The prognostic value of anti-paternal antibodies and leukocyte immunizations on the proportion of live births in couples with consecutive recurrent miscarriages

Anti-paternal antibodies directed towards paternal leukocytes have been used to predict the prognosis for the subsequent pregnancy in women with consecutive recurrent miscarriages (CRM) and also to determine if the patient has become immune after paternal leukocyte immunization. The predictive value is controversial, as these antibodies are not essential for pregnancy to develop, and only occur in a minority of parous women. This study tried to determine the predictive value of these antibodies when assessed separately for women with five or more abortions and compared to women with three or four abortions. The patients were assessed separately so that the higher live birth rate in the latter group would not obscure meaningful results in the former group with a poor prognosis. Antibody production, whether spontaneous, or induced by immunization, raised the live birth rate in primary and tertiary aborters with three, four, five or more abortions. Anti-paternal antibodies increased the proportion of live births from 18.5 to 53. 7% (P /= 5 CRM and 3-4 CRM respectively. Both immunization with paternal leukocytes per se and the ability to express anti-paternal antibodies were associated with an increased proportion of live births in the next pregnancy. Multivariate analysis showed that that the odds ratio for a live birth was approximately four times greater in women who were immunized and produced anti-paternal antibodies than in control patients. The lack of anti-paternal antibodies at initial testing could serve as a marker for the benefit of immunization with paternal leukocytes; the subsequent presence as a prognostic marker for the subsequent pregnancy.     

Pregnancy outcome following exposure to gonadotrophin-releasing hormone analogue during early pregnancy: comparisons in patients with normal or elevated luteinizing hormone

The outcomes of established pregnancies following the treatmentof infertile women with pituitary down-regulation before andduring treatment with ovulation induction and either intrauterineinsemination or timed intercourse were reviewed. Once startedon gonadotrophin-releasing hormone analogue (GnRHa) treatment,the patients were maintained on GnRHa therapy throughout thefollowing luteal phase to facilitate the start of the next treatmentcycle if no pregnancy was established. This resulted in patientstaking GnRHa until a positive pregnancy test indicated cessationof the treatment. The aim of our study was to determine whetherexposure to GnRHa during early pregnancy constituted a risk.Patients who were diagnosed as having elevated follicular phaseluteinizing hormone (LH) concentrations during their investigationswere analysed as a separate cohort to assess whether this diagnosishad implications with respect to pregnancy outcome. Out of 226recorded clinical pregnancies, 173 were traced and the datacollated: 16 cases resulted in clinical abortions, two wereectopic pregnancies and 155 women had live births at variousages of gestation. There were three pregnancies which were complicatedby congenital abnormalities. Patients with elevated LH concentrationson examination showed a higher rate of total pregnancy lossthan those with normal LH concentrations, despite the fact thatthe LH was suppressed during the cycle in which they conceived.The results suggest that pregnancy outcome is not adverselyaffected by GnRHa administration during the luteal phase ofthe conception cycle, and that the group diagnosed as havingelevated LH concentrations may retain their propensity to higherrates of pregnancy loss even when their LH concentrations aresuppressed during treatment.     

Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies

BACKGROUND: Some cases of recurrent miscarriage and later pregnancy complications have a thrombotic basis. Factor V Leiden is a common thrombophilic mutation. METHODS: The prospective outcome of untreated pregnancies amongst 25 women heterozygous for the Factor V Leiden allele who had a history of either recurrent early miscarriages only (three or more miscarriages at <12 weeks gestation; n = 19) or of late miscarriage (>12 weeks gestation; n = 9) was studied. Control groups of women with a similar pregnancy history but who had a normal Factor V genotype were also studied. RESULTS: The live birth rate was significantly lower amongst women with a history of recurrent early miscarriage who carried the Factor V Leiden allele (6/16; 37.5%) compared with that amongst those with a normal Factor V genotype (106/153; 69.3%; odds ratio 3.75, 95% confidence intervals 1.3-10.9). The live birth rate was 11.1% (1/9) amongst those with a history of late miscarriage carrying the Factor V Leiden allele and 48.9% (22/45) amongst those with a normal Factor V genotype. CONCLUSIONS: Attention should be directed at screening women with recurrent miscarriage associated with placental thrombosis for Factor V Leiden and a policy of targeted thromboprophylaxis during future pregnancies should be assessed in the form of a randomized controlled trial.     

