Maternal Immune Dysfunction and Pregnancy Complications

The immune system undergoes incredible changes to support a healthy pregnancy. These changes begin at the moment of implantation when the immune system mounts an initial inflammatory response that begins to shift to favor a robust anti-inflammatory response (reliant on Th2 and Treg) to protect the growing baby. You can read about the miraculous maternal immune system here.

Successful pregnancy depends on the optimal function of the maternal immune system, and maternal immune dysfunction has been implicated in many pregnancy complications, including infertility, pregnancy loss, preeclampsia, and preterm birth.

Immune dysfunction can occur without an autoimmune diagnosis

Something I often see in my practice is the presence of immune dysfunction in otherwise healthy people. This means you don’t necessarily have to be diagnosed with an autoimmune disease (AID) to have an immune imbalance.

And further, it’s entirely possible to have pre-clinical autoimmunity many years before the manifestation of symptoms (1).

I am pointing this out because it’s clinically relevant to understand the importance of immune health during preconception, pregnancy, and postpartum for all individuals. If infertility or recurrent miscarriage is a concern, these may be a sign that the immune system needs support, even in those without a diagnosis of AID.

“There is extensive evidence demonstrating that infections and/or immune dysfunction negatively impact every aspect of human reproduction from gamete production and establishment and maintenance of pregnancy to fetal and neonatal health” (2).

Autoimmunity, however, is on the rise, likely due to various factors such as exposure to environmental toxins, increasing microbiota dysbiosis, and nutrient deficiency due to increased intake of ultra-processed foods (3). The COVID-19 pandemic has also been linked to the rise in autoimmunity. Researchers have observed significantly higher rates of new-onset autoimmune diseases after COVID infection (4).

According to a Danish study, around 3.9% of pregnant women had an AID in 1989, and in 2013, the prevalence of AID during pregnancy rose to almost 16% (5).

It is well known that most AIDs pose a higher risk of pregnancy complications such as preeclampsia, fetal growth restriction, preterm birth, and C-sections (6). These risks may be related to autoimmune disease activity before conception or during pregnancy.

For instance, women with active inflammatory bowel disease (Crohn’s or ulcerative colitis) 6-12 months before and leading up to conception are at increased risk of miscarriage, fetal growth restriction, preterm birth, and Cesarean delivery. And not all autoimmune diseases carry the same type of risk; those with rheumatoid arthritis active during pregnancy have a greater risk of complications, and those with multiple sclerosis may have less risk of pregnancy complications than other autoimmune conditions (6).

Infertility and Maternal Immune Dysfunction

Many things, including endometriosis, anovulation, and problems with the fallopian tubes, can cause infertility in females. About 16% of infertility is idiopathic, meaning there is no explanation (2). Some researchers believe that unexplained infertility may be due to immune dysfunction, although the molecular mechanisms behind this connection aren’t entirely clear (2,7).

However, it has been suggested that unexplained infertility is due to a lack or loss of maternal immune tolerance (7, 8, 9).

Click here to read about maternal immune tolerance and how to support a healthy immune response.

Women with unexplained fertility may have altered immune components, including an imbalance in pro-inflammatory and anti-inflammatory cytokines and Th1 and Th2 cells. Elevated auto-antibody levels have also been observed, even in women with no signs of active autoimmune disease (10, 11).

Koshak et al. (2022) observed that 84% of women with unexplained infertility had at least one auto-antibody that was outside the normal range. The most common ones were (in decreasing order): anti-thyroglobulin, antithyroid microsomal, beta-2 glycoprotein IgM, antigliadin IgA, antinuclear, and anti-cardiolipin IgM (11).

Recurrent Pregnancy Loss and Maternal Immune Dysfunction

It is common practice to screen women struggling with recurrent pregnancy loss (RPL) for antiphospholipid syndrome. This autoimmune disease results in blood clots in arteries and veins throughout the body. Antiphospholipid syndrome is estimated to affect 5-20% of women with RPL (12).

Although there are no clear guidelines on screening for other autoantibodies in cases of RPL, growing research favors more thorough screening for AID/preclinical AID (12). Vomstein et al. (2021) noted that women with RPL have several immune markers that differ from healthy controls, including altered natural killer cells (in the uterus and peripheral circulation) and T-regulatory cells (Treg) (13).

A growing abundance of literature shows a connection between certain autoantibodies and RPL, suggesting multiple autoimmune connections, including autoimmune thyroid and connective tissue diseases (12).

