Recurrent Pregnancy Loss, Unexplained Infertility, and the Inflammation Connection
There are few things more frustrating in fertility care than being told that everything looks normal when you know something isn’t working.
The semen analysis is normal. The tubes are open. Hormones fall within the expected ranges. You may even have genetically normal embryos. And still, pregnancy doesn’t happen, implantation fails, or another pregnancy ends far too soon.
“Unexplained” is a diagnosis I have always found unsatisfying. It tells us what conventional testing hasn’t found. It doesn’t necessarily tell us that there is nothing else worth looking for.
In a recent Health Youniversity conversation, I spoke with Dr. Jan Rydfors, a Stanford-trained OB-GYN who has spent decades working with unexplained infertility and recurrent pregnancy loss. Our conversation focused on an area he believes deserves much more attention: chronic inflammation.
Inflammation is a broad subject, and it has many possible sources. Insulin resistance, stress, poor sleep, gut health, autoimmune activity, endometriosis, adenomyosis, nutrient status, and environmental exposures can all contribute to the body's inflammatory burden. For someone trying to conceive, these seemingly separate issues may be important pieces of the same fertility picture.
Why Inflammation Matters in Fertility
Inflammation is part of a healthy immune response. We need it to fight infection, respond to injury, and repair damaged tissue. Problems can develop when that inflammatory response stays activated long after its immediate job is done.
That ongoing activation can influence metabolic health, hormones, circulation, immune signaling, and the environment surrounding the reproductive organs. From a fertility perspective, this matters because developing eggs and sperm, implantation, and early placental development are all taking place within that larger biological environment.
I have talked about this with my fertility patients for years. Your ovaries and uterus do not function independently from the rest of you. Reproductive health is influenced by what is happening with blood sugar, digestion, sleep, stress, circulation, nutrition, and immune function.
Dr. Rydfors takes that same whole-body perspective when he evaluates unexplained infertility and recurrent pregnancy loss.
Pregnancy Requires Sophisticated Immune Communication
Pregnancy asks the immune system to do something rather extraordinary.
An embryo contains genetic material from both parents, so early pregnancy requires carefully coordinated immune tolerance. The immune system still needs to protect the mother while allowing implantation and placental development to proceed.
When inflammatory signaling is already elevated elsewhere in the body, that communication may become more complicated. This is one reason Dr. Rydfors considers chronic inflammation when investigating implantation failure and recurrent pregnancy loss.
There are many causes of miscarriage, including chromosomal abnormalities, which become more common as egg age increases. Inflammation is one possible contributor, particularly when pregnancy losses or implantation failures remain unexplained after the usual evaluation.
Insulin Resistance: A Fertility Issue We Should Be Talking About
One of the first places Dr. Rydfors looks is metabolic health.
When cells become less responsive to insulin, the body compensates by producing more of it. Higher insulin levels can affect ovarian hormone production, including androgen levels, and may interfere with ovulation and normal cycle patterns.
This connection is well recognized in PCOS, but insulin resistance isn't limited to people with a PCOS diagnosis. Changes in blood sugar regulation and metabolic health can occur over time, sometimes before standard laboratory values make the problem obvious.
Your menstrual cycle can offer clues. If cycles are consistently long or ovulation is happening later than expected, I want to know why. The cycle itself gives us useful information about what is happening elsewhere in the body.
Visceral fat also enters this conversation because it is metabolically active tissue. It produces inflammatory signals of its own and is closely associated with insulin resistance. Nutrition, movement, sleep, stress management, and, when appropriate, supplements or medications can all become part of improving the metabolic environment before conception.
Stress Is Physiology
People struggling with infertility have heard “just relax” far too many times.
Stress deserves a more intelligent conversation.
Your nervous system responds to pressure through measurable biological pathways involving cortisol, epinephrine, blood sugar, immune signaling, sleep, and inflammation. Fertility treatment itself can add another layer, with appointments, medications, financial decisions, waiting for results, and the emotional toll of unsuccessful cycles.
The goal isn't to eliminate stress from your life. Few of us could accomplish that even if we tried. We can, however, give the nervous system regular opportunities to shift out of a prolonged stress response.
This is one reason practices such as acupuncture, Qigong, meditation, breath work, walking, adequate sleep, and time in nature can have a place in preconception care. They are ways of working with physiology, rather than simply telling someone to relax.
The Gut-Inflammation Connection
Our conversation also turned to gut health, which makes sense when you consider how closely the digestive and immune systems interact.
A diverse microbiome depends, in part, on what we feed it. Fiber, colorful vegetables and fruits, herbs, spices, and other polyphenol-rich plant foods support the organisms that produce compounds such as butyrate. Butyrate helps nourish the cells lining the intestinal wall.
When that barrier becomes compromised, bacterial components and other substances may cross into circulation and trigger immune activity. This increased intestinal permeability, commonly called “leaky gut,” is one pathway being studied in relation to chronic systemic inflammation.
One of the simplest takeaways from our conversation was variety. Eating nutritious food is important. Eating a greater variety of nutritious foods gives the microbiome an even broader range of substrates to work with.
Endometriosis Can Be Quiet
Endometriosis deserves particular attention because it is fundamentally an inflammatory condition and can exist without the symptoms people commonly associate with it.
