Progestogens and pregnancy loss.

Progestational agents are often prescribed to prevent pregnancy loss. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. Progestogens have therefore been used at all stages of pregnancy including luteal-phase support prior to pregnancy, threatened miscarriage, recurrent miscarriage, and to prevent preterm labor. In luteal support, a Cochrane review reported that progestogens were associated with a higher rate of live births or ongoing pregnancy in the progesterone group (odds ratio 1.77, 95% confidence interval (CI) 1.09-2.86). Evidence suggests that progestogens are also effective for treating threatened miscarriage. Again, in a Cochrane Database review, progestogens were associated with a reduced odds ratio of 0.53 (95% CI 0.35-0.79) when progestogens were used. In recurrent miscarriage, progestogens also seem to have a beneficial effect. A meta-analysis of progestational agents showed a 28% increase in the live birth rate (relative risk 0.72, 95% CI 0.53-0.97). For the last 30 years, progestogens have been used to prevent preterm labor. Recent meta-analyses also report beneficial effects. This review summarizes the literature and the author's experience using progestogens to prevent pregnancy loss.

Recurrent miscarriage and hCG supplementation: a review and metaanalysis.

Human chorionic gonadotropin (hCG) has been used to prevent subsequent miscarriages after previous recurrent miscarriages. In addition to the luteotrophic effects, hCG has uterine immune and autocrine actions. hCG also affects cytokine expression. A Cochrane database systematic review has indicated that hCG seems to prevent further miscarriages, (OR for miscarriage = 0.26, 95% CI 0.14-0.52). However, the trials in the Cochrane database were not matched for the number of miscarriages, 1°, 2° or 3° aborter status, maternal age, etc. and no account was made for chromosomally abnormal pregnancies. All of these impact on the subsequent prognosis and may confound the results. The previous trials in the literature all assessed urinary (u-hCG) rather than recombinant hCG (r-hCG), raising the question whether the effect on pregnancy outcome is due to hCG itself, or other urinary proteins present in u-hCG. A new trial is indicated in which r-hCG is compared to u-hCG and the most effective compared to placebo. Treatment and placebos arms should be stratified for the prognostic factors above and the results corrected for fetal chromosomal aberrations. Until such a trial is carried out, the use of hCG supplementation is empiric.

Sixth meeting of the European Forum on antiphospholipid antibodies. How to improve the understanding of the antiphospholipid syndrome?

The main objective of these meetings is to promote international collaboration in various clinical and research projects. This paper is the summary of the 2007 Ljubljana meeting, and offers an overview of the proposed projects. The technical and methodological details of the projects will be published on the forum's web site (http://www.med.ub.es/MIMMUN/FORUM/STUDIES.HTM).

Autoantibodies as predictors of pregnancy complications.

Certain autoantibodies which are found in autoimmune diseases including CTDs can impair fertility. Reproductive failure may present as pregnancy loss, either as miscarriage, intrauterine fetal death or stillbirth. There are also late obstetric complications such as intrauterine growth restriction, pre-eclampsia and pre-term birth. This review summarizes the possible influences of autoantibodies in reproductive failure, and particularly their predictive value (if available). The aPLs detectable by lupus anticoagulant, anti-cardiolipin or anti-beta2 glycoprotein I assays are associated with pregnancy loss and have a positive predictive value (PPV) of 75%. In spite of the general consensus on the management of pregnant aPL-positive women, few well-designed clinical trials have been reported and there is also insufficient data about the PPV of treatment. Anti-thyroid antibodies have been associated with pregnancy loss, and indeed have a PPV of 40%. However, no antibody is pathognomic for pregnancy loss. It may be more appropriate to assess a combination of antibodies rather than one antibody. However, a large meta-analysis of published trials is required in order to determine the prevalence of each particular autoantibody and different combinations of antibodies in different forms of reproductive failure.

Anti-phospholipid antibodies and infertility.

