Introduction: Autoimmunity and Miscarriage

During pregnancy, your immune system needs to adapt in order to avoid rejecting the fetus, which is genetically different from you. Many changes in your body and at the maternal-fetal interface also involve the immune system. Therefore, imbalances in immune function, including autoimmunity, may contribute to miscarriage. 

Many people have some autoimmune pathologies, such as antibodies, with no symptoms. For example, antinuclear antibodies are detectable in 25% of the population, but the overall incidence of autoimmune disease is less than 5-7% ¹. Therefore, while the antibody alone may increase the risk of autoimmune diseases, other factors are necessary to tip off a full-on autoimmune disease. Sometimes, the hormone and immune changes during a pregnancy can trigger autoimmune diseases. However, these pre-existing mild autoimmune pathologies may cause miscarriage. 

The immune system is so vast and complex, and scientists still don’t fully understand how it works. The immune changes in the placenta and decidua are often different from the changes in the blood. One of the reasons we still don’t know a lot about these changes is because many of them are unique to humans. It’s very difficult ethically and logistically to study placental changes in an ongoing pregnancy ².  

Autoimmunity may contribute to many of the ~50% recurrent miscarriage cases where the cause is unknown. There could also be other types of immune abnormalities that may lead to a miscarriage. 

In this article, we’ll explain:

• How the immune system changes during miscarriage 
• What we know so far about options for management and treatment 
• Specific autoimmune conditions and how they affect pregnancy

How Your Immune System Adapts for Conception and Pregnancy

Helper T cells are orchestrators of your immune system. They tell your immune system to attack germs and cancer cells or make peace with things that are different from your cells, such as food and the fetus. Pregnancy is one such time where the immune system needs to make peace. 

There are many types of helper T cells, but some of the most important ones in autoimmunity and pregnancy include ³:

• Th1, which is important for fighting off germs that infect inside the cells, such as viruses and bacteria. Too much Th1 function along with too much Th17 function can cause many autoimmune diseases
• Th2, which is important for fighting off germs that infect outside the cells, such as parasites. Too much Th2 function along with Th17 function can cause allergic diseases (asthma, allergies, hives, anaphylaxis, and eczema)
• Th17, which is important for fighting germs like fungi, bacteria, and tuberculosis. It protects against germs that infect outside the cells during pregnancy. However, too much Th17 function is linked to many autoimmune and allergic diseases.
• Regulatory T cells or Tregs, which are your immune system’s peacemaker. They reduce excessive Th1, Th2, and Th17 functions. So, Tregs prevent allergic and autoimmune diseases without making you more susceptible to infection. 

Immune Changes During Preconception

In your uterine lining, Tregs reduce proinflammatory signals from other types of immune cells. Tregs increase during the luteal phase (after ovulation to period) to ensure that embryos can implant. Progesterone from the corpus luteum increases Tregs. If the uterine lining fails to immunologically adapt for the implantation, a miscarriage can occur. 

After the implantation, pregnancy hormones such as beta-hCG and progesterone also increase the number of Tregs to maintain the pregnancy ^{4 5}.  

During pregnancy, the immune system shifts toward Th2. Many pregnant women find their allergic diseases get worse and autoimmune conditions improve. A shift towards Th1 can lead to immunological rejection of the fetus, causing preeclampsia and miscarriage ^{6 7 8}.

Autoimmunity and Pregnancy

Can Autoimmunity Without Autoimmune Disease Affect Conception and Pregnancy?

Autoimmune diseases happen when many things go wrong at the same time, because your body has many checks and balances to prevent autoimmunity. 

First, the immune system destroys self-attacking immune cells early in their development. Second, when a few of them survive this process, Tregs suppress them. Third, when the immune cells that survive make self-attacking antibodies, the rest of the immune system may not mount a response to it. 

A full-blown autoimmune disease may only happen if all three of these processes fail. However, one or two of these failures can interfere with pregnancy and cause miscarriage, even without any other symptoms or diagnoses. 

For example, antiphospholipid antibodies and thyroid antibodies can cause miscarriage, even without any other symptoms ⁹. Among women with thyroid antibodies and recurrent miscarriage despite normal thyroid function, treatment with levothyroxine can reduce miscarriage rate by 75% ¹⁰. For more details on this, see our thyroid article. 

How Autoimmune Diseases Affect Pregnancy ^{11 12 13}

Autoimmunity happens when the immune system mistakenly attacks itself. Autoimmune diseases are more common among women, especially during childbearing years. 

Proteins that are being attacked can be part of many different tissues. Some of those tissues are more important for conception and pregnancy than others. 

For example, autoimmune diseases of the eye usually won’t affect your chances to stay pregnant. And if the treatment can be administered locally, it won’t affect your baby in the uterus. 

