Uterine artery Doppler and subendometrial blood flow in patients with unexplained recurrent miscarriage

Objective

To evaluate uterine artery blood flow and subendometrial blood flow in women with unexplained recurrent miscarriage (RM) compared to normal fertile women.

Design

Case control study.

Settings

Departments of Obstetrics and Gynaecology, Cairo university and, Beni Souif University, Cairo, Egypt.

Patients and methods

Women were divided into two groups: those with history of unexplained recurrent miscarriage (study group, no. = 40), and those with no history of miscarriage and at least one child born at term (control group, no. = 40), transvaginal 3D power Doppler ultrasonography was performed to all patients in the second phase of non-pregnant unstimulated cycle to detect uterine artery pulsatility index (UAPI) and subendometrial area to detect subendometrial blood flow presented by the indices vascularisation index (VI), flow index (FI), and vascular flow index (VFI). The indices between the two groups were compared.

Results

UAPI was significantly higher in the study group (p = 0.000), on the other hand VI (p = 0.000), FI (p = 0.000), VFI (p = 0.000) were significantly lower in the study group. A significant positive correlation was found between UAPI and recurrent miscarriage in the study group (r = 0.8, p = 0.00), whereas a significant negative correlation was found between VI (r = −0.56, p = 0.00), and FI (r = −0.79, p = 0.00) and recurrent miscarriage in the study group, but no significant correlation was found between endometrial thickness and endometrial volume between the two groups. However the application of binary logistic regression analysis model found that adding variables has not significantly increased the ability to predict the occurrence of miscarriage.

Conclusion

The presence of good uterine and endometrial blood flow is an important prerequisite for successful implantation and continuation of pregnancy as shown by higher uterine artery blood flow resistance and lower endometrial blood flow in recurrent miscarriage cases and those patients with unexplained RPL may have abnormalities in the uterine and endometrial blood flow. Despite these findings we could not find any cut off values that could predict the occurrence of miscarriage which may be attributed to small sample size and short period of follow up so larger prospective studies are needed aiming to confirm such results and reaching values that can accurately predict the occurrence of miscarriage.     

Sporadic pregnancy loss and recurrent miscarriage

Progesterone is essential for the maintenance of pregnancy, and progesterone deficiency is associated with miscarriage. The subject of whether progesterone supplementation in early pregnancy can prevent miscarriage has been a long-standing research question and has been investigated and debated in the medical literature for over 70 years. During this time, several different progestogens have been synthesised and tested for the prevention of miscarriage. In this chapter, we describe the prior evidence alongside the latest research using micronized natural progesterone as well as synthetic progestogens, which were used to treat both recurrent and threatened miscarriage. The totality of evidence indicates that women with a past history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone. The clinical implications of the findings are discussed.     

Parental karyotype and subsequent live births in recurrent miscarriage

OBJECTIVE: To compare the subsequent live birth rate in recurrently miscarrying women with and without parental balanced chromosomal aberrations. DESIGN: Retrospective comparative cohort study. SETTING: Tertiary referral unit in a university hospital. PATIENT(S): Nine hundred sixteen patients with 3-16 miscarriages before 20 weeks: 99 patients with and 817 patients without chromosomal aberrations. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Outcome of the subsequent pregnancy in terms of live births or repeat miscarriage. RESULT(S): Of the 916 patients, 661 subsequently conceived, 73 (73.7%) with parental chromosomal aberrations and 588 (71.9%) without aberrations. In patients with and without chromosomal aberrations, 33 of 73 pregnancies (45.2%) and 325 of 588 pregnancies (55.3%), respectively, resulted in live births. The difference is not statistically significant. There was a similar prevalence of aberrations in primary, secondary, and tertiary aborters. The prevalence of aberrations was not related to the number of previous miscarriages. Translocations, inversions, and mosaicism were followed by a similar live birth rate. CONCLUSION(S): Patients with parental chromosomal rearrangements do not have a significantly lower live birth rate than patients without aberrations. Parental karyotyping might not be a good predictor of the outcome of subsequent pregnancies.     