Further experience with intravenous immunoglobulin in women with recurrent miscarriage and a poor prognosis

PROBLEM: Women with three or more unexplained miscarriages have a 60% chance of a subsequent live birth. Intravenous immunoglobulin (IVIG) has not been conclusively shown to improve this prognosis. This study assessed the effect of IVIG in patients expected to have a poor outcome if untreated, i.e. women with five or more abortions, who have aborted after paternal leukocyte immunization or who continue to abort despite expressing anti-paternal complement dependent antibody. METHODS: Seventy-six women received IVIG in a dose of 400 mg/kg body weight, in one day (total 30-45 g) in the follicular phase of a cycle in which pregnancy was planned. A booster dose was administered when pregnancy was diagnosed. Their results were compared to an untreated control group of 74 women. RESULTS: Thirty-five (49%) pregnancies in treated women have resulted in live births or passed their previous stages of abortion compared to 23 (31%) in control patients (P = 0.04). CONCLUSIONS: These figures indicate that IVIG may prevent further miscarriages in this poor prognosis population. These figures are especially significant considering the doubt concerning the efficacy of IVIG in patients with three miscarriages and therefore a relatively good prognosis.     

Treatment of Recurrent Spontaneous Abortion by Immunization With Paternal Lymphocytes: Results of a Controlled Trial

PROBLEM: It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded. METHOD: A double-blind placebo controlled trial was instituted in women with unexplained recurrent spontaneous abortion, comparing immunization with 400 million paternal to 400 million maternal (autologous) lymphocytes. The groups were compared in a paired sequential trials chart, by logistic regression, and, in addition, a meta-analysis of this and other published trials was carried out. RESULTS: The live birth rate among pregnancies in paired couples with paternal lymphocyte immunization was 68% compared to 47% in the women who received their own cells. The results bordered on, but did not achieve, statistical significance. The women in each group were thoroughly investigated to exclude known causes of recurrent pregnancy loss and appeared to have been well matched in all variables. Women with lymphocytotoxic antibodies against paternal lymphocytes were excluded. Unlike our previous study there was not association between the time to conception and the chance of a successful outcome. Indeed, the time to conception was relatively short, 12 wk in all groups. The meta-analysis supported an overall modest favorable experience with paternal cells. CONCLUSION: The study is consistent with a general trend favoring paternal over maternal lymphocyte immunization but reinforces the need for larger multicenter controlled trials as well as more detailed biological study in humans to understand the nature of the maternal-fetal interface and its breakdown.     

Genetic variant of luteinizing hormone in women with a history of recurrent miscarriage

Because the biological and clinical significance of a geneticvariant of luteinizing hormone (LH) is unclear, we thereforeevaluated the occurrence of variant LH in women with a historyof recurrent spontaneous abortion (RSA) and related it to specificLH concentrations, luteal function and pregnancy outcome. Ofthe 85 RSA women, 30 (35.3%) had variant LH (28 heterozygousand two homozygous), and 55 women (64.7%) a normal wild-typeLH ratio. These frequencies are similar to those reported fromthe general Finnish population. No significant differences wereobserved in specific LH concentrations based on LH status (7.2± 1.4 IU/l, mean ± SEM, variant LH, versus 8.5± 1.6 IU/l, wild-type LH). Variant LH was twice as commonin women with body mass index (BMI) > 25 kg/m² (9/15, 60.0%)than in those with BMI 25 kg/m² (21/70, 30.0%, P < 0.05).The presence of variant LH was not associated with any cleareffect on endocrine variables such as endometrial maturationor mid-luteal phase oestradiol and progesterone concentrations.During follow-up, 23 women with variant LH (76.7%) and 41 withwild-type LH (74.5%) became pregnant: 14 miscarried (21.9%,six with variant LH and eight with wild-type LH) and two hadectopic pregnancies, whereas 48 (75.0%) succeeded (17 with variantLH and 31 with wild-type LH). LH concentrations before pregnancywere similar in women with a successful outcome (8.0 ±1.3 IU/l) or with a miscarriage also in that pregnancy (7.4± 1.4 IU/l). In conclusion, variant LH is common in RSAwomen who are relatively overweight (BMI > 25 kg/m²) butits presence is not reflected in endometrial maturation andmiscarriage rates.     

