Skip to main content

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

Abstract

Background

Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) during in vitro fertilization (IVF) treatment are still tough problems without effective treatments; thus, they are important research topics. There is controversy on whether low molecular weight heparin (LMWH) improves pregnancy outcomes in women with unexplained RPL and RIF. Moreover, currently, there is a paucity of reports on the role of LMWH in the entire population undergoing frozen-thawed embryo transfer (FET) cycles. This study aimed to estimate the effects of LMWH on pregnancy outcomes in women undergoing FET cycles.

Methods

There were 1881 female patients included in the study. Of the 1881 patients, 107 underwent preimplantation genetic diagnosis cycles, which were analyzed individually. The patients were divided into two groups: the LMWH group received injections of 4100 IU/d LMWH from the day of transfer until 14 ± 2 days posttransplant, the control group was the comparison group (without LMWH use). The baseline characteristics and reproductive outcomes of the patients were reviewed.

Results

Of the 1774 women with normal FET cycles, no significant differences were found in the number of embryos implanted (1.31 ± 0.02 vs. 1.28 ± 0.02), embryo implantation rate, biochemical pregnancy rate, clinical pregnancy rate, live birth rate, late abortion rate, and ectopic pregnancy rate between the two groups. The LMWH group had a higher early abortion (17.8% [76/427] vs. 12.5% [55/439], p = 0.030). In the sub-group analysis, among the patients who underwent more than four transfers, the LMWH group had a lower late abortion rate (1.7% [1/60] vs. 13.2% [7/53], p = 0.043). Similarly, of the 107 women who underwent preimplantation genetic diagnosis cycles, the reproductive outcomes were comparable between the two groups.

Conclusion

In the general population and PGD patients, LMWH did not improve pregnancy outcomes. Therefore, the routine use of LMWH is not recommended for early treatment.

Peer Review reports

Background

For those infertility couple, in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is one of the most effective and successful assisted reproductive technologies (ARTs). Infertility affects approximately 15% of couples, and IVF/ICSI contributes to 1–5% of all newborns in developed countries. Embryo implantation, a low-efficiency process in the menstrual cycle and assisted reproductive technologies, is a key step in establishing pregnancy [1, 2]. Therefore, it is imperative to identify effective treatments. Meanwhile, recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) during IVF treatment are still tough issues without effective treatments [3, 4]; thus, they are hot research topics.

RPL is characterized by the occurrence of two or more pregnancy failures before 20–24 weeks of gestation, which affect approximately 2.5% of couples of childbearing age [5,6,7]. RPL can be caused by chromosomal abnormality, infection, structural and functional abnormalities of the reproductive system, and autoimmune disorders. Although various therapies have been evolved to prevent pregnancy loss in these patients, effective treatment are still elusive and urgently needed. Current studies have demonstrated that low molecular weight heparin (LMWH) has the effect in improving reproductive outcomes in unexplained RPL; however, the results are conflicting [8,9,10].

There is no standardized definition of RIF. Nonetheless, RIF is defined as three or more consecutive transfers of at least four high-quality embryos in fresh or frozen cycles without clinical pregnancy in most studies [11, 12]. RIF can be caused by chromosomal abnormalities, uterine anatomical abnormalities, and maternal immune dysfunction [13]. Previous studies have estimated the function of LMWH in RIF, but the conclusions are controversial [14,15,16].

Heparin was discovered in 1916, late in the 1930s, unfractionated heparin (UFH), the first therapeutic form was introduced. Currently, a variety of different types of heparin are clinically applied, include UFH, LMWH, and synthetic heparins [17]. LMWH has a longer half-life, more stable dose-response relationship, better safety profile, reduced monitoring requirement, shorter oligosaccharide/monosaccharide chain, and higher anti-Xa/anti-IIa ratios, which make it more attractive than other heparin forms [18]. Since the anticoagulative and anti-inflammatory function of LMWH, it is now extensively used for the treatment of RPL and RIF, either alone or in combination with other agents. However, it tends to be broadly used in frozen-thawed embryo transfer (FET) cycles in IVF/ICSI treatment. Our study aimed to investigate the effect of LMWH on pregnancy outcomes in women with different numbers of transfer cycles, ages, numbers of transferred embryos, and preimplantation genetic diagnosis (PGD) cycles.

