The Role of Immune-modulating Treatments in Recurrent Pregnancy Loss

About the expert

Dr. Michael Strug, Physician Scientist

Physician scientist specializing in Reproductive Medicine

Dr. Michael Strug is a physician-scientist specializing in Reproductive Medicine, with clinical expertise in recurrent pregnancy loss, implantation failure, and endometrial disorders. He completed his DO and PhD at Michigan State University, residency in OB/GYN at Spectrum Health, and a fellowship in REI at Stanford, earning national research recognition and multiple awards along the way.

Silvia Hecher:

At LEVY Health, we see many women and couples dealing with recurrent pregnancy loss. Reviewing the literature, we often find one study suggesting a therapy helps, while another shows no significant benefit. From your perspective, what is the main problem with the current study landscape, especially regarding immune-modulating therapies?

Dr. Michael Strug:

The biggest issue is variability across studies. Older studies, for example, often used different definitions for RPL—typically three or more losses—whereas now, major societies like ASRM and ESHRE define RPL as two or more losses. There's also inconsistency in what counts as a pregnancy loss, and huge variability in the timing of interventions. Some treatments are given during the luteal phase, some after a positive pregnancy test, others after a fetal heartbeat is detected. We now know that some treatments need to start at the time of ovulation, so perhaps studies with a deviating protocol were not able to show any benefit.

Another issue is that broad immune suppression risks interfering with beneficial immune processes, which might explain some inconsistent outcomes.

I believe the future lies in better understanding the specific mechanisms causing RPL and developing more targeted therapies instead of generalized immune suppression.

Silvia Hecher:

Building on that, could part of the issue be that studies don’t stratify patients enough? Should women with specific conditions—say thyroid disorders, blood clotting issues, or elevated antinuclear antibodies (ANAs) —be studied separately?

Dr. Michael Strug:

Absolutely. Some newer studies have tried to be more targeted, for example focusing on women with elevated cytotoxic natural killer cells (NK cells) or specific antibodies like antiphospholipid or ANAs. This approach gets us closer, but even here, testing methods aren’t always reliable. For instance, NK cell assays aren't well-validated and aren't routinely used in the US. Better patient selection and reliable diagnostic platforms are essential before we can draw stronger conclusions.

Silvia Hecher:

How are the underlying mechanisms leading to very early pregnancy losses in weeks 4–7 different from those causing later losses in weeks 11–13?

Dr. Michael Strug:

Blood clotting conditions like antiphospholipid syndrome tend to cause later pregnancy complications rather than early losses. The new APS diagnostic guidelines emphasize later issues like fetal growth restriction and preeclampsia, suggesting distinct underlying mechanisms. Again, this points to the need for personalized evaluation. Not every woman with RPL has the same problem, and unexplained losses might sometimes stem from genetic issues within the fetus itself—beyond what standard chromosomal testing detects.

Silvia Hecher:

Most studies on RPL are conducted in IVF centers. Understandable for easier patient recruitment, but do you think this introduces bias?

Dr. Michael Strug:

A bit, yes. IVF patients tend to get more extensive testing and monitoring, so the data are richer. Furthermore, IVF should not be routinely recommended for RPL because most RPL patients aren’t infertile—they can conceive naturally—so IVF may not necessarily address the root cause for them unless losses are attributed to aneuploidy, and even in that scenario, they may not be a good candidate for IVF.

Silvia Hecher:

We see that in many cases, the first treatment suggested, without any diagnostic workup, is progesterone. What's right or wrong about that?

Dr. Michael Strug:

Progesterone is a low-risk intervention with mixed evidence. The currently recommended dosing is 400 milligrams twice daily for micronized progesterone. Large studies like PRISM and PROMISE suggest a possible benefit in women with three or more prior losses or active bleeding, but not universally. I generally offer it because it’s low risk. However, it's important to explain to patients that it's unlikely to be a “cure”. If the underlying issue is, for example, a fetal chromosomal abnormality, or a thyroid disorder, progesterone won’t change the outcome. So while it won’t do any harm, it won’t fix the problem if you haven’t done a proper diagnostic workup. Furthermore, after 11-13 weeks of pregnancy, the placenta produces far more progesterone naturally, so as of then, adding progesterone is no longer useful in any case.

Silvia Hecher:

Because of the inconclusive study landscape, we’ve seen that some physicians refuse to offer any treatment, while others try a combination of several treatments, hoping that one will work — aspirin, heparin, corticosteroids, IV infusions. What’s your take on these two extremes?

Dr. Michael Strug:

Both extremes have problems. Doing nothing might miss opportunities to help with low-risk treatments like aspirin or progesterone. But treating a patient with everything at once prevents us from understanding what’s actually effective—and some interventions may even cause harm.

I’m cautious with immune therapies. For example, intralipids have not shown consistent benefit and may have adverse effects. Intravenous immunoglobuline therapy, short IVIG, is more promising: a well-designed study showed benefits for women with four or more losses, which ESHRE now acknowledges. But IVIG carries risks—it’s a blood product, can trigger allergic reactions, and is expensive and time-consuming.

I don't usually recommend corticosteroids; despite decades of study, they haven't convincingly improved outcomes.

Silvia Hecher:

Focusing on diagnostics: A woman presents after her second loss with no prior evaluation. What tests would you recommend, and should it be a stepwise approach?

Dr. Michael Strug:

I recommend a full workup right away rather than stepwise, to avoid missing important pieces. Here's what I would include:

• A structural evaluation, with a saline sonogram, hysteroscopy, or at minimum, a high-quality ultrasound.
• Chronic endometritis screening: Although endometrial biopsy is invasive, treating identified infections can improve outcomes.
• Bloodwork: Thyroid testing, diabetes screening, antiphospholipid antibodies.
• Parental karyotyping if a chromosomal issue is suspected, or they have not had chromosomal testing of miscarriage.
• Genetic testing of previous pregnancy tissue, if available, to differentiate between aneuploid and euploid losses.

Couples who have experienced recurrent pregnancy loss want to know what has caused them. Evaluating early, ideally after the second recurring pregnancy loss, gives patients answers faster and helps providers tailor the treatment.

Silvia Hecher:

Thank you!