Posted on October 26th, 2020by Dr. Daniel Steinin Infertility Conditions

The Immune System and Pregnancy: How Your Body Can Turn on Itself

Many women and couples suffering from recurrent pregnancy loss (RPL) ask whether these losses are due to rejection of the embryo or fetus by the woman’s body. Much is written about immunology in pregnancy, and its role in reproductive success and loss.

Immunology refers to the body’s acceptance or attack of foreign substances or toxins (“antigens”). The purpose of the immune system is to discriminate between “self” and “non-self” (i.e. own vs foreign) antigens, and to develop an army of cells and chemicals that will “remember” and attack foreign antigens if they ever re-enter the body. In humans, the immune system begins to develop at the embryo stage. Pregnancy presents the immune system with a unique challenge. For the mother, the embryo contains antigens from both her own body (self) and from the father (non-self). Due to the presence of paternal antigens, rejection of the embryo by the mother would be expected. Fortunately, evolution has provided extraordinary mechanisms by which the mother recognizes the fetus as self. While some of these mechanisms have been well-demonstrated through scientific studies, other mechanisms remain poorly understood.

The placenta, which is located between mother and fetus, is in contact with the mother’s blood and carries oxygen and nutrition from mother to fetus, and hormones and toxins from fetus to mother. Fetal blood is generally not exposed to maternal blood minimizing exposure of fetal antigens to maternal immune cells. Almost all human cells have a specific pattern of antigens attached to the cell surface that identify a cell as self – sort of a biological bar code. These are called Human Leukocyte Antigens [HLA]. When a cell enters the body with an HLA antigen pattern different from the body’s own pattern, immune cells (antibodies) attack that cell. Fetal HLA antigens undergo modifications that allow them to remain hidden from maternal antibodies and evade recognition and rejection. In addition to these antibodies, the body produces T-lymphocytes (T-cells) that either recognize and destroy infected cells (cytotoxic T cells) or regulate the actions of other immune cells (T-helper cells). Some T-helper cells (TH1 cells) produce special chemicals (cytokines) that increase immune cell activity while other T helper cells (TH2 cells) produce cytokines that reduce the immune response. In order to adequately suppress the action of aggressive immune cells and allow a pregnancy to avoid rejection, a high ratio of TH2 to TH1 cytokines must exist. T regulatory cells promote successful implantation of the embryo and invasion of the placenta into the uterine wall. A reduction in T regulatory cells has been reported in women with recurrent miscarriages, and in women with unexplained infertility.

Unlike antibodies and T-cells, which must have previous recognition of an antigen in order to recognize and attack it (adaptive immunity), the body produces other immune cells, Natural Killer (NK) cells that attack foreign cells without ever had prior exposure (innate immunity). NK cells are found in maternal circulation (peripheral NK cells) and in the uterus (uterine NK cells). Their role in successful implantation and miscarriage remains uncertain. These two NK cell populations are distinct from one another and differ in their activity. Peripheral NK cells kill foreign cells (cytotoxic) whereas uterine NK cells are not cytotoxic – they foster implantation. While some studies showed an association between abnormal uterine NK cell levels and RPL, most studies have not shown an association between the numbers of peripheral or uterine NK cells and pregnancy outcomes. Therefore, often-used treatments involving intravenous immunoglobulins (IVIG) and steroids are expensive and likely of no value.

Phospholipids (PLs) are components of human cell membranes. In the placenta, PLs help placental cells attach to one another and invade the uterine wall and arteries . In some women the body produces anti-phospholipid antibodies (APA) that attack PL and cause clots to develop in placental blood vessels reducing blood supply to the developing fetus. APA also interfere with invasion of the placenta into the uterine wall. APA have been linked to an increased incidence of first- and second-trimester miscarriages as well as fetal growth restriction. Women with elevated APA have been shown to experience RPL more frequently than women without APA. Common APAs linked to RPL include lupus anticoagulants (LA), anticardiolipin antibodies (aCL), and anti beta2-glycoprotein. Antiphospholipid Syndrome (APS) is a disorder in which a woman with RPL, fetal death after 10 weeks gestation, and/or severe fetal growth restriction, is found to have one or more of these antibodies in her circulation. APS is currently the only immune-mediated cause of RPL loss for which there is proven treatment, a combination of aspirin and blood thinners like Heparin and Lovenox.

In conclusion, proper immune function is essential for successful pregnancy to occur. It is critical for women and couples with RPL, however, to understand that while some recommendations for tests and treatments are based on solid scientific evidence, many others are based on faulty science or speculation, and lack evidence to support their use. A proper evaluation by a highly reputable team of reproductive specialists is advised for all patients and couples suffering from recurrent pregnancy loss.

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