Are Natural Killer Cells Affecting My Pregnancy?

If you’re dealing with “unexplained” long-term infertility or recurrent miscarriage, you’ve likely been extremely frustrated, angry, and sad, and you want answers. If it can’t be explained by hormonal, structural, genetic, or male sperm issues, then what is it?

One answer offered is that your immune system may be malfunctioning. You may have overactive or an overabundance of “natural killer cells” (NK cells). It’s certainly a memorable and potentially scary phrase, but what exactly are they?

NK cells are lymphocyte or white blood cells that help everyone battle illness and disease. (So far, so good.)

Dr. Zev Williams, Division Director at Columbia University’s Fertility Program, says that NK cells are actually a good thing. “Most of the time they are like guard dogs; they float through your blood picking up signals from troublemaker immune system threats like viral or cancerous cells.”

NK cells are present in the uterine lining as well, or rather there are immune cells with similarities to NK cells, called uterine NK cells (uNK cells), but they don’t function exactly the same way. It is known that these uNK cells are present during a healthy pregnancy.

What Can Go Wrong?

Some reproductive immunologists believe that there are miscommunications in the immune system that result in too many or misguided NK cells, so that the body may be identifying the embryo or fetus as a “foreign” potentially dangerous entity, potentially leading to failed implantation or miscarriage.
Although British scientists were the first to discover uNK cells, California-based Dr. Alan Beer was a pioneer in reproductive immunology in the United States, beginning in the 1990s.

Dr. Raphael Stricker, the current Medical Director of the Alan E. Beer Medical Center for Reproductive Immunology says that the center has treated 2,700 patients since they regulated their process 15 years ago.

It’s important for doctors to show them that they’re not ‘doing’ anything wrong.“We’ve seen some patients with three to five, even nine miscarriages,” he said. “The psychology of these women is worse than anything. It’s important for doctors to show them that they’re not ‘doing’ anything wrong. We have shown that these procedures are safe for the woman and safe for the baby that results for many of the women who do get pregnant.”

What Is Reproductive Immunotherapy?

Reproductive immunologists most often do blood tests to determine a patient’s NK cell levels. There is some disagreement as to whether the blood NK cells and the uNK cells are similar enough to depend only on the blood samples. Some doctors may instead or in addition do a uterine sample test, which requires a biopsy, believing that the uNK cells are the ones that matter because they are directly involved in pregnancy development. (But the biopsy is invasive, and sometimes avoided.)

Often, testing for NK cells is accompanied by testing for other disorders that overlap with high NK cell levels.

Stricker says they do a battery of tests to try to determine why a patient has pregnancy failure (unable to conceive) or pregnancy loss (miscarriage). They test for NK cells, thyroid function, insulin regulation, and blood clotting patterns. Depending on what the doctors find, they help make adjustments before the patient then pursues natural childbirth or IVF treatment.

Treatment may involve suppression or modulation of the immune system before implantation or as needed through the early stage of embryo and fetus development.
Every patient has a tailored treatment plan. Among several other treatments including steroids, intravenous immunoglobulin (IVIG) and intralipid infusions (injections of fatty fluids including soy oil, egg yolks, glycerine and water) may be used to control NK cells and cytokines (inflammation cell “messengers”). For reducing anticoagulation heparin and aspirin may be prescribed.

IVIG infusions are the primary treatment, particularly for Stricker at the Beer Center. IVIG is “purified” pooled immunoglobulin products made from human plasma from at least a thousand donors. Stricker indicates that IVIG suppresses NK cell number and activity (and affects other immune system functioning), and that a number of papers support this treatment, including this clinical trials review in the Journal of Assisted Reproduction and Genetics, this study in the American Journal of Reproductive Immunology, and this study from the journal Fertility and Sterility.

As a precaution, before every patient is treated, Stricker says, “We see how the NK cells respond to IVIG in a test tube.” (Although some clinics consider intralipid infusions a breakthrough alternative for NK cell modulation, Stricker says that they don’t routinely endorse intralipid treatment due to questions of safety and efficacy.)

