Increases in immune cells associated with reduced risk of miscarriage

Researchers in a 2024 study measured leukocyte (white blood cell) levels in women preparing for pregnancy, and found that miscarriage risk was lower with high total leukocytes. Specific immune cells examined include monocytes, eosinophils, basophils, lymphocytes and neutrophils.

The immune system is made up of many different cells, each with different roles to help defend us from infection. The cells of the immune system are generally known as leukocytes, or white blood cells.

Some common leukocytes include:

• Monocytes (that can develop into macrophages that can “eat” bacteria)
• Eosinophils (fight parasites and other infections)
• Basophils (these release histamine to initiate inflammation to fight an infection)
• Lymphocytes (which includes B cells, T cells and natural killer or NK cells)
• Neutrophils (these are the “first line of defense” and respond to initial infections)

Imbalances in these cells can lead to problems with the immune system and other conditions. Liu et al. (2024) wanted to see if changes in leukocyte levels are associated with miscarriage. To do this, they measured leukocyte levels in the blood in people preparing for pregnancy, to see if there were any links to miscarriage risk.

---

Study details

This section covers key details of how the study was performed, including the number of patients and their characteristics, how they were treated, and other methods used. For those who aren’t interested in these details, and just want to see the results, you can go ahead and skip this part.

• This is a retrospective study that took place in 2016 in China.
• Couples that were preparing for pregnancy within 6 months were given a blood test.
• Women were between 20-49 years old and didn’t have infertility.
• This study included 1,075,038 patients, with 35,529 miscarriages (3.3%).
• The main outcome was a miscarriage before 28 weeks gestation.

They used different statistical models to see how leukocyte levels affect the risk of miscarriage. These models statistically adjusted for different factors. The one I’ll be referring to here is their third model, that adjusted for maternal age, paternal age, higher education, nationality, smoking status, alcohol consumption, BMI, hypertension, diabetes, history of adverse pregnancy outcomes, abnormal vaginal discharge and hazardous substance exposure.

Miscarriage risk varies with leukocyte counts

This study included 1,075,038 patients, with 35,529 miscarriages (3.3%). Patients had their blood drawn ~6 months before pregnancy, and their white blood cells were counted.

First let’s look at how the total leukocyte count affects miscarriage risk, which includes all the white blood cells. The reference (normal) range for leukocytes was 4.0-10.0 billion/L:

• Patients with less than 4.0 billion/L had a 14% increased risk of miscarriage (adjusted odds ratio [95% CI]: 1.14 [1.09-1.20]).
• Patients with more than 10.0 billion/L had a 26% reduced risk of miscarriage (adjusted odds ratio [95% CI]: 0.74 [0.69–0.79]).

Next, let’s look at how the neutrophil count affects miscarriage risk. The reference (normal) range for neutrophils was 2.0-7.0 billion/L:

• Patients with less than 2.0 billion/L had a 6% increased risk of miscarriage (adjusted odds ratio [95% CI]: 1.06 [1.01–1.12]).
• Patients with more than 7.0 billion/L had a 33% reduced risk of miscarriage (adjusted odds ratio [95% CI]: 0.67 [0.63–0.72]).

Next, let’s look at how the eosinophil count affects miscarriage risk. The reference (normal) range for eosinophils was 0.05-0.5 billion/L:

• Patients with less than 0.05 billion/L had a 4% reduced risk of miscarriage (adjusted odds ratio [95% CI]: 0.96 [0.93–1.00]).
• Patients with more than 0.5 billion/L had a 29% increased risk of miscarriage (adjusted odds ratio [95% CI]: 1.29 [1.09–1.53]).

Next, let’s look at how the monocyte count affects miscarriage risk. The reference (normal) range for monocytes was 0.12-0.80 billion/L:

• Patients with less than 0.12 billion/L had no change in the risk of miscarriage.
• Patients with more than 0.80 billion/L had a 13% reduced risk of miscarriage (adjusted odds ratio [95% CI]: 0.87 [0.76–1.00]).

There were no differences in miscarriage risk for basophil counts or lymphocyte counts. Lymphocytes include B cells, T cells and NK cells.