Antiphospholipid syndrome (APS) or the presence of antiphospholipid antibodies (aPL), usually presents as pregnancy loss. However, aPL have also been reported to affect implantation, placentation, and early embryonic development. The binding of aPl to beta2GP1 may lead to breakdown of the phospholipid adhesion molecules between different elements of trophoblast. As aPL affect placental growth and function, aPl may prevent implantation presenting as infertility. Lupus anticoagulant and anticardiolipin antibody have been implicated in the prothrombotic effects of APS. Antibodies to other phospholipids such as anti-phosphatidylserine, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl Inositol etc. may be more relevant in infertility. Their role remains to be clarified. There is theoretical evidence from animal models and clinical infertility practice that aPL has a role in infertility. However, a large-scale meta-analysis has failed to confirm the association. To determine whether infertility or even pregnancy loss is associated with aPL, it is necessary to know that the embryo is chromosomally normal. Pregestational diagnosis has shown that up to 60% of embryos may be chromosomally aneuploid in failed in vitro fertilization (IVF); hence, may confound our understanding concerning the association between aPL and infertility, failed IVF or even pregnancy loss.

ART in recurrent miscarriage: preimplantation genetic diagnosis/screening or surrogacy?

Recently, assisted reproductive techniques have been used to prevent further miscarriages in women with recurrent miscarriage. One approach uses either screening or diagnosis of embryonic chromosomes prior to embryo replacement [preimplantation genetic screening (PGS)/preimplantation genetic diagnosis (PGD)]. The second approach involves surrogacy. However, PGS/PGD assumes that the embryo is chromosomally abnormal, and that the mother should receive a chromosomally normal embryo. Surrogacy assumes that the embryo is normal and that the maternal environment needs to be substituted. This article examines the place of both techniques in different types of recurrent miscarriage, and tries to give guidelines as to which technique is preferable depending on the likelihood of an embryonic chromosome aberration. In repeated fetal aneuploidy or in the older patient, PGS or PGD are preferable. However, with high numbers of miscarriages, or in autoimmune pregnancy loss, surrogacy is preferable. In the light of recent work, it is uncertain which treatment mode is indicated in balanced parental chromosome aberrations. In conclusion, both techniques have a place, but probably only in those patients with a poor prognosis in whom assisted reproductive techniques will be shown to improve the subsequent live birth rate above the spontaneous rate.

The association between sporadic somatic parental aneuploidy and chromosomally abnormal placentae in habitual abortions.

To determine whether there is a correlation between the proportion of aneuploid cells in peripheral lymphocytes and the karyotype of the abortus in recurrent miscarriage. 40 couples with recurrent miscarriage and their abortuses were cytogenetically analyzed according to the analysis of 60 cells per proband. Women were divided into two groups according to the proportion of chromosomally abnormal cells in the abortus. Chromosomal analysis was performed using G-banding with trypsin-Giemsa in parental peripheral blood and in the abortus. 20 of the 40 abortuses had a chromosomally abberant karyotype. 65% of parents aborting an embryo with with an increased proportion of chromosomally aberrant cells, had more than 10% aneuploid cells in their peripheral lymphocytes. However, only 12.5% of couples aborting an embryo with chromosomally normal cells had increased rates of aneuploidy. An increased proportion of aneuploid cells was found in the lymphocytes of recurrently aborting couples who repeatedly abort chromosomally abnormal fetuses. Mitotic instability in the lymphocytes may indicate a predisposition to instability at meiosis leading to a chromosomal abberations in the embryo and its subsequent abortion.

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.

Features of shoulder dystocia in a busy obstetric unit.

OBJECTIVE: To assess the incidence and complications of shoulder dystocia and whether those complications could be avoided. STUDY DESIGN: Retrospective analysis of shoulder dystocia between 1996 and 1999 to determine whether macrosomia, diabetes, height of head at full dilatation, length of second stage or instrumental delivery could predict shoulder dystocia. Fetal asphyxia, brachial plexus injury, maneuvers used to free the shoulders and experience of the attendant were also assessed. RESULTS: There were 56 cases of shoulder dystocia in 24,000 births, 59% after spontaneous delivery. McRoberts maneuver was used in 48 deliveries but sufficed as a solitary procedure in nine cases. The addition of suprapubic pressure was sufficient for 25 patients and 27 when bilateral episiotomy was also used. Corkscrew procedures were required in 12 patients. Midwives were involved in 35 cases and required assistance in 27. Macrosomia > 4,000 g was a feature in 20 infants and diabetes in 6. Neither the height of the head nor the length of the second stage was helpful. There were 13 cases of Erb's palsy, seven after vacuum delivery and six after spontaneous delivery. Eight of these cases were associated with McRoberts procedure and suprapubic pressure, two with no procedure and three with the corkscrew procedure. CONCLUSION: If all infants > 4,000 g had been delivered by cesarean section, there still would have been 36 cases of shoulder dystocia. If the ultrasonically estimated weight were used to select patients for cesarean section, seven cases would have been diagnosed. To lessen the degree and incidence of fetal injury, labor ward staff are urged to become as familiar as possible with the techniques of freeing the shoulders.