However, if the autoimmunity affects the entire body, it might affect conception and pregnancy. This type of autoimmunity may require systemic therapy, and the medications used can be harmful to your baby. In addition, systemic inflammation from these conditions may disrupt conception. 

Some autoimmune diseases are aggravated by pregnancy, while others improve. Th1-dominant conditions tend to improve during pregnancy, but the few autoimmune diseases that are Th2-driven may worsen. These Th2-driven diseases may include some cases of lupus and Hashimoto’s. 

Other autoimmune diseases generally are Th1-dominant, including:

• Inflammatory bowel disease (IBD)
• Celiac disease
• Type 1 diabetes
• Psoriasis and rosacea
• Vitiligo
• Rheumatoid arthritis
• Some cases of Hashimoto’s

Whereas, multiple sclerosis is driven by Th1, Th2, and Th17 dominances.

Many women with autoimmune diseases carry pregnancies to full term, while others may struggle with conception due to the autoimmunity. Pregnancy may also trigger autoimmune disease in women who are otherwise predisposed for autoimmune diseases. 

Let’s take a look at four specific autoimmune conditions and how they impact conception and pregnancy. 

Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE or lupus) presents with skin lesions (although they might not be present) as well as joint, heart, blood cell, and even neurological dysfunctions. Because lupus is mostly a Th2-dominant condition, it may worsen during pregnancy ¹⁴.

Lupus may increase the rate of first-trimester miscarriage by up to 10% and second trimester  by up to 6%, compared to 1-3% among women without lupus. The antiphospholipid antibodies (aPLs) in lupus can cause miscarriage. Some features of the disease up to a year before conception increase the risk of obstetrical complications: 

• Kidney complications (lupus nephritis)
• Presence of anti-Ro/SSA and/or anti-La/SSB antibodies
• aPL antibody or SLE-associated antiphospholipid syndrome
• Protein in the urine (proteinuria)
• Reduced platelets (thrombocytopenia)
• High blood pressure in the arteries (arterial hypertension)
• Poor obstetric history

Pregnant women with lupus require close perinatal monitoring. This includes regular OB/GYN check ups every four weeks. Ultrasound evaluation is focused on:

• Fetal growth, to exclude intrauterine growth restriction, which usually  requires induced childbirth
• Uterine blood flow, starting at 20 to 24 weeks—o exclude placental insufficiency 
• Fetal echocardiography  is one of the main complications of SLE in pregnancy and occurs when the anti-Ro/SSA and/or anti-La/SSB antibodies block the fetal heartbeat (AV block)

The standard treatments for SLE include hydroxychloroquine and corticosteroids, which carry risks of birth defects and pregnancy complications ^{15 16}. However, studies have shown that in mothers with SLE, it is safer to continue hydroxychloroquine than to discontinue the medication during pregnancy  ^{17 18}. Your doctor may adjust the dosage of corticosteroids. They will also regularly check for gestational diabetes, especially if  steroids are used in therapy ¹⁹.

Sjögren’s Syndrome

Sjögren’s syndrome is an autoimmune disease that mainly affects skin, excretory glands, and the lungs. It usually affects women in their 40s.

Anti-Ro/SSA and/or anti-La/SSB antibodies may block fetal heartbeat (AV block). However, in a large study, the miscarriage rates among women with Sjögren’s was 13.06%, which was comparable to the general population ²⁰.

Antiphospholipid syndrome 

APS is an autoimmune disease characterized by the presence of thrombotic events. A thrombotic event refers to one or more confirmed clinical episodes of a blood clot occurring in an artery, vein, or small blood vessel, validated by imaging studies or tissue biopsy. Antiphospholipid antibodies can cause blood clots that lead to vein clots, deep vein thrombosis, and miscarriage. 

About 50% of people with lupus also have APS, and half of patients with APS also have lupus ²¹. However, you can have APS, or even be asymptomatic, without having lupus.  . 

Image caption: About 50% of people with APS also have lupus, and about 50% of people with lupus also have APS. Therefore, around 33% of people who have either lupus or APS have both conditions. 

To learn more about antiphospholipid syndrome, along with diagnoses and treatments, see our antiphospholipid syndrome article here. 

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) usually affects joints, but other organs, such as heart and lung tissue can be damaged too. Because RA is a Th1-dominant condition, RA usually improves during pregnancy, thus rarely leading to pregnancy complications or miscarriage. 

Immune Thrombocytopenia 

Immune thrombocytopenia is an autoimmune disease that attacks platelets (thrombocytes), thus reducing their numbers (thrombocytopenia). This can lead to severe bleeding during pregnancy. However, if the antibodies cross the placenta or somehow get mixed with the fetal blood, they rarely affect the platelet count in the fetus.