Leptin and leptin-binding activity in women with recurrent miscarriage: correlation with pregnancy outcome

BACKGROUND: Previous studies in humans and mice have suggested the importance of leptin in fetal growth. Recurrent miscarriage may be a result of abnormal placental and/or fetal development and therefore abnormal leptin levels may be associated with this form of pregnancy loss. METHODS: Leptin and leptin-binding activity (LBA) were measured in blood obtained from women who had a history of recurrent miscarriage (n = 53) during weeks 5-6 and 7-8 of pregnancy, and the concentrations were correlated with subsequent pregnancy outcome. RESULTS: Concentrations of leptin ranged from 1.4-62.8 ng/ml, but there was a strong correlation (r = 0.825, P < 0.001) between leptin values at weeks 5-6 and 7-8 in the same woman. Women who subsequently miscarried had significantly lower plasma leptin concentrations on both weeks 5-6 (13.34 +/- 2.1 ng/ml) (P < 0.05) and 7-8 (13.71 +/- 2.4 ng/ml) (P < 0.01) of pregnancy, than women who subsequently had a term birth (22.04 +/- 2.43 ng/ml week 5-6, 24.76 +/- 3.66 ng/ml week 7-8). LBA values ranged from 1-8.5% but there was no significant difference in LBA in blood obtained from women who subsequently miscarried or had a live birth. CONCLUSIONS: The significantly lower concentrations of leptin in women who subsequently miscarried suggest that leptin may play a role in preventing miscarriage. However, as there was a considerable overlap between the values of leptin in women who subsequently miscarried, and those that had a live birth, these measurements are of limited use in the prediction of pregnancy outcome in these women.     

Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH

BACKGROUND: It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations. METHODS: A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used. RESULTS: The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (<1, < or =0.7, <0.5 IU/l) to discriminate between women with 'low' or 'normal' LH were applied to our study population. No significant differences were found with respect to ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy between 'low' and 'normal' S7 LH women as defined by those threshold values. CONCLUSIONS: Our results do not support the need for additional exogenous LH supplementation in down-regulated women receiving a recombinant FSH-only preparation.     

IVF/ICSI outcome and serum LH concentration on day 1 of ovarian stimulation with recombinant FSH under pituitary suppression

BACKGROUND: Down-regulation with GnRH agonist has been suggested to result in a profound suppression of LH bioactivity, reduced estradiol synthesis, and thus impaired IVF and pregnancy outcome. The aims of this study were: (i) to assess the usefulness of serum LH measurement on stimulation day 1 as a predictor of ovarian response, conception and pregnancy outcome in patients treated with long-term down-regulation with GnRH agonist and recombinant FSH, and (ii) to define the best threshold LH value, if any, to discriminate between women with different outcomes of IVF. METHODS: Records of 2625 cycles in 1652 infertile women undergoing IVF (n = 1856) and/or ICSI (n = 769) treatment were reviewed. RESULTS: The range of LH concentrations on stimulation day 1 overlapped among non-conception cycles, conception cycles, ongoing pregnancies and early pregnancy losses. Receiver operating characteristic (ROC) analysis showed that serum LH concentrations on stimulation day 1 were unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.51; 95% CI: 0.49-0.54) or ongoing pregnancies versus early pregnancy loss groups (AUC(ROC) = 0.52; 95% CI: 0.47-0.57). Stratification for various low serum levels of LH did not reveal significant differences with respect to conception or pregnancy outcome among different LH levels on stimulation day 1. CONCLUSIONS: Serum LH concentration on stimulation day 1 cannot predict ovarian response, conception and pregnancy outcome in women receiving long-term down-regulation during assisted reproduction treatment.     