Prothrombin G20210A mutation in cases with recurrent miscarriage: a study of the mediterranean population

Background: Thrombophilic predisposition may be one of the underlying causes of recurrent miscariage (RM). The purpose of this study was to evaluate the Prothrombin G20210A mutation in cases with history of RM. Material and methods: A total of 104 cases, 55 with diagnosis of RM and 49 control cases, were included in this controlled study. In all cases, in addition to full examination tests, Prothrombin 20210A mutation analysis was carried out by means of Polymerase Chain Reaction (PCR). Results: Mean number of the abortion was 3.51±0.74 in the RM group and 0.08±0.27 in the control group (p<0.05). As a consequence of comprehensive examinations, in 24 (43.6%) of 55 RM cases at least one etiologic factor was put forth. Prothrombin G20210A mutation was observed in six (10.9%) cases of the RM group and one (2.04%) in the control group (p<0.05). Four of the six cases (66.7%) of Prothrombin G20210A mutation had a subsequent pregnancy. Among these four pregnancies, there was one spontaneous loss at 14 weeks of gestation and one severe pre-eclampsia. Conclusion: Our data together with literature suggest that Prothrombin G20210A mutation may be associated with RM. We recommend this genetic testing as a screening tool for women with history of RM.     

Peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial

We, the Editors and Publisher of The Journal of Maternal-Fetal &; Neonatal Medicine, have retracted the following article:

Alaa M. Ismail, Ahmed M. Abbas, Mohammed K. Ali &; Ahmed F. Amin; Peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial, The Journal of Maternal-Fetal &; Neonatal Medicine, http://10.1080/14767058.2017.1286315

While this article was peer-reviewed and accepted according to the Journal’s policy concerns were subsequently raised regarding the accuracy and reliability of the data. The Editors-in-Chief were made aware of previous versions of the article which showed significant changes to the underlying data. After an investigation the authors of the paper were contacted but were unable to provide the original data to verify their results. The authors have been informed about the retraction.

We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.

The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.     

Anti-annexin as a marker in patients with recurrent miscarriages

ObjectiveTo investigate the possible role of anti-annexin A5 antibodies in inducing recurrent miscarriage.DesignCross-sectional study.SettingBenha University Hospital.Participants and interventionsPregnant women during the first trimester of pregnancy with a history of three or more consecutive pregnancy losses were compared to Multigravidae women during the first trimester of pregnancy with no history of pregnancy losses for group II. Women were screened for anti-annexin A5 antibodies.ResultsThere were no statistically significant correlations between anti-annexin A5 antibodies in both groups (P>0.05).ConclusionThe present study did not confirm that anti-annexin A5 antibodies have significance in predicting RM when measured in healthy women.     

Office hysteroscopic findings in patients with two,three, and four or more,consecutive miscarriages

ABSTRACT

Objectives To assess hysteroscopic findings in patients with two, three, and four or more, consecutive miscarriages, and to compare the prevalence of uterine abnormalities between women with different numbers of such miscarriages.

Methods Two hundred and sixty-five women with two or more consecutive miscarriages were enrolled in the study. Patients were divided into three groups according to the number of their miscarriages: Group 1 (two miscarriages, n =?151), Group 2 (three miscariages, n =?69), and Group 3 (four or more miscarriages, n =?45). All participants underwent a diagnostic hysteroscopy. Congenital (arcuate uterus, septate uterus, unicornuate uterus) and acquired uterine abnormalities (intrauterine adhesions, polyp and submucous myoma) were recorded. The hysteroscopic results were compared between the groups.

Results No anomalies were detected in 152 patients (57%), whereas 43 (16%) had a septate uterus, 30 (11%) an arcuate uterus, three (1%) a unicornuate uterus, 18 (7%) intrauterine adhesions, 17 (6 %) endometrial polyps, and two (1%) a submucous myoma. No significant differences were found between the groups with regard to either congenital or acquired uterine abnormalities.