Additionally, a mismatch of maternal immune cells and paternal human leukocyte antigens may play a part in RPL (13). Paternal factors are often an afterthought regarding pregnancy complications, but the interaction between the maternal and paternal immune systems is a key to a successful pregnancy.

For example, a paternal antigen has been proposed as a factor in preeclampsia, where the maternal immune system reacts to paternal components in the placenta. If you want to learn more about this fascinating phenomenon, I detail it in my blog, Why Do You Get Preeclampsia?

Preeclampsia and Maternal Immune Dysfunction

There are many risk factors for preeclampsia (PE). Still, it’s possible that maternal immune dysfunction is the common denominator, exacerbated by the paternal antigen (14).

T-cell dysregulation has been linked to preeclampsia, which, fascinatingly, resembles the immunological imbalance seen in autoimmunity.

“Similar to the Th cytokine imbalances seen in autoimmunity, PE [preeclampsia] is associated with an imbalance in both systemic and local pro-inflammatory Th1 and Th17 cytokines (TNFα and IL-17) and a decrease in suppressive Treg and Th2 cytokines (IL-10 and IL-4)” (14).

It has been suggested that maternal immune priming to paternal antigens may help prevent preeclampsia. This consists of 3-6 months of sexual cohabitation without barrier contraceptives before conception (15). This priming allows the development of maternal immunological tolerance to paternal antigens, preventing a hyperactive immune response during pregnancy.

Maternal immune dysfunction has also been linked to preterm labor (16) and increased risk of postpartum depression (17, 18, 19).

A cascade of immune mechanisms is responsible for initiating labor, including increased production of inflammatory cytokines and a decreasing Treg population (16, 20).

“During pregnancy, the adaptive immune limbs of both the mother and the fetus must tolerate each other in order to maintain pregnancy until term. A breakdown of this fetomaternal tolerance may lead to labor. In term pregnancy, lack of the tolerogenic state results in physiologic labor. However, a premature retreat of this tolerogenic state might lead to preterm labor” (16).

Can you prevent preterm labor and other pregnancy complications by supporting the maternal immune system?

Based on my clinical experience and the available science, the answer is, most likely, yes.

One of the most widely studied immune-supporting substances is vitamin D.

A 2015 systematic review conducted by the World Health Organization found that women who were supplemented with vitamin D were 64% less likely to experience preterm birth. Additionally, vitamin D supplementation improved birth weight–infants of mothers who supplemented were 60% more likely to weigh more than 5.5 lbs at birth (21).

However, for those who supplemented vitamin D + calcium, the risk of preterm birth increased.

I think the issue with supplementing calcium in many cases is that it typically isn’t done with patient bioindividuality in mind, and often the important cofactors, vitamin K2 and magnesium are forgotten, and thus a lot of issues can get exacerbated due to lack of cofactors and nutrient imbalances.

A 2019 Cochrane review supporting these findings concluded that supplementation with vitamin D, but not vitamin D with calcium, may reduce the risk of preterm birth and other pregnancy complications (22).

It is thought that vitamin D helps suppress the pro-inflammatory Th1 response that initiates labor, and thus, for women who are vitamin D deficient, supplementation helps correct the immune dysregulation that triggers early labor (23).

Abundant research on the importance of optimal vitamin D levels during pregnancy offers tremendous insight into the importance of the maternal immune system for a healthy pregnancy.

Read more about the importance of vitamin D during pregnancy and postpartum here.

What to do if you are concerned about pregnancy complications from immune dysfunction

Whether you are planning for a pregnancy or recently discovered you are expecting, it’s likely that having a healthy pregnancy is at the top of your mind. Learning about potential pregnancy complications can be scary, especially when you know you may be at higher risk.

The first step is to work with your healthcare provider as early as possible to check your autoantibody levels, lower any persistent inflammation, and check your vitamin D status and other nutrients.

Next is to begin making dietary and lifestyle changes to support your immune system.

Nutrient-dense whole foods are utterly necessary for a balanced immune system because the immune response relies on nutrients like vitamin D, vitamin A, zinc, magnesium, and dietary protein, among many others.

Managing stress is also at the top of the list because stress profoundly affects immune health (24).

Are you a clinician who wants to learn more about the best ways to monitor immune health in your patient’s preconception, pregnancy, and postpartum years?

Click here to learn more about my blood chemistry course, the world’s FIRST blood work interpretation course to use research-based ranges specific to pregnancy and postpartum!

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