Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin.

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.

[Attitude and considerations of sperm donors in relation to insemination]. / Saeddonorers holdninger og overvejelser i forbindelse med donorinsemination.

The object of the study was to examine sperm donors' motivations and emotional reactions to the role as donors and to measure their willingness to provide information about themselves to recipients and offspring. It was designed as a prospective trial in which 26 subjects who were actively functioning as sperm donors at our fertility clinic at the time of investigation were asked to fill in a questionnaire and return it anonymously and voluntarily. Eight percent of the donors stated purely altruistic motivation, 32% purely financial and 60% a combination of both. The acceptance rate for providing non-identifying, phenotypic, descriptive information to recipients is 76%, for providing medical information it is 60% and the provision of psychosocial information is accepted by 28% to 40% depending on the item. Twenty percent of donors are willing to continue donation if the present rules of anonymity are revoked, 20% were undecided. In conclusion, most donors do not seem to feel any close relationship to donor offspring and at least 60% found anonymity to be essential for their continued functioning as donors.

Psychosocial aspects of donor insemination. Attitudes and opinions of Danish and Swedish donor insemination patients to psychosocial information being supplied to offspring and relatives.

BACKGROUND: The purpose of this study was to evaluate the attitudes and opinions among donor insemination recipient couples with respect to the informing of offspring and relatives, the effects of donor insemination on sexual life and marital status, and their concerns about the risk of getting a sexually transmitted disease. METHODS: A questionnaire study design. Three hundred and sixteen (194 Danish and 122 Swedish) couples were included. RESULTS: Answering rate among the Danish couples was 89% and among the Swedes 75%, (p < 0.01). Fifty percent of the Danish couples and 66% of the Swedes were of the opinion that the treatments should be kept secret from good friends, (p < 0.05). Sixty-seven percent of the Danes and 87% of the Swedes found it important that knowledge about the inseminations was not made common knowledge to all interested parties, (p < 0.005). Parameters in which there were no differences between Danes and Swedes: Fifty-one percent of the couples would withhold information about the insemination from the child even when it was old enough to understand this information. Seventy percent of the couples would prefer not to know themselves, whether they had been conceived by donor insemination. Nineteen percent of the Danish couples would not have accepted donor insemination if the legislation guaranteeing donor anonymity had not been in existence. Eighty percent thought that their sexual life was unaffected during the course of the treatment. When asked, 95% were still married to the same partner with whom they began the treatment. Eighty-five percent of the couples were worried about getting a sexually transmitted disease through the treatment. CONCLUSION: The results suggest that secrecy about the treatment and donor anonymity have a high priority among Danish and Swedish recipient couples, irrespective of the different legislation in the two countries.

Psychosocial aspects of donor insemination. Sperm donors--their motivations and attitudes to artificial insemination.

STUDY OBJECTIVES: To examine sperm donors' motivations and emotional reactions to the role of donors and to measure their willingness to provide information about themselves to recipients and offspring. DESIGN: A prospective trial in which the 26 subjects who were actively functioning as sperm donors in our fertility clinic at the time of investigation were asked to fill in a questionnaire and return it anonymously and voluntarily. MAIN RESULTS: 8% of the donors stated purely altruistic motivation, 32% purely financial and 60% a combination of both. The acceptance rate for providing non-identifying, phenotypic, descriptive information to recipients is 76%, for providing medical information it is 60% and the provision of psychosocial information is accepted by 28% to 40%, depending on the item. 20% of donors are willing to continue donation if the present rules of anonymity are revoked. CONCLUSIONS: Most donors do not seem to feel any close relationship to donor offspring and at least 60% found anonymity to be essential for their further functioning as donors.

Placebo-controlled trial of active immunization with third party leukocytes in recurrent miscarriage.

OBJECTIVE: To investigate whether active immunization with third party leukocytes improves pregnancy outcome in women with unexplained recurrent miscarriages. DESIGN: A double-blind prospective placebo-randomized trial. PATIENTS: Sixty-six patients with unexplained recurrent miscarriages achieved pregnancy after having received active immunization or placebo. INTERVENTIONS: Among the patients who achieved pregnancy, 43 were immunized with third party leukocytes and 23 received autologous leukocytes. MAIN OUTCOME MEASURES: Frequency of new miscarriages in actively immunized women compared with placebo. RESULTS: In the total group of patients, 71% of the actively immunized patients had a successful pregnancy compared with 48% of the placebo treated patients (not significant, RR = 0.6; 95% confidence limits = 0.3-1.1). In a subgroup of patients with primary recurrent miscarriages the success rate was 76% compared with 38% in the placebo group (p < 0.02, RR = 0.4; 95% confidence limits = 0.2-0.9). In this subset of patients, median birthweight was also significantly higher in actively immunized patients than in placebo treated patients (3445 g versus 3000 g; p < 0.05). CONCLUSIONS: Active immunization did not provide any benefit in the overall group of women with recurrent miscarriages. However, among women with primary recurrent miscarriages it may improve outcome with respect to the number of livebirths and birthweight.