Methods

Study design and patients

In total, 1881 of patients were enrolled in this study. Among them, 107 underwent PGD cycles, which were analyzed individually. All the data were from Clinical Reproductive Medicine Management System/Electronic Medical Record Cohort Database (CCRM/EMRCD). The inclusion criteria were as follows: (1) underwent FET cycles; (2) had at least one failure of embryo transfer (including fresh embryo transfer or FET cycles). The exclusion criteria were as follows: (1) endometriosis and/or adenomyosis; (2) uterine malformation, including congenital uterine dysplasia, uterine fibroids, endometrial polyps, and intrauterine adhesions; (3) tubal factors, including hydrosalpinx; (4) LMWH contraindications, such as active bleeding; and (5) other autoimmune diseases, such as thyroid disorders.

Grouping method

The patients were split into two groups depending on the use or nonuse of LMWH. The LMWH group received injections of 4100 IU/d LMWH from the day of transfer until 14 ± 2 days posttransplant. The control group was the comparison group (without LMWH use). Human β-chorionic gonadotropin (HCG) levels were measured at 14 ± 2 days posttransplant in all groups. Laboratory data included routine blood, liver function, and blood coagulation test data in the LMWH group at 14 days posttransplant. If serum HCG was positive, the injection of LMWH was continued until 35 ± 2 days posttransplant. Ultrasonography to determine clinical pregnancy 35 days after transplantation. Laboratory data, including routine blood, liver function, and blood coagulation test data, were also obtained in the LMWH group at 35 ± 2 days posttransplant to evaluate the safety of LMWH.

Endometrial preparation

The detailed endometrial preparation protocol for freeze-thaw cycles has been described in previous article, including the classification of endometrial types and thickness measurement methods [19]. For estrogen-progesterone (EP) cycles, oral estradiol ([Progynova]; Bayer, Germany) administration began on day 2–3 of the target cycle and lasted about two weeks. When the thickness of the endometrium reaches 8 mm and above, the patient is asked to add oil-based progesterone (60 mg), at the same day, the thickness of endometrial was recorded using transvaginal ultrasound examination. To avoid cavity fluid and other unfavorable conditions, patients were hospitalized and re-measurement of endometrial thickness on the morning of the transplantation day. Luteal supplement was altered to vaginal progesterone gel (90 mg, Crinone 8%; Merck Serono) and oral dydrogesterone (20 mg Duphaston; Abbott) after embryo implantation.

Statistical methods

IBM SPSS, 21.0 (IBM Corp., Armonk, N.Y., USA) was employed. Numerical data were shown as the mean ± standard deviation (SD), while categorical variables were shown as % (n/N). The Man-Whitney test and chi-square test were utilized for continuous and categorical variables, respectively. Two-tailed P < 0.05 was considered as statistical significance.

Results

Baseline characteristics and reproductive outcomes in women undergoing FET cycles

