneous abortion, women with recurrent abortions (RSA) had lower sHLA-G than women with only one abortion. In particular, RSA women were characterized by the absence of sHLA-G1 isoform, suggesting a possible implication in abortion event.     

Up-Regulated Expression of CD56+, CD56+/ CD16+, and CD19+ Cells in Peripheral Blood Lymphocytes in Pregnant Women With Recurrent Pregnancy Losses

PROBLEM : To analyze immunophenotypic profiles of peripheral blood and humoral autoimmune responses in women with a history of recurrent spontaneous abortions (RSA). METHOD : Peripheral blood lymphocyte subsets by flow cytometry and autoantibodies to phospholipids and nuclear components by ELISA were measured in non pregnant and pregnant women with RSA of unknown etiology. Thirty-five pregnant and eighty-one nonpregnant women with RSA were studied. Seventeen nonpregnant and twenty-two pregnant normal controls were included. RESULTS : Natural killer (NK) cells (CD56+) were significantly elevated in nonpregnant women with RSA as compared with nonpregnant controls. Pregnant women with RSA demonstrated significantly increased NK (CD56+, CD56+/CD16+) and B cells (CD19+) as compared with pregnant controls. Women who miscarried the index pregnancy demonstrated significantly lower CD3+ cells in comparison with normal controls. Women with RSA and antiphospholipid antibodies showed significantly elevated NK cells when compared with women without antiphospholipid antibodies. Women with autoantibodies to nuclear components demonstrated significantly elevated CD19+/CD5+ cells when compared to women without autoantibodies to nuclear components. CONCLUSIONS : Women with RSA demonstrate an abnormal cellular immune response by increasing peripheral natural killer cells and B cells as compared with normal controls.     

Intravenous Immunoglobulin Inhibits Natural Killer Cell Activity In Vivo in Women With Recurrent Spontaneous Abortion

We previously reported elevation of natural killer (NK) cells in women with recurrent spontaneous abortion (RSA) of immune etiology. In this study, we investigated the effect of intravenous immunoglobulin G (IVIg) on peripheral blood NK activity in vivo in women with RSA. Blood was drawn prior to and 7–11 days after IVIg therapy in eight women with RSA. NK activity was measured using K562 as target cells for ⁵¹Cr-release assays. Serum IgG concentrations were also measured. All received 400 mg/kg/day of IVIg for 3 consecutive days. 1) Seven of eight women became pregnant. Five delivered a live born infant. Three out of five women (60%) who delivered a live born infant showed a significant inhibition of NK cytotoxicity post IVIg and the rest did not show any changes; 2) NK cytotoxicity was significantly increased in a woman who miscarried again; 3) A woman who miscarried a chromosomally abnormal fetus showed a significant inhibition of NK cytotoxicity after IVIg; and 4) Serum IgG concentration increased significantly from 9.3 ± 3.0 mg/ml to 23.5 ± 5.1 mg/ml post IVIg therapy. IVIg effectively inhibits peripheral blood NK activity in vivo. These results are consistent with our previous finding showing that IVIg inhibits NK cell activity in vitro. Women with RSA and elevated NK cells may benefit from IVIg treatment.     

Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion

It has been proposed that successful pregnancy is a T helper 2-type phenomenon, and that T helper (Th)1-type reactivity is deleterious to pregnancy. The objective of this study was to compare the concentrations of Th1 and Th2 cytokines produced by peripheral blood mononuclear cells from women undergoing unexplained recurrent spontaneous abortion (RSA) with those produced during normal pregnancy at a similar gestational stage. The control group consisted of 24 women with a history of successful pregnancies and the abortion group comprised of 23 women with a history of unexplained RSA. Blood from the control group was obtained at the end of the first trimester as gestational age controls for the abortion group from whom blood was collected at the time of abortion. Phytohaemagglutinin-stimulated peripheral blood cell culture supernatants were analysed for concentrations of cytokines. Significantly higher concentrations of Th2 cytokines were produced by the first trimester normal group than by the RSA group, while significantly higher concentrations of Th1 cytokines were produced by the abortion group as compared to first trimester normal pregnancy, indicating a distinct Th2-bias in normal pregnancy and a Th1-bias in unexplained RSA.     