Prognostic significance of maternal DR histocompatibility types in Danish women with recurrent miscarriages.

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.

[Habitual abortion is more frequent among women with low birth weight]. / Abortus habitualis er hyppigere hos kvinder med lav fødselsvaegt.

Information on the birth weight and gestational age at birth was obtained for 79 singleborn women with recurrent miscarriages, 60 of their male partners and, 474 female and 360 male controls. The mean birth weight of the women with recurrent miscarriages was 3265 g which was significantly lower than in female controls (p < 0.025). Of the women in the study group, 10.8% were born preterm compared with 2.9% of the controls (p = 0.01). The mean birth weight of the male partners in the study group did not differ significantly from that of the male controls. It is concluded that there is evidence for a reduced birth weight trait associated with recurrent miscarriages; the trait being manifests itself only in the woman.

Prospective study of anticardiolipin antibodies in immunized and untreated women with recurrent spontaneous abortions.

OBJECTIVE: To investigate whether active leukocyte immunization increases levels of anticardiolipin antibodies in women with recurrent spontaneous abortions. To assess the impact of anticardiolipin antibodies on pregnancy outcome in these women. DESIGN: Patients who had received various treatments in an ongoing randomized trial were studied prospectively. SETTING: A department of clinical immunology investigating women with recurrent spontaneous abortions from all over Denmark. PATIENTS: Eighty-nine patients with unexplained recurrent spontaneous abortions whose pregnancies had been completed during the course of the trial. INTERVENTIONS: After randomization, 44 patients were actively immunized with husband's or third party leukocytes, and 27 patients received placebo. Eighteen patients received anticoagulation therapy in pregnancy. MAIN OUTCOME MEASURES: Changes in levels of immunoglobulin (Ig)M class and IgG class anticardiolipin antibodies after active immunization. Frequency of new miscarriages in patients who were positive or negative for anticardiolipin antibodies. RESULTS: Neither IgM nor IgG anticardiolipin antibodies changed significantly after active immunization (P greater than 0.2). The interim results of the immunization trial showed a success rate of 68% in the treated group versus 56% in the placebo group (not significantly different). Relative risk of miscarriage in anticardiolipin antibody-positive patients compared with anticardiolipin antibody-negative patients was 1.3 (95% confidence interval 0.7 to 2.2; P = 0.4) in the combined study groups. CONCLUSIONS: Patients eligible for active immunization did not exhibit significant changes in anticardiolipin antibody levels subsequent to the treatment. The treatment did not seem to provide any overall benefit with respect to pregnancy outcome. Prospectively, the risk of miscarriage in patients positive for anticardiolipin antibodies was not significantly increased.

Study of the birthweight of parents experiencing unexplained recurrent miscarriages.

OBJECTIVE: To examine birthweight and preterm birth rates in couples with unexplained recurrent miscarriages. DESIGN: A case control study. Birth data of couples with recurrent miscarriages were obtained from midwife records. Time and sex-matched births from the same records served as controls. SETTING: A Regional Hospital in Denmark. SUBJECTS: 79 singleborn women with recurrent miscarriages and 60 of their male partners comprised the main study groups. Two control groups comprised 474 female and 360 male singleborn infants who survived day 7 postpartum. MAIN OUTCOME MEASURES: Mean birthweight in the two main study groups and in subgroups with histories of 3, 4 and greater than or equal to 5 miscarriages. RESULTS: The mean birthweight of the women with recurrent miscarriages was 3265 g (SE 70) and in female controls 3414 g (SE 23) (P less than 0.025). The 17 women with five or more miscarriages had a mean birthweight of 2991 g (SD 140) (P less than 0.001 compared with controls). Of the women in the study group 10.8% were born preterm compared with 2.9% of the controls (P = 0.01). The mean birthweight of the male partners in the study group, 3470 g (SE 68), did not differ significantly from that of 3504 g (SE 31) in the male controls (P less than 0.5). CONCLUSIONS: Women suffering unexplained recurrent miscarriages have on average had a significantly lower than normal birthweight themselves, whereas this was not observed in their male partners. This points towards the existence of a birthweight-reducing trait associated with recurrent miscarriages, the trait being manifest only in the woman.

Intravenous immunoglobulin treatment of women with multiple miscarriages.

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.

[Measurement of luteinizing hormone in urine and donor insemination]. / Urin-luteiniserende hormon måling og insemination ved donor.