Of the 1881 patients who began FET treatment between 2020 and 2021, 107 women underwent PGD cycles. First, we analyzed 1774 women with normal FET cycles. There were 882 (49.7%) and 892 (50.3%) patients in LMWH and control groups, respectively (Table 1). The results were comparable between two groups in age (32.28 ± 0.17 vs. 32.37 ± 0.16), years of infertility (4.54 ± 0.12 vs. 4.65 ± 0.12), body mass index (BMI; 23.74 ± 0.19 vs. 23.56 ± 0.12), basal serum FSH (6.65 ± 0.10 vs. 6.60 ± 0.08), basal serum LH (7.46 ± 0.33 vs. 8.06 ± 0.38), basal serum E2 (242.40 ± 27.51 vs. 263.92 ± 33.65), AMH (4.01 ± 0.12 vs. 4.13 ± 0.12), and AFC (14.65 ± 0.23 vs. 15.21 ± 0.23) between the two groups. Also, no great differences were identified in the number of embryos implanted (1.31 ± 0.02 vs. 1.28 ± 0.02), embryo implantation rate (44.9% [519/1157] vs. 45.5% [522/1146]), biochemical pregnancy rate (52.3% [461/882] vs. 51.6% [460/892]), clinical pregnancy rate (48.4% [427/882] vs. 49.2% [439/892]), live birth rate (37.9% [334/882] vs. 39.9% [356/892]), late abortion rate (2.6% [11/427] vs. 5.0% [22/439]), and ectopic pregnancy rate (1.4% [6/427] vs. 1.4% [6/439]) between the two groups. Compared to the control group, the LMWH group had a higher early abortion rate (17.8% [76/427] vs. 12.5% [55/439], p = 0.030).

Table 1 Baseline characteristics and pregnant outcome of patients undergoing FET cycles

Baseline characteristics and reproductive outcomes in women with different numbers of transfer cycles

To assess the effect of LMWH in different numbers of transfer cycles, we grouped the 1774 women into four groups (Table 2). There were 233 (41.7%) and 326 (58.3%) patients who underwent one transfer in the LMWH and control groups, respectively. No statistical differences were found in age, years of infertility, BMI, basal serum FSH, basal serum E2, AMH, and AFC between the two groups. Also, the data were comparable between the two group in the number of embryos implanted, embryo implantation rate, biochemical pregnancy rate, clinical pregnancy rate, live birth rate, late abortion rate, or ectopic pregnancy rates. The LMWH group had lower basal serum LH levels (6.29 ± 0.59 vs. 7.77 ± 0.64, p = 0.017) and a higher early abortion rate (17.5% [18/103] vs. 8.2% [12/147], p = 0.026) than the control group. There were 328 (51.6%) and 308 (48.4%) patients who underwent two transfers in the LMWH and control groups, respectively. Further, 181 (52.9%) in the LMWH group and 161 (47.1%) patients in the control group underwent three transfers. All baseline characteristics and pregnancy outcomes between the two groups were comparable. There were 140 (59.1%) and 97 (40.9%) patients who underwent more than four transfers in the LMWH and control groups, respectively. Patients using LMWH had fewer years of infertility (6.36 ± 0.32 vs. 7.22 ± 0.37, p = 0.041) and lower embryo implantation (40.6% [73/180] vs. 55.1% [65/118], p = 0.014) and late abortion rates (1.7% [1/60] vs. 13.2% [7/53], p = 0.043).

Table 2 Baseline characteristics and pregnant outcome of patients in different number of transfer cycles

Baseline characteristics and reproductive outcomes in different age groups

To assess the effect of LMWH at different ages, we grouped the 1774 women into four groups: ages < 30, 30–35, 35–40, and ≥ 40 years (Table 3). In the LMWH and control groups respectively, there were 260 (49.9%) and 261 (50.1%) patients aged < 30 years, 379 (51.3%) and 360 (48.7%) patients aged 30–35 years, 157 (45%) and 192 (55%) patients aged 35–40 years, and 86 (52.1%) and 79 (47.9%) patients aged ≥ 40 years. All baseline characteristics and pregnancy outcomes were comparable among the four age groups. To further specify the effect of LMWH at different ages and numbers of transfer cycles, we grouped the patients according to the number of transfer cycles in the four age groups (Supplementary 1). The LMWH group had a lower biochemical pregnancy rate (50% [13/26] vs. 78.3% [18/23], p = 0.041) and clinical pregnancy rate (38.5% [10/26] vs. 69.6% [16/23], p = 0.029) than the control group among patients aged < 30 years who underwent more than four transfers (Supplementary 1). The LMWH group had a lower late abortion rate (0.0% [0/32] vs. 19.0% [4/21], p = 0.042) among 30–35-year-old patients who underwent more than four transfers (Supplementary 1).

