Meta-analysis of commonly used IVF immunotherapies shows no benefit

Researchers in a 2022 study performed a meta-analysis to combine the results of studies examining the use of IVF add-ons that target the immune system, such as aspirin, heparin and corticosteroids, and found no strong evidence to support their use. The included studies mostly involved women without autoimmune disorders.

In an effort to improve success rates, many clinics use IVF add-ons that alter the immune system in some way. These include corticosteroids (like prednisone), heparin, intralipids, G-CSF, IVIG and others. These therapeutics are often described as suppressing natural killer (NK) cell function, however NK cells represent a controversial topic in IVF (you can read a bit of a summary here).

Melo et al. (2022) compared dozens of studies that spanned a number of immunomodulatory IVF add-ons. They only used randomized controlled trials (RCTs) in their meta-analyses and mainly used studies with women who had previously had implantation failure. Studies involving women with actual autoimmune disorders were scarce, so this study is mainly addressing the use of immunotherapies in women with implantation failure, or those with a good prognosis.

⚠️ Remembryo summarizes and interprets IVF research for educational purposes. Posts highlight selected findings and may simplify or omit study details, including methods, analyses, author interpretations, limitations, and protocol specifics (such as timing, dosing, or eligibility criteria). These summaries are not a substitute for the original study. Always review the full publication before treatment decisions.

🔗 Original studies are referenced in this post or within the linked Remembryo posts.

💡 Reminder: Terms underlined with a dotted black line are linked to glossary entries. Clicking these does not count toward your paywall limit.

Table of Contents

Aspirin

Women who used aspirin didn’t show a statistically significant improvement in live birth rates compared to women who didn’t use it (23.6% vs 23.0%, 6 studies, 1626 participants, risk ratio [95% CI]: 1.04 [0.81-1.33]). The quality of evidence was reported as moderate and the studies didn’t examine adverse effects.

The data was broken down and a subgroup analysis was performed using good prognosis women, women with previous implantation failure, or women with a thin endometrium, and there was still no benefit found.

Heparin

Women who used subcutaneous heparin didn’t show a statistically significant improvement in live birth rate compared to those who didn’t (26.8% vs 17.3%, 3 studies, 386 participants, risk ratio [95% CI]: 1.55 [0.80-3.00]). The quality of the data was very low. The safety of heparin in pregnancy is well established.

Corticosteroids

Women who used corticosteroids (such as prednisone) didn’t show a statistically significant improvement in live birth rate compared to those who didn’t (23.7% vs 20.8%, 5 studies, 549 participants, risk ratio [95% CI]: 1.25 [0.74-2.10]). The quality of the data was low. The use of corticosteroids can lead to insomnia and mild euphoria, and persistent use beyond the first trimester may lead to increased risk of infections or mental disorders in children.

Granulocyte colony-stimulating factor (G-CSF)

Women who used intrauterine G-CSF did show an improvement in live birth rate compared to those who didn’t (21.1% vs 13.8%, 5 studies, 744 participants, risk ratio [95% CI]: 1.52 [1.11-2.10]). The quality of the data was low. Fatigue and bone and muscle pain were indicated as adverse effects.

A subgroup analysis found that women with a thin endometrium benefit the most, however the quality of evidence for this was low.

Intralipids

Women who used intralipids didn’t show a statistically significant improvement in live birth rate compared to those who didn’t (25.2% vs 14.0%, 2 studies, 244 participants, risk ratio [95% CI]: 1.78 [0.95-3.34]). Both studies involved women with previous implantation failure. The quality of the data was very low. There were no adverse effects until higher doses were used, which led to increased infection risk, acute kidney injury, venous thromboembolism, allergic reactions, and fat embolism.

Intravenous immunoglobulin (IVIG)

Women who used IVIG didn’t show a statistically significant improvement in live birth rate compared to those who didn’t, however this was based on a single small RCT (15.4% vs 12.0%, 1 study, 51 participants, risk ratio [95% CI]: 1.28 [0.32-5.16]). The quality of the data was low. Studies that reported on adverse effects didn’t note any issues.

Human Leukemia Inhibitory Factor (hLIF)

Women who used hLIF showed a statistically significant decrease in live birth rate compared to those who didn’t, however this was based on a single RCT (13.7% vs 29.2%, 1 study, 150 participants, risk ratio [95% CI]: 0.47 [0.24-0.91]). The quality of the data was low. This study also found serious adverse effects but they weren’t indicated.

Peripheral blood mononuclear cells (PBMCs)

PBMCs are collected from blood and include a variety of immune cells such as lymphocytes, monocytes and macrophages. This isn’t the same as platelet-rich plasma (PRP), because in PRP these cells are removed.

Women who used PBMCs showed a statistically significant improvement in live birth rate compared to those who didn’t (32.7% vs 16.0%, 2 studies, 312 participants, risk ratio [95% CI]: 2.03 [1.33-3.10]). These studies were done in women with previous implantation failure. The quality of the data was very low.

Conclusions

This study examined the use of numerous IVF add-ons, including aspirin, heparin, corticosteroids, intrauterine G-CSF, intralipids, IVIG, hLIF and PBMCs. A significant benefit was found only with intrauterine G-CSF and PBMCs and no other treatment, while hLIF had a negative effect. Overall the quality of the data was low to very low (except aspirin which was moderate).

Please note that the existing studies are based primarily on women with implantation failure or a good prognosis. More studies are needed in women with autoimmune disorders to determine if this population benefits.

Recommendations on the use of IVF add-ons from several international societies were included, such as the American Society for Reproductive Medicine (ASMR), the British Fertility Society (BFS) and the Canadian Fertility & Andrology Society (CFAS). In most cases, they all didn’t recommend the use of these treatments, often indicating that more research is needed and they should be limited to research settings. It’s not clear when these recommendations were made.

The authors point out that before this research is done, it’s important to address the underlying immunological factors that cause infertility in the first place. Tests need to be developed that can clearly identify these patients and then treat them with medications that specifically act on these factors to see if there’s a benefit. While NK cells are commonly implicated, questions remain about their specific role, testing methods, affected patient groups, and the threshold for their involvement in infertility.

Reference

Melo P, Thornton T, Coomarasamy A, Granne I. Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction. Fertil Steril. 2022 Jun;117(6):1144-1159. doi: 10.1016/j.fertnstert.2022.04.015. PMID: 35618357.

If you liked this post and want to support what I do, please consider a paid subscription, Patreon or donate through PayPal!

About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.