ASRI releases 2025 immune therapy guidelines for recurrent pregnancy loss

The American Society for Reproductive Immunology has provided the first evidence-based guidelines for immunotherapy use, and recommends immunotherapies like corticosteroids only in cases of recurrent pregnancy loss with confirmed immune abnormalities.

The American Society for Reproductive Immunology (ASRI) has released the first evidence-based clinical guidelines for immunological treatment of recurrent pregnancy loss (RPL). RPL, defined as two or more pregnancy losses, affects up to 5% of couples. While immune dysfunction (eg. elevated NK cells, Th1 dominance, or autoantibodies) is implicated in many unexplained cases, treatments have often been used broadly without biomarker guidance or standard criteria.

To address this, ASRI convened its Clinical Reproductive Immunology Fellowship (CRIF), a global group of certified reproductive immunologists, to assess the evidence. The guidelines reflect both published data (especially systematic reviews and RCTs) and current clinical practice, aiming to promote rational, evidence-informed care.

Disclaimer: This post summarizes the new ASRI guidelines and shares my own analysis of the evidence behind them. While these guidelines represent an important step toward standardizing immunotherapy use in RPL, some of the supporting studies appear to have limitations. Other, more well-known assisted reproduction groups, including the HFEA, ESHRE and ASRM, do not recommend immunotherapies due to a lack of high-quality evidence. Because of this, these recommendations should be interpreted with caution.

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Immune markers for reproductive immunology

A biomarker (or marker) is something that can be measured and associated with a biological process or disease, like temperature for a fever.

Abnormal numbers, percentages, or activity of immune cells has been associated with RPL. The following immune markers are referenced in the guidelines, so here’s a quick breakdown!

• Natural Killer (NK) cells
  • uNK cells (in uterus): Involved in implantation.
  • pbNK cells (in peripheral blood): Often tested but less relevant to implantation.
  • Some studies suggest increased uNK or pbNK cells (or their activity) is associated with RPL.
• Th1/Th2 cells
  • Th1: Promote inflammation (involving cytokines IL-2, IFN-gamma, TNF-alpha).
  • Th2: Anti-inflammatory (IL-4, IL-10).
  • A high Th1/Th2 ratio may indicate immune overactivation.
• Regulatory T cells (Tregs)
  • Promote immune tolerance and prevent over-inflammation.
  • Low Treg levels are linked to miscarriage and failed implantation.
• Th17 cells
  • Drive inflammation and autoimmunity.
  • High Th17 or high Th17/Treg ratio may increase RPL/RIF risk.
• Autoantibodies
  • Antiphospholipid antibodies (aPL): Cause clotting, miscarriage.

Only some immune therapies show a benefit, and these are often tied to specific biomarkers like NK cell levels or Th1/Th2 ratios based on existing evidence. The ASRI discourages using these treatments without documented immune abnormalities, though they don’t always specify which tests must be used, and it’s unclear whether different immune markers are interchangeable.

Corticosteroids

Corticosteroids (eg. prednisolone, prednisone, dexamethasone, and betamethasone) are oral anti-inflammatory medications commonly used to suppress immune responses in autoimmune diseases. They reduce inflammation and shift immune responses toward Th2 dominance. They’ve shown promise for RPL, especially when immune markers are abnormal.

• Strongly recommended for women with unexplained RPL and immune abnormalities (eg. ANA positive, uNK >5%, and other positive autoantibodies)
• Conditionally recommended for unexplained RPL without immune abnormalities, because they may benefit patients with undetected immune issues.
• Dose: 10–20 mg/day started preconception and continued through the first trimester
• Generally safe in pregnancy, though long-term use may slightly increase the risk of preterm birth, low birth weight and preeclampsia.

Deeper ASRI corticosteroid analysis

Curious about how strong the evidence really is? After posting this, I received messages questioning the integrity of the ASRI recommendations. That prompted me to dig deeper into the studies they cited, especially around corticosteroids. You can find my full analysis below.