Table 3 Baseline characteristics and pregnant outcome of patients in different age

Baseline characteristics and reproductive outcomes in different numbers of transferred embryos

To assess the effect of LMWH in different numbers of transferred embryos, we grouped the 1774 women into four groups (first group, one transferred embryo; second group, one transferred blastocyst; third group, two transferred embryos; fourth group, two transferred blastocysts) (Table 4). In the LMWH and control groups respectively, 119 (44.9%) and 146 (55.1%) patients had one transferred embryo, 488 (49.8%) and 492 (50.2%) patients had one transferred blastocyst, 220 (50.1%) and 219 (49.9%) patients had two transferred embryos, and 55 (61.1%) and 35 (38.9%) patients had two transferred blastocysts. To further specify the effect of LMWH at different ages and numbers of transferred embryos, we grouped the patients according to the number of transferred embryos at different ages (Supplementary 2). The LMWH group had a higher early abortion rate [13.0% [6/46] vs. 0.0% [0/45], p = 0.037) among patients aged < 30 years who had two transferred embryos (Supplementary 2).

Table 4 Baseline characteristics and pregnant outcome of patients transferred different number of embryos

Baseline characteristics and reproductive outcomes of patients undergoing PGD

Of the 1881 patients who began FET treatment between 2020 and 2021, 107 women who underwent PGD cycles were analyzed separately. There were 50 (46.7%) and 57 (53.3%) patients in the LMWH and control groups, respectively (Table 5). The results were comparable between two groups in age (30.00 ± 0.51 vs. 30.46 ± 0.45), years of infertility (2.42 ± 0.27 vs. 2.53 ± 0.25), BMI (23.30 ± 0.32 vs. 22.89 ± 0.33), basal serum FSH (5.98 ± 0.24 vs. 5.96 ± 0.24), basal serum LH (5.89 ± 0.74 vs. 6.98 ± 1.47), basal serum E2 (66.55 ± 10.01 vs. 71.30 ± 12.31), AMH (4.38 ± 0.45 vs. 3.81 ± 0.30), and AFC (16.62 ± 0.80 vs. 16.19 ± 0.67). No statistical differences were found in embryo implantation rate (60% [30/50] vs. 56.1% [32/57]), biochemical pregnancy rate (66% [33/50] vs. 64.9% [37/57]), clinical pregnancy rate (60% [30/50] vs. 56.1% [32/57]), live birth rate (42% [21/50] vs. 38.8% [26/57]), early abortion rate (23.3% [7/30] vs. 18.8% [6/32]), late abortion rate (3.3% [1/30] vs. 0.0% [0/32]), and ectopic pregnancy rate (3.3% [1/30] vs. 0.0% [0/32]) between the two groups.

Table 5 Baseline characteristics and pregnant outcome of patients undergoing PGD

Discussion

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.

Conclusions

In the general population, women using LMWH had higher early abortion rate compared to the control group, subgroup analysis showed it only presented in patients who had embryo implantation failure once and aged under 30. However, LMWH did not improve the pregnant outcomes in the general population and PGD patients, therefore, the routine use of LMWH is not recommended for early treatment.

Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

APAs:

Antiphospholipid antibodies

ARTs:

Assisted reproductive technologies

EP:

Estrogen-progesterone

FET:

Frozen-thawed embryo transfer

HCG:

Human β-chorionic gonadotropin

IVF:

In vitro fertilization

ICSI:

Intracytoplasmic sperm injection

LMWH:

Low molecular weight heparin

MMPs:

Matrix metalloproteinases

PGD:

Preimplantation genetic diagnosis

RIF:

Recurrent implantation failure

RPL:

Recurrent pregnancy loss

SD:

Standard deviation

TIMPs:

Tissue inhibitors metalloproteinases

UFH:

Unfractionated heparin

References

  1. Yang Y, He JP, Liu JL. Cell-cell communication at the embryo implantation site of mouse uterus revealed by single-cell analysis. Int J Mol Sci. 2021;22.

  2. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7:185–99.