Shared HLA antigens in couples with 5 or more, compared to 3 or 4 consecutive recurrent miscarriages.

OBJECTIVE: Couples with consecutive recurrent miscarriages (CRM) are not generally believed to share more HLA antigens with their spouses than expected by chance. This paper attempted to determine the situation in patients with five or more miscarriages. METHODS: The number of shared HLA class I and class II antigens, HLA phenotype, and the ability to mount an antibody response in a large cohort of 425 couples with CRM was assessed, according to whether the patient had three or four, or five or more miscarriages. RESULTS: There was no significant difference in the frequency of shared HLA antigens in women with five or more miscarriages when compared to three or more miscarriages or control patients. No specific HLA antigen or phenotype was associated with CRM in male or female partners of either group. The number of shared antigens did not influence ability to develop anti paternal antibodies (APA). Moreover, HLA antigen sharing had no influence on the subsequent pregnancy after paternal leucocyte immunization. CONCLUSION: Class I and Class II HLA antigens are not diagnostic for immunologically mediated abortion, do not predict the ability to mount an antibody response, or the outcome of a subsequent pregnancy.

Allogenic leukocyte immunization after five or more miscarriages. Recurrent Miscarriage Immunotherapy Trialists Group.

Rather than investigate whether paternal leukocyte immunization improves the live birth rate in women with three or more abortions, we analysed the results of patients expected to have a poor outcome in a subsequent pregnancy if untreated, i.e. women with five or more abortions and no anti-paternal complement-dependent antibody (APCA) at initial testing. The analysis included the results of patients treated by us over the last 8 years and the results of randomized and non-randomized trials reported by the Recurrent Miscarriage Immunotherapy Trialists Group. Patients with a previous live birth were classified into two groups: secondary aborters if there was an initial live birth followed by miscarriages, or tertiary aborters if there were miscarriages followed by a live birth and at least three subsequent miscarriages. The results were evaluated separately for primary, secondary and tertiary aborters who demonstrated APCA activity as a result of immunization. The 107 primary aborters had double the live birth rate if immunized, with an overall benefit of 31%. The 45 tertiary aborters had an almost 3-fold increase in the live birth rate, with an absolute benefit of 50%. The number of patients needed to treat to achieve one extra live birth was three to four primary aborters or two tertiary aborters. Immunization had little beneficial effect in secondary aborters but was effective in preventing abortion in primary or tertiary aborters with five or more abortions.

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 400 mg/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.

The effect of serum follicular phase luteinizing hormone concentrations in habitual abortion: correlation with results of paternal leukocyte immunization.

A prospective study was carried out on 153 couples with recurrent abortions who desired pregnancy. The object was to determine the incidence of raised luteinizing hormone (LH) levels; to compare the outcome of further pregnancies in habitually aborting women with and without raised circulating LH concentrations; and to assess whether the efficacy of paternal leukocyte immunization is affected in the presence of raised LH concentrations. Of the 153 women with recurrent abortions (> 3) included in this study, 56 (36.6%) had follicular phase serum LH concentrations > 10 mIU/ml. Of the 103 pregnancies that were followed prospectively, 65 (63.1%) resulted in a birth of a live infant. There was no significant relationship between the pregnancy outcome and LH concentrations. Women who underwent immunization with paternal leukocytes had significantly more live births (75.8%) than those who were not immunized (43.6%). However, the live birth rate was lower after paternal leukocyte immunization in the presence of raised LH concentrations or a raised LH/follicle stimulating hormone (FSH) ratio.