One Woman’s Story

Jane Reed was a patient of Dr. Beer’s in the late 1990s. She had had six miscarriages in a row before she started working with him. Under his care, and with Clomid from a fertility specialist, she had four children. She became a patient advocate, and with her college degree in biology and fascination with the process, she became a medical researcher for the Beer Center and other doctors.

She says that her treatments were expensive and difficult at times, but not dangerous for her. She is convinced that the testing and immunotherapy treatment made the difference. “It costs your sanity to wait months and months not knowing what’s wrong and what to do.” She advises women: “Do your research; this isn’t a cure-all for everyone, but it doesn’t hurt to test.”

Risks and Costs

As anyone considering or pursuing assisted reproduction knows, of course, there are risks as well as costs.

Suppressing the immune system could involve some health risk to patients, from slower illness recovery and mild allergic reactions to more serious conditions.

Not every treatment plan is the same and every clinic sets its own pricing, but a starting range is $2,200-2,700. For example, at the Beer Center, medical record review is $50-$300, initial consultation is $600, and initial testing runs $1500 to $1800. Immunotherapy treatment could cost several hundred or several thousand more; subsequent testing also increases the investment.

Why Is This Controversial?

Some doctors and researchers believe that the risks and costs of these treatments outweigh the benefits, and that there are still too many unknowns.

Williams says that although some studies have shown that women who have had a miscarriage often have higher NKC levels, “it hasn’t been proved that the higher NK cell levels are the cause of the miscarriage. They may be just coexisting conditions. I’m supportive of new research but so far the research hasn’t been conclusive in favor of these immune system treatments.”

As researchers and doctors, Williams says, “We have four questions: 1-Do higher NK cells cause miscarriages? 2-Does lowering NK cells prevent miscarriage? 3-Do the treatments currently identified actually help? 4-Can these treatments actually be causing harm?”

Dr. Danny J. Schust, Professor of Obstetrics and Gynecology, Department of Obstetrics, Gynecology, and Women’s Health Center for Reproductive Medicine and Fertility, University of Missouri School of Medicine, sees both sides: “I don’t want to argue with others in the community. There is consensus in the community that the immune system plays a very important role in ensuring a healthy pregnancy. It’s also agreed that some women have a dysfunction in the immune system that causes problems with pregnancy including miscarriage.”

“But we still don’t understand it well enough. There’s a really high background rate of patients with recurrent pregnancy loss (RPL) who do well [can carry to term] if you leave them alone. But if you do enough tests, you’re going to find something to change. You’re going to get false positives and do interventions and it’s going to seem like you helped them.”

Patients have to decide if they want to pursue a “cutting edge” approach.

This 2015 research review published in Human Reproduction cites the doctor’s oath to “first do no harm,” saying that despite decades of study, there isn’t sufficient evidence for treatment and that, although doctors administering IVF require licensing, there’s no licensing or regulation for reproductive immunotherapy.

Schust says: “Some doctors and patients want to be early adopters; I take the more conservative approach and wait for pretty absolute proof something works. It concerns me that even without this proof, doctors are charging patients for expensive testing and treatment that may or may not be helpful to them. This work should be done in carefully controlled and monitored studies in which patients agree to participate in these experimental procedures.”

“I like the way several doctors do this,” he says. “They pursue immunology research along with evidence-based medicine, but they don’t focus on it. They use clinical trials and they don’t charge the patients.”

Stricker believes strongly in the Beer Center approach. He says: “There are many supportive, published peer-reviewed studies on this topic from around the world, and the immune treatment approach to pregnancy has gone way beyond ‘experimentation’ based on controlled trials that have already been done.”

“Although further controlled trials are always welcome and treatments can always be improved,” Stricker says, “there is no blockbuster drug here that will make lots of money for a pharma company, so it is unclear who would finance the controlled trials of the future. Conversely, thousands of women with recurrent pregnancy loss and pregnancy failure need help now, and we are providing that help based on published peer-reviewed studies.”

Reproductive immunotherapy may be an option, but do your homework and decide what opportunities and risks make sense for you.