Are you paying attention to these predictive preeclampsia blood tests?

Preeclampsia involves high blood pressure alongside maternal kidney dysfunction (typically manifesting as edema, proteinuria, or abnormal creatinine levels), multiple organ failure, and abnormal placental or uterine function. It is one of the leading causes of maternal and fetal morbidity and mortality and requires immediate medical attention.

It’s possible for someone with a history of normal or low blood pressure to develop preeclampsia. This is one reason why blood pressure is measured at every prenatal visit.

Because preeclampsia has an elevated risk of maternal and fetal morbidity and mortality, the medical team will intervene if necessary by delivering the baby as soon as it’s considered safe, but this might require a premature delivery.

The need to induce labor means that the premature infant may require a stay in the neonatal intensive care unit and struggle with lung, nervous system, or immune system function.

In addition to the potential health risks of preterm delivery, the parents’ bonding with the baby and the breastfeeding relationship during the first days and weeks of life can be disrupted.

The stress of a high-risk pregnancy, a premature delivery, and baby’s NICU stay are all factors that can predispose mothers to postpartum depression and anxiety.

And the effects of preeclampsia on the mother’s cardiovascular system can continue beyond pregnancy and postpartum; people with a history of preeclampsia have a vastly increased risk of developing hypertension, cardiovascular events, stroke, and more than women without a history of preeclampsia (1).

In addition to the potential adverse outcomes to baby and mom, research has shown that preeclampsia can increase the risk of autism and developmental delays in the growing child.

The Childhood Autism Risks from Genetics and the Environment Study found that children with autism were twice as likely to have been exposed to maternal preeclampsia in utero, and this risk increased with more severe preeclampsia (adjusted OR: 2.36; 95% CI, 1.18-4.68) (2).

Severe preeclampsia was associated with a five-fold increased risk of developmental delays (adjusted OR: 5.49; 95% CI, 2.06-14.64), and the researchers suggested that the strength of this relationship was due to placental insufficiency in the observed cases (2).

However, a more recent meta-analysis found a milder association between preeclampsia and autism, albeit still statistically significant (OR: 1.36; 95% CI, 1.12–1.60) (3).

Detecting preeclampsia as early as possible is a crucial intervention strategy, which is why blood pressure is thoroughly monitored throughout pregnancy.

In my nutritional therapy practice, I go one step further and investigate preeclampsia blood tests that make early intervention possible.

Given how serious and disruptive preeclampsia is, knowing how to spot slight abnormalities on blood tests is a critical step towards early intervention with functional health strategies and may even prevent preeclampsia from occurring.

Here, I’ve compiled information from key studies looking at lab markers that may detect elevated risk of preeclampsia.

This blog covers:

uric acid (UA)
gamma-glutamyl transferase (GGT)
alkaline phosphatase (ALP/alk phos)
homocysteine (HCY)
neutrophil-to-lymphocyte ratio (NLR)
lactate dehydrogenase LDH

Three interconnected preeclampsia blood tests: Uric acid, GGT, & ALP

In a 2021 prospective cohort study of 1,041 pregnant women, Chen et al. found that when UA, GGT, and ALP are elevated beyond the normal range in early pregnancy (median 13.4 weeks, 95% range 7.1–18.0), preeclampsia risk increases (4).

Let’s look more closely at each of these markers.

Uric Acid (UA)

During pregnancy, uric acid (UA) excretion increases due to increased filtration and decreased reabsorption (5).

Serum uric acid levels fall in early pregnancy, reaching a low point by 22 to 24 weeks, followed by a gradual rise. The increased clearance is necessary to handle the increased production from the placenta and fetus.

Increased uric acid levels may play a causal role in the etiology of gestational hypertension (4).

“Hyperuricemia has been shown to stimulate the renin-angiotensin system, inhibit neuronal nitric oxide synthase and induce endothelial dysfunction. In addition, UA has been reported to induce trophoblastic production of pro-inflammatory interleukin-1β through activation of inflammatory pathways. These underlying mechanisms may partly explain the role of UA in BP progression and the development of HD (4).”

