Abnormal immunoglobulin subclass patterns in women with a history of recurrent miscarriage.

OBJECTIVE: To determine whether IgG subclass patterns differed between nonpregnant women, healthy pregnant women, and pregnant women with a history of recurrent miscarriage. DESIGN: Controlled clinical study. SETTING: An academic setting. PATIENT(S): Group 1 was comprised of 10 nonpregnant women, group 2 of 10 healthy pregnant women, group 3 of eight pregnant women with a history of recurrent miscarriage and whose pregnancies on this occasion went to term, and group 4 of 10 women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Serum levels of total IgG and IgG 1, 2, 3, and 4. RESULT(S): The results obtained showed that normal pregnancy was associated with a significant increase in total IgG production and an increase in IgG subclasses 1, 2, and 3. Women with a history of miscarriage, but who had a successful pregnancy on this occasion, showed a similar pattern of IgG subclasses. Women with a history of miscarriage and whose pregnancy again ended in miscarriage showed a different IgG subclass pattern. CONCLUSION(S): Pregnancies that ended in miscarriage showed a different pattern of IgG subclasses than those that continued to term. The changes seen in immunoglobulin patterns could be linked to changes in cytokine production.     

The selenium status of women with a history of recurrent miscarriage

Objective To assess the relationship between selenium levels in human blood and hair, and the risk of recurrent miscarriages.
Design Case–control study.
Participants Two groups of non-pregnant women: 18 women with one or more successful pregnancies and no history of miscarriage (control group); 26 women with a history of recurrent miscarriage (≥ 3) with no subsequent successful pregnancies (study group).
Methods Samples of venous blood and scalp hair were collected and the selenium content analysed by inductively coupled plasma mass spectrometry.
Results No significance difference was found between the level of selenium in the blood samples of the women in each group. There was a significant reduction in the mean hair selenium level in the recurrent miscarriage group compared with the control group (0.14μg/g vs 0.34μg/g). Further analysis of the recurrent miscarriage group revealed no relationship between levels of serum or hair selenium with parity. There was a significantly greater proportion of women in the control group who ate cereals, vitamin supplements, and liver or kidney.
Conclusion There was evidence of selenium deficiency in women with recurrent miscarriages compared with a control group of women with a good reproductive performance. This difference was seen in hair samples but not serum samples and therefore may not represent a simple nutritional deficiency. The importance of selenium deficiency in miscarriage has still not been determined.     

Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage

Objective: We sought to determine subsequent pregnancy outcomes in a cohort of women with a history of unexplained recurrent miscarriage (RM) who were not receiving medical treatment.

Study design: This was a prospective cohort study, of women with a history of three unexplained consecutive first trimester losses, who were recruited and followed in their subsequent pregnancy. Control patients were healthy pregnant patients with no previous adverse perinatal outcome.

Results: A total of 42 patients with a history of unexplained RM were recruited to the study. About nine (21.4%) experienced a further first trimester miscarriage, one case of ectopic and one case of partial molar pregnancy. About 74% (23/31) of the RM cohort had a vaginal delivery. There was one case of severe pre-eclampsia. The RM group delivered at a mean gestational age of 38?+?2 weeks and with a mean birthweight of 3.23?kg. None of the neonates were under the 10th centile for gestational age. Overall, there was no significant difference in pregnancy outcomes between the two cohorts.

Conclusion: Our study confirms the reassuring prognosis for achieving a live birth in the unexplained RM population with a very low incidence of adverse events with the majority delivering appropriately grown fetuses at term.     

Screening for coeliac disease in women with a history of recurrent miscarriage or infertility

Because subclinical coeliac disease may decrease fertility or complicate pregnancy, we screened women with recurrent miscarriage of unknown aetiology (   n = 63  ), unexplained infertility (   n = 47  ) and infertility with a known cause (   n = 82  ), for anti-endomysium antibodies in serum to find undiagnosed coeliac disease. One woman (1.6%) with recurrent miscarriage, another woman (2.1%) with unexplained infertility and one woman (2.0%) in the control group (   n = 51  ), were considered to have coeliac disease. We could not demonstrate a higher frequency of coeliac disease in women with infertility or recurrent miscarriage, but suggest that undiagnosed coeliac disease is common in women.     

Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage

OBJECTIVE: To examine the effects of dydrogesterone on the production of Th1 and Th2 cytokines by lymphocytes from women undergoing unexplained recurrent spontaneous miscarriage (RSM). DESIGN: Controlled prospective, clinical study conducted in a maternity hospital and a university-based immunology laboratory. SETTING: Faculty of Medicine, Kuwait University and Kuwait Maternity Hospital. SAMPLE: Thirty women with unexplained RSM. METHODS: Peripheral blood mononuclear cells (PBMC) from women with unexplained RSM were isolated from venous blood by density gradient sedimentation and stimulated with phytohaemagglutinin (PHA). Culture supernatants assayed for interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-6 and IL-10 by ELISA. Levels of the progesterone-induced blocking factor (PIBF) were also measured. MAIN OUTCOME MEASURES: Cytokine production in the presence and absence of progesterone and dydrogesterone. RESULTS: Dydrogesterone significantly inhibited the production of the Th1 cytokines IFN-gamma (P= 0.0001) and TNF-alpha (P= 0.005) and induced an increase in the levels of the Th2 cytokines IL-4 (P= 0.03) and IL-6 (P= 0.017) resulting in a substantial shift in the ratio of Th1/Th2 cytokines. The effect of dydrogesterone was blocked by the addition of the progesterone-receptor antagonist mifepristone, indicating that dydrogesterone was acting via the progesterone receptor. Dydrogesterone induced the production of PIBF. CONCLUSION: Dydrogesterone inhibits the production of the Th1 cytokines IFN-gamma and TNF-alpha from lymphocytes and up-regulates the production of the Th2 cytokines IL-4 and IL-6, inducing a Th1 to Th2 cytokine shift.     

