Effect of low-molecular-weight heparin in women undergoing frozen-thawed embryo transfer cycles: a retrospective cohort study

Embryo implantation is a complicated physiological process that includes proliferation and differentiation, adhesion and migration, and extracellular matrix remodeling. It can be influenced by many factors, such as abnormal uterine cavity anatomy, reduced endometrial receptivity, immune disorders, pre-thrombotic state, advanced age, excessive BMI, abnormal thyroid function, and psychological factors. For decades, researchers have investigated effective treatments to improve pregnancy outcomes in IVF cycles.

Previous research has shown that impaired placental function may cause arterial thrombosis, which can lead to subsequent abortion. In addition, venous thromboembolism is more prevalent during gestation compared to arterial thrombosis [20]. To ensure the nutritional supply to the fetus, maternal blood flow is exchanged with the fetus through the placental intervillous space from about 10 weeks of gestation onwards [21]. In the last century, a relationship between RPL and antiphospholipid antibodies (APAs) was identified. APAs increase the generation of thrombin, leading to thrombotic damage in the placental [22]. LMWH is commonly used clinically for the treatment of acute VTE; thus, it was used to prevent miscarriage in women with APS by its antithrombotic function [23]. LMWHs may be useful in controlling endometrial differentiation and receptivity by regulating IGFBP-1, PRL, and IGF-I in assisted reproduction [24]. By increasing placental production of matrix metalloproteinases (MMPs) and tissue inhibitors metalloproteinases (TIMPs), LMWH might also regulate trophoblast invasiveness [25].

Therefore, many clinicians have attempted to use it in FET cycles to improve reproductive outcomes in ART treatment, and not just in RPL or RIF. Currently, there is little research regarding the role of LMWH in the entire population undergoing FET cycles [26]. In our study, LMWH had no obvious advantage in decreasing the risk of abortion or increasing the rate of conception in women with or without PGD. It’s reported that advanced age greatly increase the chance of adverse pregnancy outcomes, which could impair the safety of both mother and baby[27]. Dmitry et al. showed that patients aged < 35 or 35–37 years had a higher chance of a good perinatal outcome by transferring a single 5- or 3-day embryo, and patients aged > 40 years had a higher chance of a good perinatal outcome by transferring two 3-day embryos [28]. To exclude the effects of age and the number of transferred cycles and embryos, we performed further subgroup stratification analysis. Among the patients who underwent more than four transfers, the use of LMWH reduced the late abortion rate. While patients aged 30–35 years who underwent more than four transfers had a lower late abortion rate in the LMWH group. In this study, LMWH reduced late abortion when the patients underwent more than four transfers, which is consistent with the findings of studies on RPL and RIF [29]. However, previous studies have generally been insufficiently subgrouped, have observed a simple outcome indicator, and few have explored the role of LMWH on late abortion rate. Studies have shown that the main causes of late abortion were APAs, cervical incompetence, infections, and placental insufficiency [30]. All the patients in our study were APAs negative, and LMWH did not show the tendency of reducing late abortion rate in the whole population, therefore, it’s unreasonable to draw the conclusion that LMWH make contribution for the protection of late abortion. A meta-analysis also reported that LMWH could not significantly reduced the chance of abortion in non-thrombophilic patients in fresh cycles [31]. To further investigate the relationship between LMWH and late abortion, large sample and multi-center studies are needed. Genetic factors are the main causes of early miscarriages [32]. In our study, we excluded this factor from the PGD. However, LMWH has no obvious advantage in decreasing the risk of abortion or increasing the pregnancy rate. A limitation in the PGD cycles was the insufficient samples to process the subgroup analysis.

In contrast to other heparin components, LMWH has a favorable safety profile as an anticoagulant. Many studies reported the effectiveness of LMWH as a therapeutic method for unexplained RPL (URPL). However, due to the mechanism of LMWH, side effects such as allergic reactions and thrombocytopenia are inevitable in pregnant women [33]. Therefore, To avoid some possible side effects such as bleeding, rash, liver and kidney impairment, patients on LMWH should be strictly monitored [34]. Moreover, a study reported some maternal and fetal complications after using LMWH for the treatment of URPL [9]. In our study, LMWH increased early abortion rate in the whole population, further subgroup analysis showed that this happened only in patients who had embryo implantation failure once and aged under 30. However, the limited sample could not support us to draw the conclusion that using LMWH resulted higher early abortion rate. Given the side effects of LMWH and few studies explored its function on early abortion, We proposed that the using of LMWH in these younger patients caused abnormal bleeding and induced pregnancy loss in early stage. In the light of the above findings, we need to balance the use of LMWH. According to our findings, LMWH is not recommended for routine use in patients without confirmed immune disorders in the first two cycles in FET treatment.