Conclusions Patients with two, three, and four or more consecutive miscarriages have a similar prevalence of uterine anatomical abnormalities. Diagnostic hysteroscopy should be carried out after two such miscarriages.     

Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: A meta-analysis of non-family-based studies

Purpose

The HLA-G 14-bp insertion/deletion polymorphism had been inconsistently associated with recurrent miscarriage (RM) risk. We examined the association by performing a meta-analysis.

Methods

Eligible articles were searched in PubMed, EMBASE and CNKI without language limitation. We included all the articles about two or more miscarriages associated with HLA-G 14-bp polymorphism. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed by the STATA10.0 software.

Results

17 studies were included, representing 1786 cases and 1574 controls. The current meta-analysis showed that 14-bp polymorphism was not associated with RM risk in all genetic models and allele contrast(+14 bp vs. −14 bp: OR = 1.13; 95 % CI, 0.96,1.32; +14 bp/+14 bp vs. −14 bp/−14 bp: OR = 1.16, 95 % CI, 0.85, 1.59; +14 bp/−14 bp vs. −14 bp/−14 bp: OR = 1.21, 95 % CI, 0.92,1.58; dominant model: OR = 1.33; 95 % CI, 0.99,1.78; recessive model: OR = 1.06; 95 % CI, 0.79,1.43). Moreover, a significant heterogeneity was evident across studies. On the other hand, the subgroup analysis demonstrated that there was a significant association between HLA-G 14-bp polymorphism and patients with three or more miscarriages(+14 bp vs. −14 bp: OR = 1.27; 95 % CI, 1.04, 1.55; dominant model: OR = 1.52; 95 % CI, 1.16, 1.99; and model +14 bp/−14 bp versus −14 bp/−14 bp: OR = 1.51; 95 % CI, 1.15, 1.97;).

Conclusions

Our comprehensive meta-analysis indicated that there was insufficient evidence to demonstrate a conclusive association between the HLA-G 14-bp insertion/deletion polymorphism and the risk of RM. But HLA-G 14-bp insertion/deletion polymorphic variation was associated with RM risk in patients with three or more miscarriages. Larger and well-designed studies may eventually provide a better, comprehensive understanding of the association between the HLA-G 14-bp insertion/deletion polymorphism and RM in the future.     

A comparison of the uterine and intraovarian arterial flows in nonpregnant women having a history of recurrent spontaneous miscarriage associated with antiphospholipid syndrome