    Article  PubMed  Google Scholar 

  3. Busnelli A, Reschini M, Cardellicchio L, Vegetti W, Somigliana E, Vercellini P. How common is real repeated implantation failure? An indirect estimate of the prevalence. Reprod Biomed Online. 2020;40:91–7.

    Article  PubMed  Google Scholar 

  4. Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T. Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod. 2006;21:3036–43.

    Article  CAS  PubMed  Google Scholar 

  5. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.

    Article  Google Scholar 

  6. Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373:2141–8.

    Article  CAS  PubMed  Google Scholar 

  7. Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6:98.

    Article  PubMed  Google Scholar 

  8. Abou-Saif AH, Alkholy EA, Hammad RH, Hassan AH. The effect of low molecular weight heparin in recurrent pregnancy loss: changes in radial uterine artery blood flow and peripheral blood NK cell fraction. Egypt J Immunol. 2018;25:75–85.

    PubMed  Google Scholar 

  9. Schleussner E, Kamin G, Seliger G, Rogenhofer N, Ebner S, Toth B, et al. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162:601–9.

    Article  PubMed  Google Scholar 

  10. Wang G, Zhang R, Li C, Chen A. Evaluation of the effect of low molecular weight heparin in unexplained recurrent pregnancy loss: a meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med. 2021:1–8.

  11. Sun Y, Zhang Y, Ma X, Jia W, Su Y. Determining diagnostic criteria of unexplained recurrent implantation failure: a retrospective study of two vs three or more implantation failure. Front Endocrinol (Lausanne). 2021;12:619437.

    Article  PubMed  Google Scholar 

  12. Cimadomo D, Craciunas L, Vermeulen N, Vomstein K, Toth B. Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists. Hum Reprod. 2021;36:305–17.

    Article  CAS  PubMed  Google Scholar 

  13. Vomstein K, Voss P, Molnar K, Ainsworth A, Daniel V, Strowitzki T, et al. Two of a kind? Immunological and clinical risk factors differ between recurrent implantation failure and recurrent miscarriage. J Reprod Immunol. 2020;141:103166.

    Article  CAS  PubMed  Google Scholar 

  14. Berker B, Taşkin S, Kahraman K, Taşkin EA, Atabekoğlu C, Sönmezer M. The role of low-molecular-weight heparin in recurrent implantation failure: a prospective, quasi-randomized, controlled study. Fertil Steril. 2011;95:2499–502.

    Article  CAS  PubMed  Google Scholar 

  15. Hamdi K, Danaii S, Farzadi L, Abdollahi S, Chalabizadeh A, Abdollahi Sabet S. The role of heparin in embryo implantation in women with recurrent implantation failure in the cycles of assisted reproductive techniques (without history of thrombophilia). J Family Reprod Health. 2015;9:59–64.

    PubMed  PubMed Central  Google Scholar 

  16. Potdar N, Gelbaya TA, Konje JC, Nardo LG. Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis. Hum Reprod Update. 2013;19:674–84.

    Article  CAS  PubMed  Google Scholar 

  17. Onishi A, St Ange K, Dordick JS, Linhardt RJ. Heparin and anticoagulation. Front Biosci (Landmark Ed). 2016;21:1372–92.

    Article  CAS  PubMed  Google Scholar 

  18. Fouda UM, Sayed AM, Abdou AM, Ramadan DI, Fouda IM, Zaki MM. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet. 2011;112:211–5.

    Article  CAS  PubMed  Google Scholar 

  19. Bu Z, Yang X, Song L, Kang B, Sun Y. The impact of endometrial thickness change after progesterone administration on pregnancy outcome in patients transferred with single frozen-thawed blastocyst. Reprod Biol Endocrinol. 2019;17:99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walker ID. Arterial thromboembolism in pregnancy. Best Pract Res Clin Haematol. 2003;16:297–310.

    Article  PubMed  Google Scholar 

  21. Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114:397–407.

    Article  CAS  PubMed  Google Scholar 

  22. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408–13.