The Effectiveness of Allogeneic Leukocyte Immunization in Unexplained Primary Recurrent Spontaneous Abortion

PROBLEM: Unexplained primary recurrent spontaneous abortion (RSA) can be viewed as a partner-specific problem for which immunization with allogeneic leukocytes is being offered as therapy. Published data from randomized controlled trials have produced conflicting results regarding treatment effectiveness. The aim of this study was to perform a subgroup analysis of the data from a recent worldwide collaborative meta-analysis using the raw data for patients with primary RSA entered into randomized controlled trials of immunotherapy. METHODS: Data from randomized controlled trials in eight centers were included in this analysis. Individual patients were included only if they had had three or more spontaneous abortions, no previous pregnancy beyond 20 weeks' gestation, no identifiable cause for the abortions, and no evidence of antipaternal antibodies. Meta-analysis by centre and logistic regression analysis were performed to determine the overall effect of treatment in achieving live birth and to identify variables that affect the prognosis for a successful outcome. RESULTS: In the meta-analysis by center, immunotherapy significantly improved the live birth rate (common odds ratio = 1.94, 95% confidence interval (CI) = 1.20 to 3.12). In the analysis by patient, the likelihood of a successful outcome was also significantly better with treatment (relative risk = 1.46, 95% CI 1.19 to 1.69). The absolute treatment effect was 16.3% producing a number needed to treat of 6. The number of previous abortions had a significant negative correlation with live birth rate, such that for each additional pregnancy loss beyond three, the likelihood of live birth was reduced by 23%. CONCLUSION: Allogeneic leukocyte immunization is an effective treatment for unexplained primary RSA when pretreatment antipaternal antibodies are absent. Better diagnostic tests are required to identify patients who may derive maximal benefit from this therapeutic approach.     

A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth rates

BACKGROUND: The effect of early- and mid-follicular LH concentrations on the ovarian response and pregnancy outcomes was evaluated in women receiving pituitary down-regulation with a GnRH agonist and ovarian stimulation with recombinant FSH (rFSH) during IVF/ICSI treatment. METHODS: Blood samples were collected prospectively from 701 cycles (560 patients) of assisted reproduction and analysed retrospectively. On the basis of LH concentrations on stimulation day 7/8, the patients were divided into two groups: LH<1.2 IU/l (n=179) and LH>or=1.2 IU/l (n=522). Cycle outcomes were also compared on the basis of a ratio of mid- to early-follicular LH concentrations (0.5, n=491). RESULTS: Patients with low LH concentrations were found to have a significant reduction in the late-follicular estradiol concentrations (P<0.001), the number of oocytes retrieved (P<0.01) and the number of usable embryos (P<0.01), and they required significantly more rFSH (430 IU difference, P<0.01). These differences did not translate into a significant change in live birth rates. Conversely, a ratio of or=50%) was associated with a significant reduction in live birth rates per embryo transfer and per cycle started (27.3 versus 19.0%, P<0.05 and 22.2 versus 15.8%, P<0.05, respectively). CONCLUSIONS: Low mid-follicular levels of LH have a significant impact on ovarian response but not on live birth rates. A fall in LH level of >or=50% from the early- to mid-follicular phase resulted in a lower live birth rate.     

Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study

The purpose of the present study was to determine whether adrenalandrogen suppression with dexamethasone (DEX) during ovulationinduction improves the outcome of in-vitro fertilization (IVF)cycles. A total of 25 patients with serum dehydroepiandrosteronesulphate (DHEAS) concentrations>2.5 µg/ml were randomizedto receive either 0.5 mg DEX daily or placebo during ovulationinduction with leuprolide acetate down-regulation plus humanmenopausal gonadotrophins (HMG). Nine patients undergoing asubsequent IVF cycle were crossed over to the other treatmentgroup. Ovarian responsiveness and IVF outcome variables analysedincluded number of follicles>12 mm in diameter, serum oestradiolconcentrations on the day of human chorionic gonadotrophin (HCG)administration, number of ampoules of HMG administered, numberof oocytes retrieved, percentage of oocytes fertilized, numberof embryos transferred, implantation rate and numbers of clinicalpregnancies and live birth pregnancies. The 31 randomized IVFcycles revealed a trend towards a higher implantation rate forthe placebo-treated group compared to the DEX-treated group(24 versus 10%P=0.07). The remainder of the IVF cycle variablesrevealed no statistically significant differences. In conclusion,the suppression of adrenal androgens with DEX in women withDHEAS concentrations >2.5 µg/ml appears to have nobeneficial effects on ovarian responsiveness or clinical orlive birth pregnancy rates.     

Immunotherapy for Recurrent Pregnancy Loss: Analysis of Results From Clinical Trials

PROBLEM: Up to 80% of unexplained recurrent spontaneous abortions (RS A) are thought to have an immunologic mechanism. Yet clinical trials using immunotherapy to treat women experiencing RSA have low treatment effects. The present study was undertaken to explain the low treatment effects. METHODS: Results of clinical trials using allogeneic leukocyte immunization and intravenous (IV) immunoglobulin (Ig) are compared. The mechanisms of pregnancy loss are reviewed in light of data on frequency of karyotype abnormalities in trophoblast of failing pregnancies. RESULTS: Results of two independent analyses using allogeneic leukocyte immunization as immunotherapy for all women with RSA revealed live birth ratios of 1.16 (P = 0.03) and 1.21 (P = 0.02). When the analysis was limited to primary aborters, the live birth ratio increased to 1.46 (P = 0.006). Live birth ratio after immunotherapy for all RSA using IVIg was 1.88 (P = 0.04). Because of low treatment effects, confounders to treatment success of maternal age and number of previous abortions were studied. Chromosomal abnormalities have been identified in 55% of concepti from RSA. The frequency of chromosomal abnormalities remained constant for up to six pregnancy losses. Women with a history of primary compared to secondary RSA had a higher frequency of karyotypically abnormal concepti (χ² = 4.54, P < 0.05). Risk factors for RSA also include number of previous losses. CONCLUSION: Chromosomal abnormalities are a significant confounder when evaluating efficacy of immunotherapy for treatment of RSA. Some women with RSA have a high risk of recurrent chromosomal problems.     

Anti-paternal antibodies by flow cytometry in the management of alloimmunization on recurrent miscarriages

PROBLEM: There is no reliable laboratory test available to diagnose immunologically mediated miscarriages. We investigated the clinical significance of maternal anti-paternal leukocyte antibodies by flow cytometry after alloimmunization. METHOD OF STUDY: The flow cytometry crossmatch (FCXM) was performed in 158 patients with a history of three or more unexplained first-trimester miscarriages without live birth. After negative FCXM patients were immunized, subsequent pregnancy outcomes and FCXM results were followed. RESULTS: Of 112 subsequent pregnancies, 83 of 100 (83.0%) FCXM-positive patients after immunotherapy had successful pregnancy outcomes, whereas seven of 10 (70.0%) FCXM-negative patients had miscarriages (P = 0.0001). The percent live birth ratio was 2.77 (CI, 1.07-7.16; P=0.0001) for FCXM-positive patients compared to FCXM-negative patients. The calculated predictive value showed that 75.6% of FCXM-negative patients would have subsequent miscarriages. CONCLUSIONS: Positive FCXM is closely associated with successful pregnancy outcome following immunotherapy. We propose that FCXM might be included in the routine laboratory tests for the management of recurrent miscarriages.     