Objective The objective was to study the relationship between values of Doppler indices characterizing the uterine and intraovarian arterial flows and presence or absence of antiphospholipid syndrome in women with history of recurrent spontaneous miscarriage in the midluteal phase of unstimulated menstrual cycle.Methods Sixty two non pregnant women attending our recurrent spontaneous miscarriage clinic were recruited for this prospective study and subsequently divided to group A (n=35) involving recurrent spontaneous miscarriage women with normal anticardiolipin antibodies values and group B (n=27) for those with abnormal anticardiolipin antibodies values. Anticardiolipin antibodies were measured in the blood using the standardized enzyme linked immunosorbent assay. B-mode, pulsed, color and power Doppler transvaginal ultrasonography was used to estimate the uterine artery pulsatility index, spiral artery resistance index, intraovarian arterial resistance index and endometrial thickness on the 21st day of a regular 28-day unstimulated menstrual cycle. The data were analyzed using the statistical software SPSS 9.0 Windows. Statistical significance was defined as p0.05.Results There was no statistically significant difference in values of Doppler indices characterizing uterine and intraovarian arterial flows in women having a history of recurrent spontaneous miscarriage (RSM) with presence or absence of antiphospholipid syndrome. There were a significantly higher number of women with normal anticardiolipin antibodies above 30 years having a history of six or more RSM [7 (31.8)] compared to RSM women with abnormal anticardiolipin antibodies [0 (0)] (p<0.028). Significantly higher incidence of the primary RSM was found in group A [16 (64.0)] compared to group B [9 (36.0)] (p0.02). A consistently similar difference pattern was observed between the mean intraovarian arterial resistance index value in group A primary RSM [0.54 (0.40–0.63)] compared to a more favorable mean intraovarian arterial resistance index value in group B secondary RSM [0.46 (0.43–0.58)] (p0.02).Conclusions Our prospective study did not confirm any statistically significant difference in values of Doppler indices characterizing uterine and intraovarian arterial flows of RSM women with presence or absence of antiphospholipid syndrome in the midluteal phase of unstimulated menstrual cycle. This finding suggests that a mild form of APS will not result in any significant impairment of angiogenesis occurring at time of implantation of fertilized ovum.Abbreviations APS Antiphospholipid syndrome - RSM Recurrent spontaneous miscarriage - ACL IgM antibodies Anticardiolipin antibodies immunoglobulin M - ACL IgG antibodies Anticardiolipin antibodies immunoglobulin G - LA antibodies Lupus anticoagulant antibodies - ELISA Enzyme linked immunosorbent assay - UTAPI Uterine artery pulsatility index - SARI Spiral artery resistance index - IOARI Intraovarian arterial resistance index - ALARA As low as reasonably achievable - ETH Endometrial thickness - LH Luteinizing hormone     

Evaluation of KIR genes in recurrent miscarriage

Purpose

Natural killer (NK) cells express killer immunoglobulin-like receptors (KIRs) which recognize HLA class I molecules on trophoblasts. KIRs could either activate NK cells or inhibit them to produce soluble factors necessary for the maintenance of pregnancy, thus they are suspected of being involved in the causes of recurrent miscarriage. The aim of this study was to evaluate whether there is any possible association between KIR genes, genotypes and recurrent miscarriage.

Methods

The present study was carried out on 40 women who had unexplained recurrent miscarriage and 90 controls. Sequence-specific oligonucleotide probes analysis were used to investigate 16 KIR genes. All data were statistically analyzed by Fisher Exact Test.

Results

The rate of Bx genotypes that consists elevated number of activating KIR genes was significantly higher (p = 0.014) in women with recurrent miscarriage when compared with the control group. Additionally, the frequency of AA genotype (AA1) of the subjects in the study group was significantly lower than the frequency of the subjects in the control group (p = 0,014). Furthermore, there were no statistically significant differences in the frequencies of the individual KIR genes between women with recurrent miscarriage and the control group.

Conclusions

Inclined balance of KIRs toward an activating state in NK cells may contribute to recurrent miscarriage.     

An analysis of the pattern of pregnancy loss in women with recurrent miscarriage

OBJECTIVE: To describe the pattern of pregnancy loss in women with a history of recurrent miscarriage (RM). DESIGN: Retrospective, observational study. SETTING: A tertiary referral center for RM. PATIENT(S): Five hundred thirty-eight subjects with RM. INTERVENTION(S): Women with antiphospholipid syndrome were treated with clexane and aspirin; some patients with uterine anomalies underwent corrective surgery, and some cases of retarded endometrium were treated with hMG. MAIN OUTCOME MEASURE(S): Pregnancy outcome, including the stage of pregnancy at which pregnancy loss occurred. RESULT(S): In women with a prothrombotic state, the miscarriage rate before the detection of fetal heart activity (early loss) in the untreated group (50%) was significantly higher than in the treatment group (17.5%). In women with a uterine anomaly, the early loss rate and the later loss rate (after detection of fetal heart activity) were both increased. Women with retarded endometrium, women with >/=6 losses, and older women (>/=41 years) are more likely to have a further early loss but not a later loss. CONCLUSION(S): An understanding of the patterns of pregnancy loss provides further insight into the mechanism of the reproductive failure, which has implications for treatment.     