In order to evaluate some concerns about the ASRI recommendations, I decided to look more closely at the studies they used to form their “strong” recommendation of corticosteroids.

They included 3 meta-analyses they used as evidence of the treatments’ effectiveness for RPL (and several others for safety/side effects which I won’t look at here):

Ma et al. (2022) — This meta-analysis included two studies that looked at prednisone/prednisolone in women with RPL with >5% uNK cells or positive ANA.

• The combined result of these two studies (Tang et al. 2013 and Sun et al. 2021) showed an increase in live birth rate (odds ratio [95% CI]: 2.45 [1.11-5.44], p= 0.03).
• They concluded that “oral immunosuppressants (including cyclosporine A or prednisolone) can improve pregnancy outcomes in patients with idiopathic RM, increase live birth rate and ongoing pregnancy rate, and reduce miscarriage rate.”
• Both studies were small and neither was statistically significant on its own. While meta-analyses can show significance even when individual studies don’t, using this as a basis for a strong clinical recommendation may be premature.

Dan et al. (2015) — This meta-analysis included three studies that looked at prednisolone in RPL patients.

• Two of these studies (Tang et al. 2013 and Tang et al. 2009) included women with uNK cells >5% and found higher live birth rates (relative risk [95% CI]: 1.58 [1.23-2.02], p= 0.0003).
• They conclude “Although our data report the improvement of prednisolone in the unexplained RM treatment, it is still premature to conclude the efficacy of prednisolone in the women with unexplained recurrent miscarriage.”
• One of the studies included here, Tang et al. 2009, is actually a study protocol that outlines the planned trial design but reports no patient outcome data. This seems to have been mistakenly treated as a completed trial, which would change the meta-analysis result. I’ve written a letter to the journal to clarify this, especially since this meta-analysis appears to be the main source cited by ASRI that supports corticosteroids for women with >5% uNK cells.

Mekinian et al. (2016) — This meta-analysis included four studies that looked at prednisolone in RPL patients (Gomaa et al. 2014, Fawzy et al. 2008, Tempfer et al. 2006 and Tang et al. 2013).

• They found an increase in live births (odds ratio [95% CI]: 7.99 [5.01-12.73]).
• They conclude that “further studies are required to clarify the efficacy and safety of immunomodulation strategies.”
• The studies used prednisolone combined with aspirin and sometimes heparin, making it hard to isolate the effect of prednisone (resulting in high heterogeneity — 71%). The only study that looked at uNK cells was the Tang et al. 2013 study, which itself wasn’t statistically significant.

Some might dispute the ASRI’s “strong recommendation” for corticosteroids based on this data.

A more recent 2025 meta-analysis by D’Ippolito et al., also published by the same journal that published the ASRI recommendations, found that corticosteroids increased both ongoing pregnancy and live birth rates in women with RPL. However, the authors state that “extreme caution should be used when considering these results” due to limited data. They also questioned the biological rationale for using corticosteroids in unexplained RPL, pointing out that the immune system’s role in pregnancy loss remains unclear, immune testing lacks consistency, study designs are often weak or conflicting, and treatment protocols vary widely.

All of this doesn’t mean corticosteroids have no benefit, but the evidence ASRI used to support a strong recommendation is limited. Given these issues, it’s probably a good idea to more closely examine the supporting data for their other recommendations (which I haven’t done).

Now let’s continue looking at ASRI’s recommendations for other immunotherapies!

Intravenous immunoglobulin (IVIG)

Intravenous immunoglobulin (IVIG) is a blood product infused through an IV that contains pooled antibodies from healthy donors. IVIG modulates both innate and adaptive immune responses and is used for autoimmune and alloimmune conditions. Studies are mixed, but moderate quality evidence shows increased live birth rates when started before conception in women with immune risk factors or ≥4 miscarriages.