Intravenous Immunoglobulin in Women With Five or More Abortions

PROBLEM: Treatment for recurrent miscarriage has usually been given to all women with three or more abortions of unknown cause. As these patients have a 50–60% subsequent live birth rate, no treatment has been shown to unequivocally improve the live birth rate. Immunoglobulin is the latest treatment to be applied. In order to determine if immunoglobulin improves the live birth rate, we analyzed the results of patients expected to have a poor outcome in the subsequent pregnancy if left untreated, i.e., women with five or more abortions, who have aborted after paternal leucocyte immunization or who continue to abort despite possessing anti-paternal complement dependent antibody (APCA). METHODS: A preliminary trial was carried out using immunoglobulin (Sandoglobulin, Sandoz, Switzerland). It was infused at a dose of 400mg/Kg body weight, in the follicular phase of a cycle in which pregnancy was planned. A booster dose was administered as soon as pregnancy was diagnosed. RESULTS: Twelve patients were treated, ten conceived. Five have had subsequent live births. Two infants were premature but their size was appropriate for gestational age. The other three infants delivered at term. CONCLUSIONS: This is still too small a group from which to draw definite conclusions about the efficacy of immunoglobulin to prevent abortion. However, five live births in ten patients is an encouraging result, especially when the expected poor obstetric outcome is considered. Hence the efficacy of immunoglobulin should be evaluated further in high risk patients.     

High risk pregnancies in hypopituitary women

BACKGROUND: Various short papers have suggested that pregnancies in women with hypopituitarism are high risk but no formal assessment of pregnancy outcome has yet been reported. METHODS: An audit was carried out concerning the outcome of 18 pregnancies in nine women who underwent ovulation induction in a single centre over 20 years. RESULTS: The live birth rate was 61%, miscarriage rate 28% and mid-trimester uterine death rate 11% with no survivors from four sets of twins. The Caesarian section rate was 100% and half of the live births were on or below the 10th centile for weight. One woman successfully breast-fed. CONCLUSIONS: Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies with application of particularly strict criteria to avoid twin pregnancies. Early elective Caesarian section is probably warranted in this group.     

Pregnancy Outcomes in Japanese Patients with SLE: Retrospective Review of 55 Pregnancies at a University Hospital

Systemic lupus erythematosus (SLE) is mainly a disease of fertile women and the coexistence of pregnancy is by no means a rare event. How SLE and its treatment affect pregnancy outcomes is still a matter of debate. We performed a retrospective analysis of 41 SLE patients (55 pregnancies) who were followed at our university hospital from January 2000 to December 2009. The mean age of patients was 30.6?±?4.8 years and mean disease duration was 6.6?±?5.3 years. After exclusion of artificial abortions, live birth rate was 84%. Significantly, more women with stillbirth pregnancies were complicated with antiphospholipid syndrome (APS) than women with live birth pregnancies (two of eight stillbirth pregnancies (25%) versus one of 42 live birth pregnancies (2%); p?=?0.014) and hypocomplementemia at conception (four of eight stillbirth pregnancies (50%) versus six of 42 live birth pregnancies (14%); p?=?0.021). Compared with nonrenal pregnancies, renal pregnancies were younger at SLE disease onset, had a lower positivity of anti-RNP antibody, and were more complicated with pregnancy-induced hypertension. Past maximum dose of prednisolone, the dose of prednisolone at conception, and percentage of past steroid pulse therapy were higher in renal pregnancies. Outcomes of pregnancies were not significantly different both for mothers and for infants between renal and nonrenal pregnancies. We conclude that it is necessary to provide SLE mothers with the proper information before pregnancy. Women with APS or hypocomplementemia should be regarded with particular attention. Optimal management of mothers and infants requires collaborative efforts of rheumatologists and obstetricians.     