When not treated, immune thrombocytopenia usually becomes more severe during pregnancy. It is usually safer to deliver vaginally, with platelet transfusion if necessary. Platelet counts above 50,000 are generally considered safe by hematologists. 

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease that weakens muscles, but it generally does not cause complications during pregnancy. 

Occasionally, mothers with myasthenia gravis need help with breathing (assisted ventilation) during labor. In addition, some supplements or drugs frequently used during pregnancy, such as magnesium, can make muscle weakness worse. 

The antibodies that cause myasthenia gravis can cross the placenta. About 20% of babies born to mothers with myasthenia gravis have temporary muscle weakness.  

Treatments That May Help Overcome Repeat Miscarriage from Immunologic and Autoimmune Causes

Immune-regulating treatments are very controversial because they have had mixed results in helping women with repeat miscarriages achieve full-term pregnancies. 

Corticosteroids, intralipid therapy, and intravenous immunoglobulins (IVIG) have not always shown great success in improving live birth rates (55% after three and 46% after four miscarriages) ²².  

Therefore, reproductive medicine societies currently have no official protocols, but some fertility doctors and clinics are using these treatments based on their clinical experience. 

Because no treatment is 100% risk-free, especially for pregnancy, your doctor will weigh the risk and benefits in their decision to prescribe. This section will share the risks and benefits for each treatment so you can work with your doctor to decide on the best path forward. 

Corticosteroids and Intravenous Immunoglobulins

Corticosteroids (also called steroids and prednisone) suppress the immune system and are often used to manage autoimmune and allergic diseases. Your body naturally produces them as cortisol and cortisone. However, when taken as a drug during pregnancy, they may increase the risk of gestational diabetes and other pregnancy complications ²³.

Some fertility doctors prescribe steroids to treat recurrent miscarriage of unknown causes with the assumption that immunologic factors and the lack of immune tolerance may play a role in miscarriage. 

Some European fertility clinics combine corticosteroids (prednisone) and intralipids and achieve higher birth rates, giving some optimism to patients with Recurrent Pregnancy Loss (RPL) ²⁴.

Other research groups investigated the safety of corticosteroids and IVIG, and the results were again quite optimistic. They found that prednisone and/or intravenous intralipids did not increase risk for adverse obstetric outcomes, such as preeclampsia, gestational diabetes mellitus, and small or large for gestational age infants ²⁵.   

In some autoimmune diseases, especially when anti-Ro/SSA antibodies are present, these antibodies may attack the AV node in the heart, blocking fetal heartbeat. In these cases, corticosteroid medications (dexamethasone or betamethasone) reduce inflammation and preserve AV node’s function. Intravenous Immunoglobulins (IVIG) can also work as additional or alternative treatment (see below). 

Intravenous Immunoglobulins 

IVIG are antibodies that block autoimmune antibodies. So far, case studies have shown promising results among women with antiphospholipid syndrome ²⁶. For other causes of miscarriages and recurrent miscarriage of unknown causes, however, IVIG doesn’t seem to significantly improve the outcomes ²⁷.

However, among women with previous miscarriage or elevated NK cells, IVIG may have comparable outcomes with intralipid therapy ²⁸.  

The drawback to IVIG is the cost of $2,000 to $3,000 per administration, whereas an intralipid dose costs around $500. This is because IVIG are blood products obtained from healthy donors. Also, IVIG is more immunogenic, which means that it can provoke an immune reaction of tissue rejection. 

Many fertility centers now only use intralipid therapy because it is less expensive and lower risk. However, some doctors still continue to use IVIG if they have observed it to be effective in their clinical experience.

Can You Have Undiagnosed Autoimmunity, and What Are the Symptoms? 

Autoimmune diseases can have various clinical presentations—from joint pain, to blurred vision, muscle weakness, heart problems, kidney dysfunction, bleeding disorders, and even obstetric complications. 

Sometimes obstetrical complications such as preeclampsia, intrauterine growth restriction, and miscarriage may precede the clinical onset of autoimmune disease and even represent as the criteria for diagnosis (for example, antiphospholipid syndrome). Having this in mind, share any other symptoms you may experience with your OB/GYN in order to consider diagnostic evaluation for these conditions. 

When to See a Reproductive Immunologist

If you already know you have an autoimmune disease, work with a rheumatologist or immunologist in your pregnancy management. 

If you have had more than two miscarriages, speak to your OB/GYN and be proactive about diagnostic tests that they are conducting. We have a recurrent miscarriage lab checklist, here, that you can share with your doctor to see if you have any gaps in your testing. If the regular recurrent miscarriage workup, such as genetic tests, hormone tests, and APS (antiphospholipid syndrome) testing etc. have not discovered a cause, consider visiting a reproductive immunologist and discuss possible immunologic causes of your pregnancy loss.