Enoxaparin and aspirin therapy for recurrent pregnancy loss due to anti-phospholipid syndrome (APS)

BackgroundRecurrent miscarriage affects 1–2% of women. Thrombophilia included antiphospholipid syndrome has been identified in about 50% of women with recurrent miscarriage. Aspirin and heparin therapy is frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime.ObjectiveTo determine maternal and foetal outcomes in women with APS managed with aspirin or enoxaparin plus aspirin during pregnancy.DesignProspective non randomized study.SettingHigh-risk pregnancy unit-Benha University Hospital.MethodsSeventy selected patients during pregnancy with clinical and/or serological findings of antiphospholipid syndrome were divided into two Groups: Group A (n = 47) had received aspirin (81 mg once daily orally) plus LMWH enoxaparin (40 mg subcutaneously/day) while Group B (n = 23) had received low-dose aspirin (81 mg day orally).Main outcome measuresMaternal outcomes included thromboembolic, haemorrhagic complications and pregnancy-induced hypertension. Prematurity, intrauterine growth restriction and neonatal death were considered as foetal complications.ResultsThere were significant differences between Groups A and B in the rate of miscarriages (4 in Group A (9%) versus 8 in Group B (35%); p = 0.02), number of live births (43/47(91%) versus 15/23(65%); p = 0.02), mean gestational age (37.86 ± 1.8 versus 36.13 ± 2.39 weeks; p = 0.005), neonatal birth weight (3252 ± 459 versus 2907 ± 618 g; p = 0.03) and rate of pre-eclampsia (3/43 (7%) versus 6/15 (40%); p = 0.009). Although not statistically significant, women in Group A tended to have lower rates of preterm births (6/43 (14%) versus 3/15 (20%); p = 0.89) and IUGR (5/43 (12%) versus 5/15 (33%); p = 0.13) than in Group B.ConclusionsUse of low dose aspirin and enoxaparin 40 mg subcutaneously daily in patients with RPL due to antiphospholipid syndrome resulted in higher live birth rates compared to low dose aspirin alone. Solid conclusions from this study are limited due to the small number of patients, non-randomization of groups and discrepancy in number between groups because the choice of the interventional drug was left to patient’s preference after counselling. A larger RCT is needed.     

Role of 1,25-dihydroxyvitamin D (vitamin D3) as immunomodulator in recurrent missed miscarriage

ObjectiveTo evaluate the immunomodulatory role of vitamin D3 in prevention of pregnancy loss in cases of recurrent miscarriage.Patients and methodsA total of 40 pregnant women with gestational age at or less than 6 weeks with recurrent miscarriage were enrolled in the present study and randomly assigned to study and control group each (n = 20 for each group) after fulfilling certain inclusion and exclusion criteria. All participants were assessed through complete history, general and obstetric history, ultrasound assessment and routine full laboratory evaluation. IFN-γ was assessed at ?6 week gestation on recruitment, then after treatment every 2 weeks till 14th week for both groups. Both groups received standard measures for cases with recurrent miscarriage. Study group participants were treated with oral vitamin D3 supplementation. Outcome measures included continuing pregnancy rate and change in INF-γ values between first and final assays.ResultsNo statistically significant difference was noted between both groups regarding baseline demographic, clinical characteristics and ultrasonographic findings. Control group participants were found to have significantly higher levels of IFN-γ compared to the study group after treatment. Risk of miscarriage was 15% lower among the study group than the control group. Continuing pregnancy rate was 70% in the study group and 55% in the control group. No significant difference was found between both groups regarding symptoms suggesting vitamin D3 side effects.ConclusionAlthough statistically insignificant, vitamin D3 oral supplementation has resulted in reducing risk of pregnancy loss up to 15% among women with recurrent miscarriage so it is a matter that is worth more attention and large scale studies with larger sample size may result in more significant results.