Screening for coeliac disease in women with a history of recurrent miscarriage or infertility.

Because subclinical coeliac disease may decrease fertility or complicate pregnancy, we screened women with recurrent miscarriage of unknown aetiology (n = 63), unexplained infertility (n = 47) and infertility with a known cause (n = 82), for anti-endomysium antibodies in serum to find undiagnosed coeliac disease. One woman (1-6%) with recurrent miscarriage, another woman (2.1%) with unexplained infertility and one woman (2.0%) in the control group (n = 51), were considered to have coeliac disease. We could not demonstrate a higher frequency of coeliac disease in women with infertility or recurrent miscarriage, but suggest that undiagnosed coeliac disease is common in women.     

Outcome of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage

Ninety-seven women who had had three or more miscarriages had also had at least one pregnancy with a singleton birth that had reached 28 weeks gestation. Information was available on these 118 babies: 30% were small-for-gestational age (birthweight less than or equal to 10th centile using figures from Scotland 1973-79), 28% were born preterm, and the perinatal mortality rate (excluding babies of less than 28 weeks gestation) was 161/1000 births, all of which are significantly increased above the prevalence for a normal obstetric population. These observations may serve to alert the clinician to the increased risk of these complications when dealing with women who have a history of recurrent miscarriage.     

The epidemiology of recurrent miscarriage: a descriptive study of 1214 prepregnant women with recurrent miscarriage

AIMS: To describe the characteristics of the prepregnant population attending the Recurrent Miscarriage Clinic (RMC) at the National Women's Hospital (NWH), Auckland, between 1986 and 2003, and to compare them with the overall obstetric booking population of the hospital. METHODS: The identifying details of 1214 prepregnant women attending the RMC were obtained. Both hospital and RMC records, which were kept separately, were retrospectively reviewed for demographic information and results of diagnostic investigations. Data from Auckland residents who attended the clinic were compared with data from all Auckland women booking or delivering at NWH. RESULTS: RMC attendees were older than the general NWH population, but had similar parity. Clinic attendees had a higher incidence of personal and family history of antepartum haemorrhage, fetal abnormalities, stillbirths and neonatal deaths than reported rates for the general population. Chromosomal anomalies were detected in 86 women, reproductive tract anomalies were found in 142 women, and polycystic ovarian syndrome was detected in 49 women. The majority (52.7%) of women had no identifiable cause for recurrent miscarriage detected. CONCLUSIONS: These data support the concept of women with recurrent miscarriage being at high risk for adverse obstetric outcomes including fetal abnormalities, stillbirths and neonatal deaths, even when the pregnancies are ongoing. We conclude that recurrent miscarriage is different from subfertility, and provide information of use in planning care for such women.     

Factor XII deficiency in women with recurrent miscarriage

Congenital thrombophilia is known to cause significant maternal complications, and possibly has an adverse effect on normal fetal development. The aim of this study was to assess the prevalence of factor XII (FXII) deficiency in women with a history of recurrent miscarriage. Two hundred and forty-one consecutive Japanese women with a history of two or more recurrent miscarriages were prospectively assessed for their etiology by conventional screening methods. Seven women were found to have reduced FXII activity (19. 2-46.1%) and prolonged activated partial thromboplastin time (33. 3-51.3 s). Of these 7 women, 6 had experienced early pregnancy losses, while 1 woman had experienced repeated mid-trimester fetal losses with coincidental gestational thrombocytopenia. In 241 women with a history of recurrent miscarriage, the prevalence of FXII deficiency was 2.9%.     

Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester

Objectives

Defective implantation is a mechanism for recurrent pregnancy loss (RPL). We sought to determine whether the serum expression of human relaxin-2 (RLX) is impaired in women with a history of RPL.

Study design

Employing a prospective case-controlled design we studied 20 pregnant women with a history of RPL and 20 age-matched women with no history of RPL (NRPL). We measured serum relaxin-2 levels by ELISA at 6–8, 10–12, 20, and 34 weeks gestation and in cord blood, and maternal uterine artery Doppler resistance index (RI) at ≥10 weeks gestation.