Miscarriage risk varies with leukocyte ratios

The information above has to do with the concentration of these white blood cells in the blood. They also looked at the ratio of these cells. For every 100 white blood cells, the reference (normal) range was:

• 50-70% neutrophils
• 0.5-5.0% eosinophils
• 1% or less basophils
• 20-40% lymphocytes
• 3-8% monocytes

Patients with a neutrophil ratio <50% had a 4% increased risk of miscarriage, while those with a ratio >70% had a 14% reduced risk.

Patients with an eosinophil ratio <0.5% had a 5% reduced risk of miscarriage, while those with a ratio >5.0% had a 21% increased risk.

Patients with a basophil ratio >1% had a 16% increased risk of miscarriage.

Patients with a lymphocyte ratio <20% had a 23% reduced risk of miscarriage, while those with a ratio >40% had an 8% increased risk. Lymphocytes include B cells, T cells and NK cells.

There was no change in miscarriage risk with monocyte ratios.

Conclusions

This study found that miscarriage risk was reduced with an:

• Increase in leukocyte count
• Increase in neutrophil count/ratio
• Decrease in eosinophil count/ratio
• Decrease in basophil ratio
• Decrease in lymphocyte ratio
• Increase in monocyte count

This is the first study to investigate pre-pregnancy blood leukocyte levels and its connection with miscarriage risk. In general, studies have shown that these cells have a supportive role for implantation and formation of the placenta during pregnancy. Not all studies suggest a supportive role, and some have found increased levels of these cells associated with miscarriage (such as NK cells and macrophages — references below).

The authors note that women with low levels of leukocytes before pregnancy may have issues in recruiting these cells to support implantation and drive away infection. Remember, these cells are involved in fighting infection, so if there aren’t many available in the blood to do so, the infection could lead a miscarriage.

For this reason, the authors recommend that patients preparing for pregnancy with low blood leukocyte counts should avoid environments that might get them sick.

Since this study found that increased leukocytes protect from miscarriage, the authors call for more research on treatments that stimulate the immune system to make more of these cells before pregnancy, especially in high-risk individuals.

There are several limitations to this study:

• Since they’re from the general population, these patients largely didn’t have infertility, recurrent implantation failure or pregnancy loss or immune disorders. It’s possible that elevated leukocytes may be detrimental for these patients.
• They didn’t perform a blood test around the time of pregnancy, only about 6 months before. However, they did a separate analysis in women who had a blood test 2 or less months before pregnancy and found similar results.
• They didn’t collect the cause of the miscarriage. It would be interesting to see if an infection/sickness was related to the miscarriage, and if this was linked to low leukocyte counts.

Some of the studies that address infertility and immunity, this one included, don’t show that these cells cause miscarriage. They only show that their levels are associated with it. Correlation doesn’t equal causation. For example, when ice cream sales increase, so do drownings. This is because of the warmer weather during the summer, which causes people buy more ice cream and go swimming. It’s not the ice cream that causes drownings, it’s the warmer weather. You wouldn’t try to stop drownings by restricting ice cream sales.

Similarly, using immunotherapies to inhibit immune cell function may not be targeting the problem of infertility, and might be why some studies show no benefit. There may be specific groups that benefit, particularly those with immune disorders (known or unknown), so more research is needed.

Related studies

There were a number of studies referenced that you might want to check out, as shown below (4 links):

Reference

Liu Y, Yang Y, Zhao C, Liu M, Xu D, Wu H, Lei J, Deng Y, Xie W, Huang J, Wu S, Zhang Y, Zhang H, He Y, Peng Z, Wang Y, Shen H, Wang Q, Zhang Y, Yan D, Wang L, Ma X. An immune window of opportunity to prevent spontaneous abortion: prepregnancy peripheral leukocytes and subsets were associated with a decreased risk of spontaneous abortion. Hum Reprod. 2024 Jan 2:dead261. doi: 10.1093/humrep/dead261. Epub ahead of print. PMID: 38166353.

If you liked this post and want to support what I do, please consider a paid subscription, Patreon or donate through PayPal!

 

---

About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

---