With an increasing number of affected couples, recurrent pregnancy loss (RPL) has become a widespread reproductive health problem. Clinically, it is defined as the loss of three or more pregnancies before the foetus reaches viability. It affects approximately 3 percent of couples attempting to conceive. Cases with multiple miscarriages with or without any viable children are also categorized as RPL.

Dr. Sarla Naglot, ICMR, New Delhi

According to the latest medical journals, uterine anomalies, antiphospholipid syndrome, inherited thrombophilia, abnormal endocrine factors, environmental factors, advanced parental age, and genetic factors may cause RPL by interfering with foetal development that eventually leads to miscarriages. Uterine abnormalities, like uterine septum and Müllerian anomalies, disrupt placenta growth by hampering the endometrium’s blood supply, resulting in miscarriages. Hormonal disorders like hyperprolactinemia, thyroid disorders, uncontrolled diabetes, luteal phase deficiency, and polycystic ovarian syndrome (PCOS) are also associated with RPL. RPL is also reported in patients with hyperprolactinemia and diabetes mellitus I. Moreover, environmental factors like obesity, smoking, excessive caffeine consumption, and alcohol intake are known to increase the risk of miscarriages.

Another significant factor influencing RPL pathogenesis is the maternal immune response against the foetus. The mother’s immune system often views the foetus, with its half-paternal genome, as a foreign body, but a protective immunological cascade gets activated during pregnancy to prevent its rejection. In RPL, autoimmune factors like antiphospholipid syndrome, antinuclear antibodies, and anti-thyroid antibodies lead to an immune reaction against the foetus causing its early rejection. Amongst the known autoimmune disorders connected with RPL, the antiphospholipid syndrome is garnering significant attention due to its high prevalence. Another factor usually seen in RPL cases is embryo chromosomal abnormalities, due to natural selection such foetuses do not survive beyond the 10th week of gestation. As one of the factors involved in RPL is maternal age, couples are strongly advised to undergo peripheral karyotyping. This particular cause of RPL is highly encountered by the new generation of would-be parents due to their late family planning. It has been reported that there is an increased incidence of foetal aneuploidy in older mothers, likely due to fewer optimally developed oocytes. On the other hand, the correlation with male partners is not yet understood. While diagnosis of RPL can be disheartening, many affected couples can carry a pregnancy successfully with available modern therapy and management procedures, especially when underlying causes are endocrine diseases, antiphospholipid syndrome, or anatomical abnormalities.

Unfortunately, around 40% of RPL cases remain unexplained even after extensive clinical investigations and are termed idiopathic RPL (iRPL). Couples afflicted by iRPL go through a difficult and frustrating ordeal, facing financial burdens and feelings of fear and uncertainty. The lack of understanding about the causes of iRPL cases also poses a significant challenge for doctors. A major limitation of RPL clinical workup is that it is mostly focused on female partners and only two clinical evaluations—semen analysis and karyotyping—are recommended for male partners. This is because RPL is not related to conception or impregnation but rather to carrying the conceptus to a live birth, undervaluing the importance of male components after fertilization. However, recent discussions about the significance of sperm in fertilization and early embryonic development have shed light on the investigation of sperm-related factors in RPL. Studies have found chromosomal abnormalities, embryonic aneuploidy, oxidative stress, fragmentation of sperm DNA, and other male contributory factors in iRPL cases. Abnormal expression of certain sperm proteins that may influence feto-maternal communication, foetal development, and embryo implantation has also been identified. Proteins play a significant role in the development and efficient function of spermatozoa, impacting functional pathways and thus, uncovering molecular insights about the role of spermatozoa in fertilization and embryo development is critical for understanding successful pregnancies. Regardless of recent advancements in RPL pathogenesis and molecular insights, it continues to raise concerns and calls for auxiliary molecular research.

The research on the correlation between oxidative stress, DNA fragmentation, and pregnancy loss is still in the early stages and requires more studies to yield conclusive results. Further explorations in this area can elucidate the potential role of male contributory factors in idiopathic cases, potentially improving iRPL management. Based on the findings of our research, we believe that iRPL patients may benefit from medical treatments targeting oxidative stress and DNA fragmentation. Traditionally, the male contribution, particularly of their spermatozoa, has been perceived as limited to fertilization, and any adverse events after conception are attributed to mothers. Biomedical research, however, emphasizes the contribution of male factors in iRPL cases after fertilization. Thus, one of the significant impacts of pre-clinical research findings on male characteristics in RPL is raising awareness in society and changing clinical standards.

In conclusion, conducting more thorough investigations on male partners in RPL can help reduce the incidence of idiopathic cases, raise public awareness, and alleviate the psychological strain on women. Understanding the role of sperm-related factors and employing a molecular approach may provide critical insights into RPL, leading to improved care and better outcomes for affected couples. By unravelling the molecular mechanisms involved in RPL, researchers can identify potential biomarkers for screening and to develop targeted treatments, bringing hope to couples facing these challenges.