Bioindividual interpretation of blood test results in pregnancy: The third trimester
If you’ve read the first two blogs in this series, you know that reproduction leads to unique physiological changes.
These significant shifts influence blood test results in pregnancy.
Surprisingly, the now widely-studied practice of functional blood chemistry analysis doesn’t adjust for pregnancy, postpartum, or lactation.
So, in order to get the most accurate and practically useful blood ranges for your patients, you have to go beyond functional medicine.
But with a full practice, a family, and trying to carve out some personal time, are you supposed to comb through hematological research to find each marker that changes due to reproduction?
We didn’t think so.
Keep reading to learn more about blood test results in pregnancy and what to be on the lookout for in the third trimester.
A review of blood test results in pregnancy: The first and second trimesters
In the first trimester, it’s especially important to closely evaluate:
- Red blood cells, hemoglobin, and hematocrit – decreased vs. non-pregnancy values
- Fibrinogen and d-dimer – increased vs. non-pregnancy values
- Alkaline phosphatase – increased vs. non-pregnancy values, 3-fold increase as pregnancy progresses
- TSH, free T4, and free T3 – TSH decreases while free T3 and free T4 generally increase in the first trimester and then decrease as pregnancy progresses
In the second trimester, pay attention to:
- Insulin – increases by approximately 29% from pre-pregnancy levels – a normal occurrence of pregnancy
- Bilirubin – all forms decrease by the second trimester
- Gamma-glutamyl transferase (GGT) – decreased vs. non-pregnancy values
- Blood urea nitrogen (BUN), creatinine, glomerular filtration rate (eGFR), sodium, & potassium – eGFR increases while BUN, creatinine, uric acid, sodium, potassium, and blood pressure decrease
Remember, the list above isn’t exhaustive. Rather, these are the most frequently tested values. For a complete list, visit the LabSmarts website.
Blood test range adjustments in the third trimester
Results of iron, ferritin, copper, protein, platelet counts, aldosterone, and uric acid will seem out-of-range when compared to non-pregnancy ranges.
Alkaline phosphatase also continues to rise and can remain elevated through all of lactation!
Iron, ferritin, and iron supplementation
But they’re also clinically important due to the standard blanket recommendation of iron supplementation during pregnancy.
In pregnancy, serum iron must increase to support the fetus, placenta, and parent. For this increase to occur, the mother’s body absorbs more iron from the food she eats, and additionally, stored iron is released (1).
The hormone hepcidin regulates this shifting of iron. Consider that the role of hepcidin is to inhibit iron from coming out of cells—in other words, it inhibits cellular iron efflux.
And as you might imagine, because the pregnant mother needs more iron in her blood, hepcidin decreases. So, the range for hepcidin in pregnancy, particularly in the second and third trimesters, will ideally be lower than in non-pregnant people.
But what does this have to do with supplemental iron in prenatal supplements?
Though we don’t have research on the specific effect of iron supplementation on hepcidin in pregnancy, we do know that in non-pregnant adults, ingestion of iron rapidly increases hepcidin…a logical effect based on the relationship between the two.
However, this effect may be problematic in pregnancy when hepcidin decreases to allow more iron access for the mother, fetus, and placenta.
“… a 2015 Cochrane review (2) of randomized trials from 15 countries showed that maternal and infant outcomes at birth were not better with daily iron supplementation compared with intermittent iron supplementation, but intermittent supplementation was associated with fewer side effects” (1).
Essentially, multiple studies suggest that iron supplementation should be highly individualized to the mother to avoid increased oxidation and possible side effects (https://pubmed.ncbi.nlm.nih.gov/11762527).
Some clinical questions to consider include:
- Did the mother experience iron deficiency anemia before conception?
- Are iron panels revealing continued low serum iron levels and high transferrin and total iron-binding capacity during pregnancy?
- Does the mother feel better or worse with iron supplementation that includes co-factors such as vitamin C?
- Is there an underlying inflammatory condition that may be affected by iron supplementation?
- What is the mother’s copper status?
In the 3rd trimester, serum iron increases, while ferritin decreases along with hepcidin.
Ferritin may increase slightly at the beginning of pregnancy due to the cessation of menstruation.
However, a steady decline in ferritin seems to be a natural pattern in pregnancy; although depending on the study, it may level off toward the third trimester.
Interestingly, Iron supplementation in women who were anemic at the start of their pregnancy resulted in better birth outcomes but did not improve iron levels or storage markers (17).
Ferritin levels higher than approximately 40 ng/ml in the 3rd trimester were shown in many studies to be highly associated with gestational diabetes mellitus, preterm or very preterm delivery, oxidative stress, and infection (16,17,18,19,20).
The optimal values for ferritin in pregnant women get progressively more narrow throughout the pregnancy. The optimal ranges by trimester are based on where ranges should be before pregnancy, the natural pattern of a 50% decrease by the 3rd trimester, the lack of alteration to iron status markers with iron supplementation, and the abundant research available regarding 3rd-trimester ferritin levels and pregnancy outcomes.
Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr. 2017;106(Suppl 6):1567S-1574S.