• Moderate quality of evidence for women with a high number of losses and abnormal pbNK cell numbers or activity, Th1/Th2 imbalance, or autoimmunity. ASRI doesn’t explicitly say if they recommend it or not, so I’m assuming they mean that it’s conditionally recommended for this population.
• Dose: 400 mg/kg IV every 1–3 weeks starting preconception
• Most side effects are mild (eg. headache or fatigue), but can worsen with more frequent treatment (4x a week). Rare anaphylactic reactions can occur, especially in patients with low IgA levels and anti-IgA antibodies.
• Select references (supporting evidence): Wong et al. (2014), Yamada et al. (2022), Habets et al. (2022)

Lymphocyte immunotherapy (LIT)

Lymphocyte immunotherapy (LIT) involves injecting lymphocytes from the male partner to induce maternal immune tolerance. Evidence is mixed (68% of the 22 RCTs published since 1985 have shown a benefit), and safety concerns exist. It is banned in the US as research-use only but is available elsewhere.

• Conditionally recommended outside the US for women with unexplained RPL
• LIT candidates are strongly recommended to have immune biomarkers (anti-paternal leukocyte antibody), with seroconversion confirmed after treatment
• Usually well-tolerated, with reports of reactions at the injection site and influenza-like symptoms, but poor lab practices have led to rare cases of infection transmission.
• Select references (supporting evidence): Francisco et al. (2022)

Intravenous lipid emulsion (intralipids)

Intravenous lipid emulsion (ILE) is an IV nutritional supplement made of fats (typically soy or egg-based) sometimes used off-label to modulate immune activity. It may reduce NK cell activity and inhibit Th1 cytokines.

• Some studies suggest benefits for women with immune abnormalities (eg. increased pbNK activity or Th1 cytokines), but RCT evidence is lacking.
• Generally safe, but should be avoided in people with allergies to soy, egg, or peanut, and those with fat metabolism disorders.
• Select references (supporting evidence): Kumar et al. (2021) and Meng et al. (2016)

Vitamin D

Vitamin D is a hormone-like vitamin taken as an oral supplement to support immune and endometrial function.
It has immunomodulatory effects and deficiency is linked to RPL, especially in women of African or South Asian descent or those living in northern latitudes.

• Preconception screening recommended for a minimum 25(OH)D level of 30 ng/mL (75 nmol/L).
• Dose: 2000–4000 IU/day
• Safe at recommended doses; very high doses over time can cause high calcium levels and related symptoms.
• Select references (supporting evidence): Chen et al. (2022)

Calcineurin inhibitors

Calcineurin inhibitors (CNIs, eg. tacrolimus and cyclosporine) are prescription oral immunosuppressants often used in transplant medicine but sometimes used off-label in RPL. Tacrolimus and cyclosporine help to modulate Th1/Th2 ratios and NK cell activity.

• Some small studies show improved outcomes in women with immune abnormalities (eg. increased Th1/Th2). More research is needed.
• Safe when used at low doses, though side effects like kidney strain and high blood sugar may require monitoring.
• Select references (supporting evidence): Cavalcante et al. (2023)

Granulocyte-colony stimulating factor (G-CSF)

Granulocyte-colony stimulating factor (G-CSF, eg. neupogen) is an injectable medication that stimulates the immune system and has been tested for improving endometrial receptivity. It may support implantation via endometrial effects and Th2 promotion.

• Trials show conflicting results depending on timing, dose, and route. Further RCTs required.
• Mild side effects like fatigue and bone pain are possible; rare serious reactions are not well studied in pregnancy.
• Select references (supporting evidence): Mu et al. (2023)

TNF-α inhibitors

TNF-α inhibitors (eg. adalimumab, etanercept) reduce inflammation but have limited data in RPL. One RCT showed increased LBR in women with immune-related RPL.

• Conflicting results from studies. More RCTs are needed.
• Generally considered safe in pregnancy, though infection risk should be assessed beforehand.
• Select references (supporting evidence): Winger et al. (2008)

Heparin with aspirin

Heparin (unfractionated or low molecular weight) is an injectable blood thinner and aspirin is an oral antiplatelet; together they help reduce clotting risks in pregnancy. This is standard treatment for antiphospholipid syndrome (APS).

