The miraculous maternal immune system: exploring maternal immune changes to improve pregnancy outcome

A few months ago, I wrote a blog focused on why women get preeclampsia. Of course, well-known risk factors like a history of hypertension, ethnicity, and age all contribute to the likelihood of preeclampsia.

However, my research uncovered even more risk factors, including preexisting insulin resistance, connective tissue disease, and younger age (less than 25 years). Undoubtedly, the most fascinating answer for why you get preeclampsia has to do with the paternal contribution to preeclampsia.

In other words, the father’s genetics significantly affect the likelihood of preeclampsia.

This finding led me to delve deeper into maternal-fetal-placental-immune crosstalk. I know it’s a bit of a tongue-twister, but it’s the most straightforward description for a complicated topic.

Based on the available science and my professional experience, I believe a better understanding of these influences on the maternal immune system will greatly improve pregnancy outcomes.

Dysfunction of the maternal immune system during pregnancy has been linked to preeclampsia, recurrent pregnancy loss, and preterm birth (1, 2).

The maternal immune system

The immune changes that occur during pregnancy are essential for a healthy pregnancy. The importance of this really can not be emphasized enough, and many pregnant people may not realize the incredible shifts in immune function that are happening from the moment of conception.

“One of the most considerable aspects of reproductive biology is the phenomenon that healthy women with a fully functional immune system can successfully carry a pregnancy to full term without immune rejection. From the point of view of the immune system, pregnancy represents a situation resembles an organ transplant. Indeed, in immunological terms, the fetus is called semi allogenic since is characterized by the presence of antigens of maternal and paternal origin” (3).

Prior to conception, a healthy woman has an adaptive immune system that operates like a balanced scale.

On either side are immune cells primed to handle various pathogenic invaders. One side (Th1) is responsible for attacking bacteria and viruses, and the other for allergens and parasites (Th2).

The center of the scale acts as a regulator, helping keep each side in balance. This part of the adaptive immune system produces regulatory thymus cells—Treg for short. Treg cells not only help prevent one side of the scale from overriding the other but also prevent immune cells from attacking self-tissue and thus prevent autoimmunity from developing.

Treg cells are needed for immunological tolerance to prevent the immune system from running rampant. And this is why Tregs are vital for a healthy pregnancy.

From the moment of conception, the immune balance quickly changes.

This happens so the maternal immune system doesn’t attack fetal antigens. Instead of viewing the growing fetus as a pathogenic invader, it makes a decision to tolerate the developing fetus. This is immunological tolerance, which is essential for fetal survival and preventing the maternal immune system from reacting to paternal antigens.

During pregnancy, immunological tolerance shifts from a Th1 pro-inflammatory response to a Th2 anti-inflammatory response.

Remember, however, that a pro-inflammatory response isn’t always bad; inflammation is a necessary part of the immune system and helps protect you from illness. In fact, the Th2 dominance during pregnancy is why pregnant women are at increased risk of infection and illness compared to non-pregnant people.

Dad’s DNA affects maternal immune responses

Antigens from the father’s DNA and seminal fluid affect the maternal immune response.

This effect can be observed in studies on preeclampsia, showing that shorter sexual cohabitation before conception is linked to an increase in preeclampsia risk (4). This phenomenon is thought to be due to the importance of maternal immune priming to paternal antigens via sperm.

Essentially, the less acquainted the maternal immune system is with the paternal immune factors in sperm, the higher the risk of preeclampsia.

As mentioned above, preeclampsia has been linked to dysfunction of the maternal immune system, potentially due to hyperreactivity to paternal antigens.

This makes complete sense when you recall that the fetus and the placenta’s DNA is 50% paternal.

As soon as implantation occurs, the maternal immune system sends various immune cells to the implantation site to begin immune regulation and tolerance. This includes abundant natural killer cells (NK), the infamous immune cells responsible for swiftly killing pathogens such as viruses and cancer cells.

Interestingly, these NK cells develop tolerance during pregnancy and turn from killers to protectors.

