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.