Results

Relaxin rose to a peak at 12 weeks, and gradually declined towards term. At all gestations, women with a history of RPL had lower RLX levels than women without. At 10–12 weeks gestation, uterine artery RI correlated with serum RLX for both RPL and NRPL. In the NRPL group at 10–12 weeks the presence of a notched waveform was associated with higher RLX levels than the absence of a notch (mean 2.1 ng/ml vs. 1.3 ng/ml, P < 0.05) and also at 20 weeks (2.1 ng/ml vs. 0.95 ng/ml, P < 0.05) but no such difference was seen in the RPL group. Umbilical venous RLX was 4-fold higher in the RPL group than the NRPL group.

Conclusion

Women with a history of RPL demonstrate attenuated levels of serum RLX across all pregnancy trimesters. How dysregulated RLX metabolism may contribute to adverse pregnancy outcome in RPL requires further investigation.     

Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage

OBJECTIVE: To identify associations or interrelations between carriage of the methylenetetrahydrofolate reductase (MTHFR) C677T, the MTHFR A1298C, the factor V Leiden G1691A, the factor II prothrombin G20210A, the human platelet antigen (HPA) 1 C12548T, and the apolipoprotein (APO) B R3500Q polymorphisms and idiopathic recurrent miscarriage (IRM). DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred forty-five women with a history of three or more consecutive pregnancy losses before 20 weeks gestation and 101 healthy postmenopausal women with at least two live births and no history of pregnancy loss. INTERVENTION(S): Peripheral venous punctures. MAIN OUTCOME MEASURE(S): Multiplex polymerase chain reaction was performed to identify the different alleles of six candidate genetic risk factors for IRM (MTHFR C677T, MTHFR A1298C, factor V Leiden G1691A, factor II prothrombin G20210A, HPA 1 C12548T, and the APO B R3500Q). RESULT(S): Allele and genotype frequencies of all polymorphisms were not significantly different between the study and the control groups. Also, no significant associations occurred between combinations of polymorphisms and the occurrence of IRM. CONCLUSION(S): Our data fall short of showing any significant association between single polymorphisms of the MTHFR, the Factor V Leiden, the Factor II Prothrombin, the HPA 1 and APO B genes or combinations of these polymorphisms and the occurrence of IRM.     

Angiopoietin-2 polymorphism in women with idiopathic recurrent miscarriage

OBJECTIVE: To investigate the relationship between idiopathic recurrent miscarriage and a polymorphism of the gene encoding for angiopoietin-2 (ANGPT2), an autochthonous modulator of angiogenesis during pregnancy. DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred thirty-one women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation, and 125 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. INTERVENTION(S): Peripheral venous puncture. MAIN OUTCOME MEASURE(S): Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify the different ANGPT2 alleles. RESULT(S): No association between mutant (mt) allele and the occurrence of idiopathic recurrent miscarriage was found. Between women with primary and secondary idiopathic recurrent miscarriage, no statistically significant differences with respect to allele frequencies were observed. CONCLUSION(S): This is the first report on the ANGPT2 gene polymorphism in women with idiopathic recurrent miscarriage, demonstrating that the investigated polymorphism is not associated with idiopathic recurrent miscarriage in a white population.     

Reappraisal of peripheral NK cells in women with recurrent miscarriage

The aim of this study was to examine the relationship between peripheral natural killer (NK) cells and recurrent miscarriage by improved methods. Peripheral NK cell measurement was carried out using flow cytometry of morning blood samples obtained in the early follicular phase, analysed within 8 h of collection. Eighty-five Chinese women with recurrent miscarriage who previously tested negative for autoantibodies, and 27 control subjects who were not using any hormonal methods for contraception, were recruited. No significant difference was found in the number of peripheral NK cells and their subsets between women with recurrent miscarriages and control subjects. Only 5% of women with recurrent miscarriage had high peripheral NK cells. The number of previous miscarriages did not appear to have an impact on the number of NK cells. In conclusion, there appears to be limited value in the routine measurement of peripheral NK cells in women with recurrent miscarriage.     

Absence of SYCP3 mutations in women with recurrent miscarriage with at least one trisomic miscarriage

Mutations within the coding regions of the synaptonemal complex gene SYCP3 have previously been reported in women with recurrent miscarriage. The present study found no mutations in any of the coding exons or the intron/exon boundaries among 50 recurrent miscarriage patients with at least one documented trisomic miscarriage, suggesting that mutations in SYCP3 do not contribute significantly to risk for recurrent miscarriage through maternal meiotic nondisjunction.     

High frequency of thrombophilic disorders in women with recurrent fetal miscarriage

OBJECTIVES: Our purpose was to examine whether genetic thrombophilias are etiological factors for recurrent fetal miscarriage or not. STUDY DESIGN: We compared the rate of thrombophilic anomalies in women with unexplained recurrent fetal miscarriages to the rate of age-matched women with successful pregnancies as a case-control study. RESULTS: A total of 101 consecutive patients with 102 age-matched controls were included in the study. The rate of Factor V (FV) Leiden mutation, Factor (F) II mutation, protein S, protein C, antithrombin III deficiencies and overall thrombophilia in patients with recurrent fetal loss was significantly higher than the frequencies in control patients. CONCLUSION: Women with recurrent fetal miscarriages have an increased incidence of thrombophilia. Genetic thrombophilias may be one of the major etiological factors for recurrent abortion and fetal demise.