الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Repeated pregnancy loss has long been recognized as a worldwide health issue; hence it is important to delineate its underlying causes, especially those of genetic ones. Thrombophilia has been one of the major causes of RPL, in which MTHFR gene polymorphism is one of the main highlighted factors, genetically speaking. RPL impact about 10-12% of couples, encompassing both clinically acknowledged and unnoticed pregnancies, with increase in the chance of recurrence up to 32% in individuals with three previous abortions.
Due to the deficiency of the data base concerning the impact of MTHFR gene mutations on RPL the present study was carried out to investigate the association between RPL and MTHFR gene mutations, to determine the contribution of genetic mutations to repeated pregnancy loss, and to identify the zygosities associated with these polymorphisms.
These carried out studies are not common and necessitates frequent updating in order to support data base and hence improve the conception outcomes and management approaches.
The main results of the present study could be summarized as follows:
Over two-thirds of the cases (69.3%) involve mothers below the age of 35, while the remaining third (30.8%) fall into the 35 years or older category. A comparable distribution pattern is noticeable in paternal ages, where 66.9% belong to the 20 to less than 40 years age group, and the other third (33.8%) are among the 40-49 years age range. The majority of women (84.2%) were married to non-consanguineous partners, while 15.8% had consanguineous partners. Parental consanguinity followed a similar trend, with 81.2% having non-consanguineous parents and 18.8% having consanguineous parents. Surprisingly, only 8.8% reported consanguinity with their husband’s parents. More than half (58.5%) of women studied had been pregnant 5 or more times and (51.5%) were nulliparous with a notable portion (63.3%) experienced 4 or more abortions. Moreover, the highest percentage of women with unexplained causes for their abortions (91.2%) highlights the complexity and challenges in identifying specific etiologies.
MTHFR gene mutation was present in 95.4% of the sample. 64.2% of this sample were heterozygous, 23.1% were homozygous and 8.1% were double heterozygous. Regarding the mutation subtypes 58.5% were C677T and 26.2% were A11298C. in addition, 24.6% had abnormal factor V Leiden mutation and 24.2 had combined MTHFR and factor V Leiden mutation.
Referring to history of previous abortion frequency 63% had 4 and more abortions while 37% had 2-3 abortions. MTHFR gene mutation, zygosity, subtypes and factor V Leiden showed no significant association with reported frequency of abortion.
Referring to MTHFR gene mutation and associated factors ,95.4% of women who had RPL had MTHFR gene mutation. Regarding maternal age, consanguinity, family history of abortion, gestational age of previous abortions and frequency of abortion, no significant results were recorded with MTHFR gene mutations.
Studying MTHFR gene mutations zygosity, 67.3% of them women were heterozygous and 24.2% were homozygous, 8.4% were double heterozygous. As for maternal age, consanguinity, family history of abortion, abortion frequency and gestational age of previous abortions, had no significant association with MTHFR gene mutations zygosity.
Regarding the mutation subtypes 58.5% were C677T and 26.2% were A11298C. In addition, 24.6% had abnormal factor V Leiden mutation and 24.2% had combined MTHFR and factor V mutation. Maternal age, paternal age, consanguinity, abortion frequency, family history of abortion, abortion among siblings, gestational age of previous abortions, showed no significant association with MTHFR gene mutations zygosity.
Referring to Factor V Leiden, 25% of sampled women had factor V Leiden mutation. 75.4% were normal with no mutation. Factor V Leiden in relation to (maternal age, paternal age, consanguinity, abortion frequency, family history of abortion, abortion among siblings and gestational age of previous abortions) recorded non-significance.
Referring to combination of MTHFR gene and factor V Leiden mutation ,24.2% of women with repeated pregnancy loss were recorded to have combined MTHFR gene and factor V Leiden mutations while, 75.8 % did not. Maternal age, paternal age, consanguinity, abortion frequency, family history of abortion, abortion among siblings, gestational age of previous abortions, hadno significant association with combined gene mutations.
6.2 Conclusion:
In conclusion, the prevalence of MTHFR gene mutations was notably high in the studied sample, with 95.4% of women experiencing RPL having these mutations. Despite the high prevalence of MTHFR gene mutations, our findings did not identify significant associations between RPL and these mutations and other factors such as maternal age, consanguinity, family history of abortion, gestational age of previous abortions, and abortion frequency. Additionally, the subtypes of MTHFR gene mutations (C677T and A1298C), zygosity, and the presence of factor V Leiden mutations individually or in combination did not show significant associations with the reported frequency of abortions or other demographic factors. This negative finding could be true finding. Further other comprehensive studies may be needed in order to confirm and support the present finding.
6.3. Recommendations:
Given the high prevalence of MTHFR gene mutations in women experiencing RPL, strategies for the prevention and management of RPL should be acknowledged, emphasized, implemented, and integrated into health-care systems either public or private.
Accordingly, and based on the results of the present study we recommend:
1- Raising public awareness about genetic role in RPL, risk factors, consequences, and screening programs through various educational strategies and media.
2- Selection of the governmental sectors for future studies is requested in order to include samples representing the general populations for studying the normal MTHFR gene distribution among Egyptian Population and its pathogenic significance.
3- Healthcare providers should also Include screening for RPL as gene Panel studies and other molecular studies such as Whole exome and Whole genome sequences.
4- Improving recording and filing systems for patients is very important for data base accuracy
Further research:
The complexity of RPL suggest the need for further research to explore additional genetic, environmental, and lifestyle factors that may contribute to RPL. Collaborative efforts are essential to expand the knowledge base and improve management approaches.
As the results also show no clear difference in MTHFR C677T/A1298C genotype distribution among the study sample; therefore, further studies on larger population and other genetic variants to better understand the pathobiology of RPL are needed.
Population study for the frequency of MTHFR gene subtype mutation among the Egyptian population is highly recommended for better interpretation of the significance of different subtypes.
Controlled studies such as cohort or case-control studies are also needed to validate the evidence obtained from the current study and give deeper insight to the findings. Case -control studies are example for a comparison between those who had positive MTHFR gene mutation among couples with RPL and those who had no history of RPL
More basic experiments are needed to conduct in-depth research on the molecular mechanism and related signal pathways of epigenetic regulation in RPL.
Future well-powered genome-wide association studies will help in the analysis of biological pathways for RPL and further help the prediction and identification of women at risk for RPL.