الفهرس 
Recurrent Miscarriage: Causes, Evaluation und ManagementOnly 14 pages are availabe for public view
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Abstract
R
ecurrent miscarriage is a major reproductive problem because it involves, according to the definition used, about 1% to 2% of women of reproductive age.
It also represents a great challenge for the clinicians because too many physio-pathologic, diagnostic and therapeutic issues concerning this condition are still unknown, debated and largely unresolved. In fact, even though many causes or risk factors for recurrent miscarriage have been identified and recurrent miscarriage is believed to be a heterogeneous condition with a multifactorial etiology, approximately 50% of recurrent miscarriages are still classified as unexplained recurrent miscarriage.
There is a general agreement about the multifactorial etiology of unexplained recurrent miscarriage, i.e. anatomical anomalies, endocrine and immunologic disorders and infections. However, vascular changes associated with the pathology of unexplained recurrent miscarriage remain poorly studied.
New diagnostic methods have improved the clinical triage of recurrent miscarriage. Several lines of study have suggested that certain coagulation abnormalities such as antiphospholipid antibodies or Factor V Leiden are causes of recurrent miscarriage.
A growing body of evidence indicates the fundamental importance of a proper maternal-fetal immune relationship for a successful pregnancy and supports the possibility that several immunologic factors are involved in early pregnancy disorders, such as unexplained recurrent miscarriage.
Antinuclear autoantibodies (ANA), a group of autoantibodies directed towards nuclear and cytoplasmatic antigens, in several studies have been detected in a significantly higher proportion of women with recurrent miscarriage compared with normal healthy control women.
ANA positivity has also been demonstrated to be associated with a markedly impaired outcome of in vitro fertilization, suggesting that ANA could have a detrimental effect on oocyte and embryo development.
These findings support the hypothesis that ANA could play a role in early pregnancy complications, including recurrent miscarriage, although the mechanisms by which they could cause pregnancy loss are only speculative at present.
Observation and evaluation of hemodynamic changes in the uterine arteries during the menstrual cycle of healthy women and the subfertile population became possible after introduction of Doppler method to clinical practice, this showed that uterine receptivity is likely to be regulated by a number of factors including uterine perfusion and is of great importance in achieving a normal pregnancy.
There is a general agreement that uterine artery pulsatility index (UTAPI) values appear to decline during the luteal phase.
These changes suggest the presence of increased uterine perfusion at the time of embryo implantation. This may be of critical importance in the assessment of infertile couples.
An impaired process of angiogenesis commencing before ovulation and extending to the period of implantation may play a role in the etiology of many early recurrent pregnancy loss and some of the unexplained miscarriages.
Published studies confirmed that pregnancy losses are occurring predominantly in the pre-embryonic and embryonic periods. Moreover, it was found that inadequate uterine arterial flows can impair the process of implantation.
Transvaginal pulsed Doppler ultrasonography allows non-invasive evaluation of uterine circulation. In a number of studies, pulsed Doppler ultrasonography demonstrated blood flow changes in the uterus and ovaries during the menstrual cycle.
There is evidence that recurrent miscarriage is associated with high uterine artery impedance which could be responsible for a suboptimal endometrial and myometrial perfusion, leading to pregnancy loss.
At present the potential role of ANA in RM, with specific application to uterine blood flow indices, remains unclear because there is scant information on the possible relationship between ANA status and uterine blood flow and vascularization indices in women with recurrent miscarriage. However some experimental data suggest a possible relation between ANA and changes in uterine flow indices in women affected by recurrent miscarriage
This case control study was conducted at recurrent miscarriage out-patient clinic in conjunction with the special fetal care unit - faculty of medicine - Ain-Shams University Maternity Hospital from May 2017 until June 2021.
A total of 104 non-pregnant women of reproductive age were enrolled and divided into two groups; study group that included fifty two women with primary unexplained recurrent miscarriage and control group that included fifty two women with at least two pregnancies at term and no miscarriages as volunteers from family planning clinic. All women were subjected to complete history taking, clinical examination, laboratory investigation with measuring of ANA titre and 2/3D TVUS power Doppler imaging for uterine blood flow indices with the VOCAL technique for assessment of and investigate the role of ANA in women with unexplained recurrent miscarriage and the evaluate the association between it and uterine blood flow indices.
Our study reported that, there were no statistically significant differences between study groups regarding baseline characteristics as maternal age, BMI, previous miscarriages and midluteal serum P levels.
Regarding two-dimensional ultrasound Doppler indices, we found that uterine artery pulsatility indices in follicular and mid-luteal phases and resistance index in mid-luteal phase were statistically significant higher in RPL group compared with control one 2.31 ± 0.56 versus 2.09 ± 0.43, 2.21 ± 0.66 versus 1.93 ± 0.35 and 0.86 ± 0.07 versus 0.84 ± 0.07 with p= 0.002, 0.006 and 0.025 respectively. On the other hand, no statistically significant difference were noted between study groups regarding uterine artery resistance index in follicular phase 0.97 ± 0.22 versus 0.94 ± 0.11 with p= 0.778.
Regarding three-dimensional ultrasound Doppler indices, we found that vascularisation and vascularisation flow indices were statistically significant higher and flow index was statistically significant lower in RPL group compared with control one 16.50 ± 10.68 versus 10.58 ± 4.78, 7.25 ± 4.26 versus 6.38 ± 2.67 and 39.19 ± 4.20 versus 42.63 ± 2.37 with p= 0.045, 0.011 and < 0.001 respectively.
Finally, number of cases with positive ANA was statistically significant higher in RPL group compared with control one 19 (36.5%) versus 6 (11.5%) with p= 0.006.
In conclusion, there is a negative correlation between ultra-sonographic uterine flow indexes and the presence of antinuclear antibodies (ANA) in women with unexplained recurrent miscarriage (uRM). ANA was noted to be involved in uRM by determining impairment in uterine blood flow hemodynamic, particularly in follicular and mid-luteal menstrual phases.
Conclusions
There is a negative correlation between ultra-sonographic uterine flow indices and the presence of antinuclear antibodies (ANA) in women with unexplained recurrent miscarriage (uRM). ANA was noted to be involved in uRM by determining impairment in uterine blood flow hemodynamics, particularly in follicular and mid-luteal menstrual phases.
Recommendations
• Measuring ANA titre and assessment of uterine blood flow indices using 3D power Doppler imaging with the VOCAL technique is recommended in any women with unexplained recurrent miscarriage.
• Management of women with positive ANA with recommended evidence based treatment could be helpful in enhancement of pregnancy outcomes.
• ANA is a vital biomarker for the screening of autoimmune factors related to systemic diseases. Its clinical application in patients with RM still shows scarce evidence. There is a need for further research into the evaluation of the best cut-off titers and determination of specific autoantibodies related to reproductive disorders.
• Due to its clinical importance, more randomized comparative clinical trials with larger sample size and more data are needed for further evaluation of study outcomes.