    Article  CAS  PubMed  Google Scholar 

  23. Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, Middeldorp S, et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost. 2013;11:270–81.

    Article  CAS  PubMed  Google Scholar 

  24. Fluhr H, Spratte J, Ehrhardt J, Steinmüller F, Licht P, Zygmunt M. Heparin and low-molecular-weight heparins modulate the decidualization of human endometrial stromal cells. Fertil Steril. 2010;93:2581–7.

    Article  CAS  PubMed  Google Scholar 

  25. Di Simone N, Di Nicuolo F, Sanguinetti M, Ferrazzani S, D’Alessio MC, Castellani R, et al. Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors. Placenta. 2007;28:298–304.

    Article  PubMed  Google Scholar 

  26. Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG. Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study. Reprod Biomed Online. 2011;22:615–20.

    Article  CAS  PubMed  Google Scholar 

  27. Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: a systematic review and meta-analysis. PLoS ONE. 2017;12:e0186287.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Martins WP, Nastri CO, Rienzi L, van der Poel SZ, Gracia C, Racowsky C. Blastocyst vs cleavage-stage embryo transfer: systematic review and meta-analysis of reproductive outcomes. Ultrasound Obstet Gynecol. 2017;49:583–91.

    Article  CAS  PubMed  Google Scholar 

  29. Potdar N, Gelbaya TA, Konje JC, Nardo LG. Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis. Hum Reprod Update. 2013 Nov-Dec;19(6):674–84.

  30. McNamee KM, Dawood F, Farquharson RG. Mid-trimester pregnancy loss. Obstet Gynecol Clin North Am. 2014;41:87–102.

    Article  PubMed  Google Scholar 

  31. Yang XL, Chen F, Yang XY, Du GH, Xu Y. Efficacy of low-molecular-weight heparin on the outcomes of in vitro fertilization/intracytoplasmic sperm injection pregnancy in non-thrombophilic women: a meta-analysis. Acta Obstet Gynecol Scand. 2018 Sep;97(9):1061–72.

  32. Jia CW, Wang L, Lan YL, Song R, Zhou LY, Yu L, et al. Aneuploidy in early miscarriage and its related factors. Chin Med J (Engl). 2015;128:2772–6.

    Article  PubMed  Google Scholar 

  33. Stefanski AL, Specker C, Fischer-Betz R, Henrich W, Schleussner E, Dörner T. Maternal thrombophilia and recurrent miscarriage - is there evidence that heparin is indicated as prophylaxis against recurrence? Geburtshilfe Frauenheilkd. 2018;78:274–82.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Karadağ C, Yoldemir T, Karadağ SD, İnan C, Dolgun ZN, Aslanova L. Obstetric outcomes of recurrent pregnancy loss patients diagnosed with inherited thrombophilia. Ir J Med Sci. 2017;186:707–13.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the staff of Reproductive Medicine Center, First Affiliated Hospital of Zhengzhou University for their cooperation and support.

Funding

This work was funded by National Key R&D Program of China (FDN-2019YFA0110900) and Key projects of medical science and technology of Henan Province (FDN-SBGJ202002049) and the Medical Science and Technology Research Project Joint Co-construction Project of Henan Province(FDN-LHGJ20210353).

Author information

Authors and Affiliations

Authors

Contributions

BS designed the study. BS and LL analyzed the data and drafted the manuscript. XL revised the manuscript. BS, LL, and XL collected data. YS contributed to the study conceptualization and review of the manuscript. All authors have contributed to the manuscript and approved the submitted version.

Corresponding author

Correspondence to Yingpu Sun.

Ethics declarations

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2021-KY-0104). All participants in the study have provided their written informed consents. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Additional file 1:

Supplementary 1 and 2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, B., Li, L., Chen, X. et al. Effect of low-molecular-weight heparin in women undergoing frozen-thawed embryo transfer cycles: a retrospective cohort study. BMC Pregnancy Childbirth 23, 335 (2023). https://doi.org/10.1186/s12884-023-05634-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12884-023-05634-1

Keywords