Some people experience severe menstrual pain, pelvic pain, or painful intercourse. Others have few obvious symptoms and don't discover endometriosis until they begin investigating infertility.
That means the absence of pain doesn't necessarily rule it out.
Endometriosis can alter the inflammatory environment within the pelvis and may affect ovarian function, egg development, implantation, and fertility outcomes. Adenomyosis can create another inflammatory influence within the uterus itself.
Dr. Rydfors also raised an interesting perspective on AMH. We usually think of AMH primarily as an estimate of ovarian reserve. A low AMH tells us something about egg quantity; it doesn't directly measure egg quality. When ovarian reserve appears lower than expected, however, he believes it is worth asking what else may be happening in the ovarian and pelvic environment rather than stopping at the number itself.
That distinction matters. An AMH result is information. It is not a verdict on your ability to conceive.
The Basics Still Matter
One theme I return to again and again in fertility care is that seemingly ordinary things can have extraordinary biological importance.
Sleep matters. Blood sugar matters. The quality and variety of food matter. Movement matters. Stress resilience matters. Nutrient sufficiency matters.
Magnesium, zinc, omega-3 fatty acids, and other nutrients are involved in immune regulation and inflammatory pathways. Dr. Rydfors specifically discussed omega-3 status and the potential usefulness of testing rather than automatically assuming someone is getting enough.
Supplements should always be individualized, particularly during fertility treatment and pregnancy. More is not automatically better. The purpose of testing and assessment is to understand what your body may actually need.
Where Reproductive Immunology Fits
For some patients with recurrent pregnancy loss or implantation failure, medical treatment may include medications intended to modify immune activity or support early pregnancy.
Dr. Rydfors discussed therapies including progesterone and, in selected circumstances, medications such as prednisone, IVIG, tacrolimus, or low-dose aspirin. These are medical treatments that require appropriate evaluation, prescribing, and monitoring.
What I found especially important in our conversation was the parallel question: what is contributing to the inflammatory burden?
If insulin resistance, endometriosis, gut dysfunction, poor sleep, chronic stress, or nutritional insufficiency is part of the picture, there may be opportunities to address those factors alongside appropriate reproductive medical care.
This is what integrative medicine should do well. We can use conventional medicine when it is needed while also paying attention to the health of the person undergoing treatment.
Can We Measure Inflammation Better?
Dr. Rydfors is also involved in developing a fascinating new approach to measuring systemic inflammation through retinal imaging.
The retina contains a dense network of blood vessels and metabolically active tissue. His company, Bonafia, is exploring whether retinal images analyzed with artificial intelligence can reveal inflammatory patterns associated with conditions and outcomes including endometriosis, preterm birth, IVF success, and miscarriage risk.
This technology is still emerging, so it should not be viewed as a replacement for an appropriate fertility or medical evaluation. I find the concept intriguing because it reflects where medicine is heading: finding better ways to recognize patterns earlier, before they become obvious disease.
Looking Upstream
If you have experienced recurrent pregnancy loss, failed embryo transfers, unexplained infertility, low AMH, long menstrual cycles, or autoimmune concerns, there may be value in widening the lens.
Look at metabolic health. Look at blood sugar. Consider gut health, sleep, nutrient status, stress physiology, and the possibility of inflammatory conditions such as endometriosis or adenomyosis. Some of these areas may need medical investigation; others are things you can begin supporting well before your next fertility treatment.
This is also why I encourage people to think about preconception as a period of preparation rather than simply a countdown to the next cycle.
Eggs and sperm develop within the environment we provide for them. The uterus, immune system, gut, metabolism, nervous system, and reproductive hormones are continuously communicating with one another. Giving yourself several months to work on that environment can create an opportunity to influence many of the factors that are within your control.
There will always be aspects of fertility we cannot control. But “unexplained” does not have to mean there is nothing left to explore.
Sometimes it means we need to ask better questions.
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Dr Rydfors received his Medical degree and specialization training from Stanford University Medical Center where he is an Adjunct Clinical Assistant Professor.
Dr Rydfors has extensive experience in the workup and treatment of unexplained infertility and unexplained miscarriages and has founded the Freyja Early Pregnancy Loss Clinic in Redwood City, California, where his team implements multidisciplinary and integrative program to prevent recurrent miscarriages and to solve unexplained Infertility
He is the initial creator and current Co-Author of the popular “Handbook in Obstetrics, Gynecology and Infertility,” now in its sixth edition, the main handbook used by the majority of Obstetricians and Gynecologists in training in the US.
He is a co-founder of Bonafia® an AI company which is using retinal imaging and AI interpretation to evaluate and reduce chronic systemic inflammation. It is using its technology for Endometriosis detection, Preterm Birth risk detection, IVF success prediction and Miscarriage risk prediction.
Freyja Clinic: https://freyjaclinic.com/
Bonafia: https://www.bonafia.com/
MARAbio https://www.marabio.com/
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By listening to the Health Youniversity podcast, you agree not to use this podcast as medical advice to treat any medical condition for yourself or others. Consult your healthcare provider for any medical issues you may have. This entire disclaimer also pertains to any guests or contributors to any Health Youniversity podcast.