They take action to protect the mother and fetus, supporting trophoblast cells, vascular remodeling, and helping deliver nutrients to the fetus (5, 6). Therefore, the behavior of NK cells may be just as crucial as Tregs during pregnancy, although they are less studied.

Tregs’ roles in fertility & pregnancy

Rodent studies have found that lacking Treg cells prevents healthy implantation, and transferring Treg cells to the mice restores healthy embryo implantation (7). Obviously, this cannot be easily or safely studied in humans.

Still, one study found that women with unexplained fertility had a 2-fold decrease in the expression of Foxp3, a protein needed for Treg production (8).

Fascinatingly, other research has suggested Treg cells may be a biomarker for the risk of miscarriage (9). Additionally, higher circulating Treg levels are associated with a 4-fold greater rate of IVF success compared to lower Treg levels (10).

The role of Tregs in maintaining a healthy pregnancy is quite remarkable, but it gets even more interesting—Treg cells are also thought to be one of the triggers of spontaneous (e.g., natural) labor. In the case of labor, the steep decline of Tregs near the end of pregnancy helps initiate labor (1, 11).

Moreover, despite the significant decrease in Tregs, the maternal immune system holds on to the memory of Tregs specific to the fetal antigen, which offers a protective effect for future pregnancies (1)!

“[The] retention of “memory” Tregs with fetal specificity, which retain the ability to generate a more effective and accelerated suppressive response when re-exposed to the same fetal antigens in subsequent pregnancies. The primary pregnancy confers Tregs with a protective regulatory memory, which may provide an immunological basis for protection against complications such as pre-eclampsia in a subsequent pregnancy” (1).

Tips to support the immune system in pregnancy

Vitamin D

Vitamin D is an essential immunoregulator, and supplementation with vitamin D has been shown to increase Tregs in healthy individuals and adults with autoimmunity (12).

The body requires more vitamin D during pregnancy, yet vitamin D insufficiency is extremely common during preconception and pregnancy (13).

Women with low vitamin D (less than 75 nmol/L or 30 ng/mL) have a 60% increased risk of miscarriage compared to women with vitamin D greater than 75 nmol/L (14).

In a study by Ji et al. (2019), women with recurrent pregnancy loss had significantly lower levels of Tregs than women with a healthy pregnancy, and two months of vitamin D supplementation corrected the imbalance in Treg cells (15).

Additionally, vitamin D helps regulate NK cells, which may be altered in those with recurrent pregnancy loss (16).

Low vitamin D has also been linked to preeclampsia and gestational diabetes.

Click here to learn how to accurately assess vitamin D and each test on a complete blood chemistry panel in our breakthrough pregnancy and postpartum-specific blood chemistry course.

Bifidobacterium probiotics

Bifidobacterium is a genus of bacteria native to the human gut and has many recognized health benefits, including immune modulation.

Bifidobacterium regulates multiple immune cells, including dendritic cells and macrophages, and upregulates Tregs. The immunomodulatory effects of Bifidobacterium may be species and strain-specific (17). If you are considering supplementing with a Bifido-based probiotic, consider working with a health professional to determine which species and/or strain will best meet your needs.

A lack of Bifidobacteria in the gut has been linked to autoimmunity and has also been observed in preeclampsia (18, 19).

In addition to Bifidobacterium, the microbiome as a whole is essential to consider during preconception and pregnancy. Dysbiosis of gut and vaginal bacteria has been linked to recurrent pregnancy loss, preeclampsia, and preterm birth (20, 21, 22).

Nutrient-dense foods to boost Tregs

In addition to vitamin D, other nutrients are essential for the development and balance of Treg cells, including protein and omega-3 fatty acids (23, 24).

Micronutrients of importance include vitamin A, zinc, selenium, and biotin (B7) (23).

Supplementation, especially in critical situations such as vitamin D deficiency, effectively improves nutrient status. However, diet as a whole can have a profound effect not only on immune function but also on gut health, including boosting Bifidobacteria. Remember, good gut bugs love fibers from garlic, onion, Jerusalem artichoke, oats, asparagus, and leeks.

References

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!

References