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How to Keep the Body from Rejecting Pregnancy

The Director of Reproductive Medicine and Immunology for the Rosalind Franklin University Health Clinics is a pioneer in her field.

Dr. Joanne Kwak-Kim’s applied research in reproductive immunology has helped thousands of women achieve successful pregnancies. Her pioneering work on the role of natural killer (NK) cells in spontaneous abortion and infertility and the use of the blood product intravenous immunoglobulin (IVIg) in suppressing those cells has no doubt helped many thousands more babies be born throughout the world.

Her first success with IVIg treatment is now a 31-year-old man. Dr. Kwak-Kim, who in 1988 was a new RFU postdoctoral fellow in reproductive immunology, suggested the therapy based on one case study in which it was successfully used for women with a history of pregnancy loss who had tested positive for antiphospholipid antibodies, autoantibodies that increase the risk of blood clots.

The patient was desperate.

“She was about 17 weeks pregnant, but the baby was only about 14 weeks’ size,” Dr. Kwak-Kim recalled. “She was on the traditional treatment with the anticoagulant Heparin, steroid prednisone and lymphocyte immunotherapy (LIT), but the baby stopped growing and there was no amniotic fluid left. The local obstetrician wanted to terminate the pregnancy, but the mother refused. I suggested trying IVIg as a final trial.

“We administered IVIg and the baby started to pick up amniotic fluid,” she recalled. “The mom delivered at 31 weeks. The baby barely weighed two pounds.

“Today, he’s as tall as that door,” she said grinning.

We look very closely, work very carefully to develop treatment plans to help our patients carry to term.
Joanne Kwak-Kim, MD, MPH

The field of reproductive immunology was young when Dr. Kwak-Kim took it up as an RFU fellow eager to explore a fundamental question: How to keep the body from rejecting pregnancy.

IVIg therapy, prepared from the serum of between 1,000 and 15,000 donors per batch, helps regulate the immune system. Dr. Kwak-Kim helped drive the research that showed it downregulates NK cell activity and expression in patients with repeated pregnancy loss (RPL). She became interested in NK cells when a blood draw of a patient who had suffered numerous unexplained miscarriages revealed a huge number of natural killer cells, a revelation that sparked the study of the innate immune cells’ role in pregnancy loss.

NKs are abundant in the uterine cavity, said Dr. Kwak-Kim, a co-developer of the natural killer cell assay. But new NKs can enter the uterus after ovulation through the circulatory system.

“There’s a dynamic change in the uterus in the days that follow implantation,” she said. “If the proportions of different kinds of NK cells are not well matched, that can lead to pregnancy loss. We spent quite a bit of time to document NK pathology and we found that use of corticosteroids or IVIg controls the NK cell pathology. When we control NK cells, the outcome is significantly improved.”

Dr. Kwak-Kim, who serves as Chicago Medical School director of reproductive medicine and immunology, professor of obstetrics and gynecology, and professor of microbiology and immunology, has built a clinical reputation by taking on some of the most challenging patients.

“We see a lot of in vitro fertilization (IVF) patients who have experienced multiple implantation failures after the embryo transfer,” she said. “Patients come to us after using their own embryo three times, then a donor embryo three times, then a second donor embryo three times. That’s nine IVF attempts. It’s a heartbreaking situation, a problem with maternal receptivity involving the maternal immune response, hormonal response and hematological response. We look very closely, work very carefully to develop treatment plans to help our patients carry to term.”

Infertility affects about 15 percent of the reproductive-age population and 5 percent of reproductive-age women struggle with RPL, according to Dr. Kwak-Kim, whose more than three decades of scholarly activity and professional leadership, including with the American Society for Reproductive Immunology, has helped advance both the science and clinical care.

“As more women delay family planning, they aren’t willing to wait for three miscarriages — the former definition of RPL — to get help,” she said. “And in the old days, there was a long wait to receive IVF. Now, if you are over or close to 40, you can get this treatment very quickly.”

Dr. Kwak-Kim’s approach, including immunological treatment with women who have a history of both failed IVF and miscarriage, results in a “take-home baby rate” of 63 percent — a very good outcome given the extreme challenges involved. Her success is closely linked to the excellence of RFU’s laboratory technology and expertise. Associate Professor Alice Gilman-Sachs, PhD, director of the flow cytometry laboratory and associate director of the clinical immunology laboratory, is a mentor and “the guru of flow cytometry,” Dr. Kwak-Kim said. Professor Kenneth Beaman, PhD, founder of the Chicago Medical School Immunology Laboratory, is a mentor and “the big shot in molecular testing.”

Immunology is the fastest-developing field in biomedical research.

“It’s such a dynamic field, a huge field,” Dr. Kwak-Kim said. “New techniques are always coming to the fore. You have to constantly update your knowledge. But when you get into the clinical translation, you have to slow down.

“You must listen very carefully to your patients. You need to understand what’s going on, but also recognize that this poor mother cannot wait until the science is completely understood. A woman’s window for getting pregnant is limited. She can’t wait for 30 or 40 years. You work with what you know and what can be translated.”

A woman’s window for getting pregnant is limited. She can’t wait for 30 or 40 years. You work with what you know and what can be translated.
Joanne Kwak-Kim, MD, MPH

Dr. Kwak-Kim’s continuing effort to understand RPL has led to new areas of investigation. Thirty years ago, she found that two-thirds of RPL patients deliver pre-term and more than 20 percent experience preeclampsia — a potentially fatal complication of pregnancy in which blood pressure spikes. African-American women are three times more likely to die from the condition, according to the Preeclampsia Foundation.

“Our findings have pushed the American Society for Reproductive Immunology to increase studies on the condition,” Dr. Kwak-Kim said. “A lot is being done. But outcomes are still not perfect. We’re managing those patients in collaboration with high-risk obstetrics practice. We’re determined to find a better way to deal with this.”

Posted August 19
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