• Recommended for patients with obstetric or thrombotic APS
• Possible benefit for RPL patients with persistent antiphospholipid antibodies (aPL)
• Conflicting evidence for RPL with or without thrombophilia. More research is needed to determine optimal dosage and timing.
• Heparin and aspirin are widely used in pregnancy and considered safe, but can increase the risk of bruising or bleeding
• Select references (supporting evidence): Hamulyák et al. (2020)

Hydroxychloroquine

Hydroxychloroquine (HCQ, eg. plaquenil) is an oral medication originally used for malaria that’s now often prescribed for lupus and autoimmune pregnancy complications. Small studies suggest benefit in RPL with autoimmunity or chronic placental inflammation.

• Can be considered for women with autoimmune diseases or inflammatory placental pathology (eg. chronic intervillositis)
• Dose: 100–200 mg twice daily, continued through pregnancy and often postpartum
• HCQ is generally safe in pregnancy, with only rare reports of eye or muscle-related side effects
• Select references (supporting evidence): El Sayeed et al. (2022)

hCG

hCG is a hormone that can be given by injection or uterine infusion to try to support implantation or early pregnancy. It can modulate the maternal immune environment, but RPL trials are small and inconsistent.

• Low quality evidence, more high quality studies are needed, particularly in identifying which patients would benefit.
• No known adverse effects have been reported in trials; safety profile appears benign
• Select references (supporting evidence): Osman et al. (2016)

Conclusions

Here’s a summary of their recommendations:

• Recommended:
  • Corticosteroids like prednisolone and prednisone (RPL with immune markers)
  • Vitamin D (preconception screen and supplement if deficient)
  • Heparin + aspirin (for APS)
• Conditionally recommended:
  • Corticosteroids (RPL without immune markers)
  • IVIG (RPL with high number of losses and immune markers)
  • LIT (RPL with immune markers for outside the US)
  • Hydroxychloroquine (for autoimmune patients or placental inflammation)
• Unclear benefit:
  • Intralipids
  • Calcineurin inhibitors like tacrolimus and cyclosporine
  • G-CSF drugs like neupogen
  • TNF-α inhibitors like adalimumab
  • hCG

While some immune therapies may help specific subgroups of patients with RPL, especially those with confirmed immune abnormalities, many treatments remain controversial or unproven with inconsistent dosing and timing of treatment. The ASRI recommends that clinicians base immunotherapy use on immune biomarkers, and cautions against treating patients without evidence of immune dysfunction.

It’s important to note that immunotherapies for RPL are controversial and generally not recommended by organizations besides ASRI. ESHRE recently published their recommendations for 27 add-ons, and didn’t recommend NK cell testing or immunology treatments. One expert reviewer for their recommendations commented that women may have undiagnosed immune disorders, which might be connected to their infertility. The HFEA and ASRM also have similar concerns. For a deeper look at the controversy, check my posts The role of the immune system in infertility and IVF and NK cells in IVF.

While ASRI’s effort to standardize immunotherapies based on immune markers is a step in the right direction, the supporting evidence, at least for corticosteroids, may be too limited for a strong clinical recommendation. More high quality studies are needed, particularly in patient groups with clear immune biomarkers, both to show that these treatments are effective and to validate the biomarkers themselves.

Reference

Cavalcante MB, Harrity C, Luu T, Fatunbi J, Nakagawa K, Zhang Y, Zhang T, Alanazi H, Wu L, Lee S, Barini R, Kwak-Kim J. 2025 American Society for Reproductive Immunology Guidelines for the Treatment of Recurrent Pregnancy Losses: Practice Recommendations From the ASRI Clinical Reproductive Immunology Fellowship. Am J Reprod Immunol. 2025 Jun;93(6):e70099. doi: 10.1111/aji.70099. PMID: 40444404.

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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.

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