Lack of soluble TNF-receptors in women with recurrent spontaneous abortion and possibility for its correction

PROBLEM: Tumor necrosis factor (TNF) and soluble TNF receptors (sTNF-Rs) system related with Th1 and Th2 and activity of NF-kappaB/IkappaB regulatory system. This study was designed to compare sTNF-R1 and sTNF-R2 production (shedding) and levels of late activated CD8+ T-lymphocytes in non-pregnant (n = 30) and pregnant (n = 20) normal women and non-pregnant (n = 20) and pregnant (n = 30) RSA women. Effects of progesterone (natural structure) injections in RSA women were studied. METHODS OF STUDY: Levels of sTNF-R1, sTNF-R2, TNF in peripheral blood serum were detected by enzyme-linked immunosorbent assay. Lymphocyte subsets were estimated by multicolor flow cytometry. NK cell cytotoxic activity of peripheral blood lymphocytes (PBL) in whole blood against K562 targets was determined using Europium-release cytotoxicity assay. Mitogen-induced proliferative response of PBL to PHA-P, Con A and PWM were determined by standard 3H-thymidine incorporation assay. RESULTS: Levels of soluble TNF-R1 and TNF-R2 in normal pregnancy were elevated when compared with non-pregnant normal women and pregnant RSA women. Levels of late activated CD8+ T-lymphocytes in normal pregnancy were decreased but no changes were detected in RSA women. After progesterone therapy (i.m. injections of 2.5% oil solution) in RSA women elevation of sTNF-R1 and sTNF-R2 to normal pregnancy ranges was observed. No changes in levels of late activated CD8+ T-lymphocytes after progesterone treatment were detected. CONCLUSIONS: Elevation of levels of sTNF-R1, sTNF-R2 and decrease of late activated cytotoxic T-lymphocytes are pronounce markers of normal human pregnancy. In RSA women there are no elevation of sTNF-R1 and sTNF-R2 levels during pregnancy. This deficiency may be restored by progesterone treatment.     

Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves live birth rates in women with recurrent spontaneous abortion

PROBLEM: The purpose of this study was to investigate whether treatment with tumor necrosis factor (TNF) inhibitors combined with intravenous immunoglobulin (IVIG) increases live birth rates among women with recurrent spontaneous abortion (RSA) concurrently treated with anticoagulants (AC). METHOD OF STUDY: Seventy-five pregnancies in patients with a history of RSA were retrospectively evaluated. The population was divided into three groups: group I: 21 patients treated with AC (anticoagulants), group II: 37 patients treated with AC and IVIG, and group III: 17 patients treated with AC, IVIG and the TNF inhibitor Etanercept (Enbrel) or Adalimumab (Humira). In groups II and III, IVIG was administered at least once during the cycle of conception and/or at least once after a positive pregnancy test. In group III, either Adalimumab or Etanercept was administered by subcutaneous injection according to standard protocols. Statistical analysis of pregnancy outcome was performed using Fisher's exact test. RESULTS: Patient populations in the three treatment groups were similar in terms of age, past miscarriages, inherited thrombophilia and autoimmunity. The live birth rate was 19% (4/21) in group I, 54% (20/37) in group II, and 71% (12/17) in group III. There was significant improvement in pregnancy outcome in group II versus group I (P = 0.0127) and in group III versus group I (P = 0.0026). The live birth rate in group III compared to group II was not significantly different (P = 0.3723). Side effects of AC, IVIG and TNF inhibitor treatment were minimal in these patients, and no birth defects were identified in their offspring. CONCLUSION: In women with RSA, addition of either IVIG or a TNF inhibitor + IVIG to the AC regimen appears to improve live birth rates compared to the treatment with AC alone. The positive effect of IVIG and TNF inhibitor therapy on pregnancy outcome merits further study in prospective clinical trials.     

Clinical Trial of Immunostimulation with a Biological Response Modifier in Unexplained Recurrent Spontaneous Abortion Patients

We determined clinically whether a killed streptococcal preparation (KSP), a biological response modifier, is as effective as paternal lymphocyte immunotherapy for unexplained recurrent pregnancy abortion (RSA) therapy. The success rate of adverse pregnancy in the study group of 23 RSA cases, who were administered low doses of KSP before and during early pregnancy, was statistically compared with that in a control group of 205 women who received paternal lymphocyte immunotherapy. The association of natural killer (NK) cell activity in the peripheral blood with pregnancy outcome was also assessed. The success rate in the study group was 73.9% (17/23), compared to 75.1% (154/ 205) observed for the controls (not significant). Most of the successful cases exhibited low levels of NK cell activity in the peripheral blood. Immunotherapy with low doses of KSP is as effective as that with paternal lymphocytes, providing a simple and safe alternative therapy for unexplained RSA. Suppression of NK cell activity by some immunoregulatory mechanism was also found to have potential benefit in terms of a successful pregnancy outcome.