However, the main contributor is the cascade created by the pregnancy-induced demand for iron. The physiological requirements of pregnancy result in decreased hepcidin and the release of stored iron from ferritin-rich cells such as macrophages and hepatocytes (3).
Third-trimester takeaway: Serum iron increases, and serum ferritin and hepcidin decrease.
We also find hormonally-influenced changes in copper during pregnancy…changes that intersect with the shifts in iron, ferritin, and hepcidin described above.
Copper and iron interact in multiple ways. For instance, iron relies on copper-dependent enzymes to travel from the small intestine into the blood.
And copper relies on iron levels that influence copper-regulating Menkes ATPase enzymes (4).
“We have been aware that excess dietary iron can decrease copper absorption, and the reverse is true in that excess dietary copper may impair iron absorption” (5).
Essentially, copper and iron (along with zinc, selenium, chromium, and, likely, all minerals) work synergistically at metabolic and genetic levels.
However, the increase in estrogen levels in pregnancy leads to specific increases in the amounts of copper in the blood.
While the mechanism of this change isn’t fully understood, evidence points to estrogen’s effect on copper transporters (6).
When exposed to just copper, the expression of copper transporters DMT1 and hCTR1 decreased, and they lessened in activity. This is the expected response.
But in the presence of copper and estrogen, the expression of these transporters remained high and active. Essentially, estrogen changes the action of these transporters so that more copper is exported into the blood!
The cell growth and proliferation that occur in both mother and fetus are fueled by this increase in copper absorption.
Clinically, studies show that in the third trimester, copper levels can double that of non-pregnant levels (7).
Ceruloplasmin, the major copper-carrying protein in the blood, also increases in pregnancy.
However, be aware that too much intrauterine copper is problematic and can contribute to growth restriction, preeclampsia, neurological disease, and developmental delays (8). Pregnancy levels should not increase above 240 µg/dL.
Third-trimester takeaway: Serum copper and ceruloplasmin increase, sometimes up to two times that of non-pregnancy levels.
Total protein, albumin, and globulin
Another effect of hemodilution is the gradual decrease of total protein throughout pregnancy, with levels bottoming out in the third trimester.
Remember, the total protein marker mainly consists of the two primary proteins found in the blood—albumin and globulin. However, over 500 peripheral proteins are included in the total protein test!
“Total protein measures the combined amount of proteins, the two major classes of which are albumin and immunoglobulin. Albumin is a carrier of many small molecules, but its main purpose is to keep fluid from leaking out of blood vessels, while immunoglobulin proteins are antibodies. To a much lesser extent, enzymes and more than 500 other proteins contribute to the total protein.” (https://labtestsonline.org.uk/tests/total-protein-test)
While hemodilution is the leading cause of total protein decrease, an interesting pattern occurs during pregnancy: albumin decreases while globulin remains steady or slightly increases.
Third-trimester optimal reference range of albumin should be approximately 2.78 to 3.73 g/dL, much lower than the non-pregnant optimal range of 4.5 to 5.
Additionally, minor proteins such as alpha2-macroglobulin, alpha1-antitrypsin, and ceruloplasmin (a major copper transporter) also increase (10).
Third-trimester takeaway: Total protein and albumin decrease while globulin remains stable or slightly decreases.
Technically named gestational thrombocytopenia or physiological thrombocytopenia of pregnancy, most women experience a decline in platelets that becomes apparent in the third trimester.
As with almost every pregnancy-specific change in blood work, gestational thrombocytopenia doesn’t lead to symptoms or an increased risk to the mom or baby. However, it may take up to two months postpartum for levels to return to normal (11).
As you might have guessed, hemodilution plays a part in the lower levels of platelets most women experience in the third trimester.
However, two other reasons explain this phenomenon: the increased consumption of platelets by peripheral tissues such as the placenta and increased platelet aggregation due to higher levels of thromboxane A2 (12, 13).
It’s important to note that while most cases of gestational thrombocytopenia are physiologically normal, approximately 20% are due to hypertensive disorders, while three to four percent are due to immune purpura.
It’s imperative to know the clinical context of the patient.
Be aware if the woman is hypertensive or has a history of HIV, hepatitis, H. pylori, rheumatoid arthritis, lupus, or antiphospholipid antibody syndrome, all contributors to immune purpura. These factors may lead to platelet levels that are decreased beyond the physiologically normal level (14).
Third-trimester takeaway: A slight decrease in platelet count, termed gestational thrombocytopenia, is physiologically normal. However, recognize risk factors contributing to levels that are lower than expected.
Learn more with a free trial of LabSmarts
Remember that B6, aldosterone, and uric acid also shift in the third trimester. So, the typical functional / optimal reference ranges won’t work for these markers, either.
To review every marker that changes in the third trimester, and access specific pregnancy and postpartum ranges, sign up for your free trial of LabSmarts.
And follow this link for a free demo of the LabSmarts software.
To learn more about what markers change during pregnancy, why they change, and how to use this information in your practice, sign up for our 6-week live masterclass…
“What You Never Learned About Blood Work in Preconception, Pregnancy, and & Postpartum.”