Worldwide Collaborative Observational Study and Meta-Analysis on Allogenic Leukocyte Immunotherapy for Recurrent Spontaneous Abortion1

PROBLEM: Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no known cure. Therefore, effective treatment is needed. Published results from controlled clinical trials of allogeneic leukocyte immunization of women suffering from RSA have given conflicting results. To address this controversy, the international raw data of all patients who had been entered into clinical trials that included a control group were collected and analyzed. The primary question to be answered was whether alloimmune stimulation of the female partner improves the subsequent live birth rate. METHODS: Fifteen clinical centers were identified worldwide because they controlled appropriate raw data. Consequently, nine randomized trials (seven double-blinded) were evaluated independently by two separate data analysis teams to assure conclusions were robust. One team also compared randomized trials to the results of six nonrandomized cohort-controlled studies to test for bias in nonrandomized trials. Factors predicting successful live births among couples with RSA were evaluated by logistic regression. RESULTS: Although the two independent analyses made use of different definitions and utilized different statistical methods, the results of both were similar. The live birth ratios (ratio of live births in treatment and control groups) with 95% confidence intervals (CI) were 1.16 (CI, 1.01-1.34, P = 0.031) and 1.21 (CI, 1.04-1.37, P = 0.024), respectively. The absolute differences in live birth rates between treatment and control groups were 8% and 10% in respective analyses. Results in randomized and nonrandomized trials were surprisingly similar despite significant differences in composition of control and treatment groups. Live birth rates were lower with older female partners, more than five abortions, with a positive ANA or with positive anticardiolipin antibodies. Live birth rates were higher if the female partner had prior to treatment serum antibodies to paternal leukocytes or converted from negative to positive with immunization. Approximately 0.5% of controls and 2.1% of treated patients experience side effects for a 1.6% treatment related effect. There was no evidence of an increased risk of adverse effects on the fetus. CONCLUSIONS: Two independent analyses of worldwide data on allogeneic leukocyte immunization for treatment of RSA suggest that alloimmunization may be an effective treatment. The treatment effect appears, however, to be small, and the data indicate that immunotherapy helps only 8% to 10% of affected couples. A current lack of diagnostic tests defining patients who most likely would benefit from immunotherapy, precludes the identification of a patient population that would benefit most from such treatment. The efficacy of treatment in such a subgroup could be expected to increase and could be of sufficient magnitude to allow the determination of more effective immunization protocols. This study does not exclude the possibility of a partial correction of a widely prevalent immunology defect by immunotherapy. The presence of such a defect would indicate a need for more effective therapy. The unexplained variation in pregnancy success rates of control groups among centers continues to present a statistical problem, limiting the statistical evaluation of retroactively obtained data.     

Fertility Among Women With Recurrent Spontaneous Abortions—The Effect of Paternal Cell Immunization Treatment

PROBLEM : The risk of women whose chief complaint is recurrent spontaneous abortions (RSA) for secondary infertility (infecundability) has not been evaluated prospectively. The effect of paternal mononuclear cell immunization on conception rates is unknown. METHOD : Two hundred women whose chief complaint was RSA were randomly assigned to be immunized with paternal mononuclear cells either before or after (up to 6 postmenstrual weeks) conception. Fertility rates (both conception and live birth) were evaluated for the group immunized before conception and compared to those for the control group, who were not immunized until after conception, using life table and multiple logistic regression analyses. RESULTS : Prospectively ascertained, age-related conception rates for nonimmunized RSA controls appeared to be similar to those for general populations. Immunization before pregnancy had no significant effect (power ± 14%) on rates of conception (66% before, 77% after) or time to conceive (median weeks before 19.5, after 27.0). Live birth rates (before 59%, after 63%) were also similar for both groups (P = 0.7). CONCLUSION : Women whose only prior complaint was RSA were not at high risk for secondary infecundability, and immunization did not alter either conception rates or time to conceive. Postponement of immunization until after conception did not affect live birth rates for women selected for study because they did not have a history of prior infecundability or early repeated miscarriages.