The pregnancy rates after artificial insemination with donor sperm (AID) were investigated in 15 patients using the Ovu-Quck urinary LH-test to determine the time of ovulation. In 15 patients the time of ovulation and AID were determined by basal body temperature charts and served for comparison. Five patients in the Ovu-Quick group and 2 patients in the control group were excluded. The pregnancy rates in the Ovu-Quick group, four (40%) of 10 patients, were not statistically different from the pregnancy rates in the control group, 4 (31%) of 13 patients. It is concluded that a simple and rapid urinary LH-test might be an important parameter for predicting the time of ovulation.

Effect of organic and inorganic mercury on human sperm motility.

The effects of mercuric chloride and methyl mercuric chloride on the motility of human spermatozoa in vitro were investigated. Organic as well as inorganic mercury compounds decreased the percentage of motile spermatozoa. After 15 min. incubation with 40 microM mercuric chloride a significant decrease in sperm motility was observed. Less than 5% of spermatozoa were motile after 30 min. of exposure to 20 microM methyl mercuric chloride. These effects could not be attenuated by addition of 5 microM sodium selenite. The ultrastructural localization of mercury was demonstrated by autometallography. Silver-enhanced mercury deposits could be demonstrated only in spermatozoa exposed to inorganic mercury. In these cells mercury grains were most abundant in membranes of midpiece and tail.

HLA or HLA-linked genes reduce birthweight in families affected by idiopathic recurrent abortion.

HLA typing was performed in 49 families, each containing at least one woman with a history of unexplained recurrent spontaneous abortion (RSA), and reproductive histories were recorded for the siblings. Abortion rate in sisters sharing two HLA haplotypes with the proband was significantly (p less than 0.01) increased, whereas abortion rates of brothers' wives seemed independent of the brothers' degree of HLA sharing with the proband. Birthweights of offspring of both the sisters and the brothers decreased with increasing HLA haplotype identity between the sibling and the proband (p = 0.05). The mean birthweight of infants of siblings sharing both parental haplotypes with the proband was 3158 g which was significantly (p less than 0.02) less than the average birthweight in Denmark (3417 g). Significantly (p less than 0.05) decreased mean birthweight in infants of brothers who were HLA-identical with the proband suggested that the disposition to growth retardation could be inherited with HLA also through the male gametes. It has been shown that, in their few successful pregnancies, women with RSA bear infants with a birthweight which is approximately 300 g less than normal. The present study demonstrated that the two obstetrical conditions, RSA and retarded fetal growth, share common genetic markers: HLA. It is suggested that HLA or HLA-linked genes causing growth retardation in fetuses are part of the putative complex of genes involved in the pathogenesis of recurrent abortion.

Idiopathic recurrent spontaneous abortion. Evidence of a familial predisposition.

Pregnancy outcome was investigated: 1) in fifteen women suffering from idiopathic recurrent spontaneous abortion (RSA) and who had experienced pregnancies with two different partners, and 2) in the mothers, the sisters and wives of the brothers of 90 consecutively referred women with RSA. After adjusting for ascertainment bias, the patients with 2 partners had an abortion rate of 72% with the first spouse (significantly increased compared with the expected rate) and a nearly 100% abortion rate with the second spouse. This suggests that, in the main, RSA is not partner-specific. The sisters of the patients had suffered a significantly increased miscarriage rate (25.3%) compared with the observed rate in a Danish control group. The wives of the brothers had an abortion rate of 18.8%, which was not significantly increased vis-à-vis the controls. The sisters showed a lifetime incidence of RSA (10.6%) which was significantly greater than comparable estimates in the literature. These results suggest the existence of a familial predisposition to spontaneous abortion in families where RSA occurs.

Uterine myoma in pregnancy.

A review was made of the medical records of 76 patients with uterine myomas during pregnancy with the aim of studying the time and method of diagnosis, symptomatology, treatment, and outcome of pregnancy. In 11 patients (15%) myomectomy was performed during pregnancy. The frequency of abortion was 18% in patients treated both conservatively and with myomectomy. Myomectomy during pregnancy is discouraged in the literature. In cases where conservative treatment cannot be practised it seems that the risk of spontaneous abortion during pregnancy is not significantly increased when myomectomy is performed.

Prognostic value of semen analyses in infertility evaluation (male fertility/life-table analysis).

The aim of the present study was to evaluate which of the various parameters of semen analysis that are most significantly related to the obtainment of pregnancy. A follow up questionnaire was sent to 1953 couples, who had been examined for infertility, and 1,480 (76%) replied. We focused on 713 of these couples, in whom the female partner had a normal fertility set-up (potentially fertile). This study suggests that sperm vitality and sperm concentration bear the most significant relation to pregnancy. Evaluation of a couple's fertility potential by means of the life-table method shows a gradual increase in the pregnancy rate of all couples, irrespective of semen quality, during a observation period of 10 years. The pregnancy rate after 5 years was 14% in a group with reduced semen quality and 44% in a group with normal semen quality.

Autoimmune associated recurrent abortions.

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.