Reproductive Immunology: Maternal Immune Tolerance of Pregnancy

The maternal immune system interacts with the growing fetus and placenta via a process of alloimmune recognition followed by induced tolerance. Because the fetus expresses paternal antigens it is foreign to the mother, yet a healthy maternal immune system is able to tolerate the pregnancy for 9 month. One consequence of this relative immune suppression during pregnancy is that women at increased susceptibility to infections some of which can also be more severe during pregnancy.

It has been proposed that many pregnancy related disorders including recurrent embryo implantation failure, miscarriage, preterm labor and preeclampsia are related to abnormal induction of tolerance. Though it’s not completely understood how immune tolerance to pregnancy is induced, there is convincing data that exposure to paternal antigens in semen prior to pregnancy allows the maternal immune system to develop tolerance by activation of maternal Treg cells. Exposure to semen has been associated with a reduction in some pregnancy disorders, improved fetal development, and improved IVF pregnancy rates.

ReproductiveImmunology_Diagram_NewayFertilityWeiss G, et al. Reproductive Sciences. 2009;16(2):216-229.

This diagram shows that at time of embryo implantation immune cells in the uterus constitute 40% of the total decidual cell population. The most common cells responsible for innate immunity are decidual natural killer cells, macrophages, dendritic cells and T-lymphocytes. It has recently been recognized that natural killer cells (NK) are very important in promoting fetal development because they secrete growth promoting factors. During later stages of pregnancy circulating maternal immune cells interact with the growing placenta. Thus, during late pregnancy systemic rather than local immune responses become more pronounced.

Women with autoimmune disorders like thyroiditis, lupus and rheumatoid arthritis have significantly increased risk for serious complications during pregnancy. Additionally, many autoimmune disorders can flare shortly after delivery while some flare during pregnancy. Autoimmune disorders disproportionately affect women especially during the childbearing years. This is at least partially related to high prevalence of immune genes which are found on the X chromosome and to hormonal changes during these years. Even women who do not have a clinically diagnosed autoimmune disease but only have subclinical autoimmunity due to presence autoantibodies and those with abnormal inflammation are at increased risk for pregnancy complication. 

Antiphospholipid antibody syndrome (APS) is one of the most well understood autoimmune disorders which causes miscarriages, stillbirth, premature birth and severe preeclampsia. APS is due to autoantibodies that cause blood clots, these clots can also cause strokes, pulmonary embolism and deep vein thrombosis. APS is treated with anticoagulants like aspirin and heparin which prevent blood clots.

Pregnant women who have Lupus are often treated with medications like Plaquenil (hydroxychloroquine) and Prednisone. Prednisone is metabolized by the placenta, and is unlikely to cause fetal malformations, but increases the risk of diabetes and hypertension in the mother. In some cases immunosuppressive drugs like imuran (azathioprine) are also used during pregnancy. Cyclophosphamide, ACE-inhibitors and Coumadin cause birth defects and have to be stopped. Heparin can be used during pregnancy to prevent bloodclots.  NSAIDs are usually only used during the first trimester.

Hashimoto’s and Graves are autoimmune disorders affect the thyroid gland. Both are due to autoantibodies which affect the function of the thyroid gland. Women with Hashimoto’s have hypothyroidism and are treated with thyroid hormone, this is especially important during pregnancy since fetal brain development depends on getting adequate thyroid hormone from the mother. In Graves disease autoantibodies cause hyperthyroidism, treatment includes drugs like PTU and methimazole.

Rheumatoid Arthritis usually improves during pregnancy but can flare after delivery; risks of pregnancy related complications are only slightly increased. Low-dose Prednisone, Plaquenil and Sulfasalazine are generally considered safe during pregnancy. There is only limited evidence about safety of biologic medicines like etanercept (Enbrel), infliximab (Remicade), and infliximab-abda (Renflexis), still many rheumatologists advise patients to continue these drugs during pregnancy.

ReproductiveImmunology_Graph_NewayFertilityDiagram: Prevalence of autoimmune diseases

Reproductive Immune Evaluation:

The reproductive immune evaluation is guided by the couple’s medical history. It may involve blood tests to look for autoimmunity and systemic inflammation, hormone levels, and an endometrial biopsy to evaluate for chronic endometriosis which is due to local inflammation and/or infection inside the uterus. In some cases, a hysteroscopy may also be indicated to closely evaluate the endometrium for inflammation.