A review of the literature shows a significant positive association between elevated uric acid and gestational hypertension and preeclampsia (6, 7, 8, 9).

According to Wu et al. (2012), measuring uric acid at the initial presentation of gestational hypertension may help predict the odds of developing preeclampsia (10).

Specifically, an increase in uric acid by one standard deviation was associated with 2.3 times the odds of hypertension progression to preeclampsia (adjusted OR: 2.33 (95% CI: 1.45-3.74) (10).

Gamma-glutamyl transferase (GGT)

Gamma-glutamyltranspeptidase (GGT) has been identified as a positive marker for hypertension and cardiovascular mortality risk in non-pregnant people (11, 12, 13).

There is a lack of literature studying the role of GGT as a marker of gestational hypertension and preeclampsia. However, Chen et al. (2021) identified a significant positive association between serum GGT and blood pressure during pregnancy (4).

The mechanism behind this connection isn’t fully understood. But the authors of the above study note,

“GGT plays a role in the generation of free radical species through its interaction with iron and other transition metals (43). Serum GGT has been positively associated with inflammatory markers such as fibrinogen, C-reactive protein (CRP), and F2-isoprostanes. Thus, elevated GGT could potentially act as an additional marker for oxidative stress and inflammation, which are, as demonstrated by Palei et al., important features of HDP (44)” (4).

Alkaline phosphatase (ALP)

Alkaline phosphatase (ALP) has been positively associated with blood pressure in healthy pregnancies (14), as well as the risk of cardiovascular disease and mortality in non-pregnant people (15).

ALP can induce vascular calcification due to its role in the hydrolysis of key calcification inhibitors (16), which may be one factor in its effect on blood pressure.

In addition to its role in vascular calcification, elevated ALP may indicate increased inflammation, as evidenced by its positive correlation with elevated c-reactive protein.

Heightened inflammation has been indicated as one key factor in the complex pathophysiology of gestational hypertension (17), and it is a recurring theme that you will see in the biomarkers discussed here.

Elevated ALP in early pregnancy has been associated with an increased incidence of preeclampsia (4).

Although it is not entirely clear if the elevations in UA, GGT, and ALP are a causative factor or a consequence of gestational hypertension, some researchers have suggested they play a role in the etiology of preeclampsia (4).

Something that UA, GGT, and ALP have in common is their interaction with inflammatory pathways in the body, and thus, investigating potential inflammatory mediators and triggers in the patient is an essential part of preeclampsia prevention.

More exploration of preeclampsia blood tests: Homocysteine

Homocysteine, a metabolite of methionine, generally stays within a tight range if the homocysteine-methionine cycle is functioning optimally.

Chronically elevated homocysteine may indicate micronutrient deficiency or genetic SNPs and has been linked to cardiovascular disease, Alzheimer’s, and vascular dementia (18).

Homocysteine levels typically fall during pregnancy due to increased glomerular filtration rate (19).

However, a 2023 review of ten studies found a strong association between elevated homocysteine between weeks 10-14 of gestation and several pregnancy complications, including preeclampsia (19).

Homocysteine may be a marker for the progression of preeclampsia, as studies have shown a significant correlation between disease severity and homocysteine (20, 21).

“Since the vascular alterations brought on by homocysteine are comparable to those brought on by hypertensive disorders of pregnancy, it can be assumed that high levels of homocysteine are linked to the hypertensive disorder spectrum. However, how hyperhomocysteinemia increases the likelihood of problems during pregnancy and other negative effects is unknown. According to a theory, high homocysteine levels lead to endothelial dysfunction, making women more likely to have it in the placental vascular system” (19).

A preeclampsia blood test you haven’t heard of: NLR

Neutrophil-to-lymphocyte ratio (NLR) is used as an inflammatory biomarker and, when elevated, indicates systemic inflammation and an active immune response (22).

During pregnancy, elevated NLR is associated with increased preeclampsia risk. Several studies have found that the neutrophil-to-lymphocyte ratio is significantly higher during the first trimester of pregnancy in those who develop preeclampsia.

One large Turkish study found that “At a cutoff level of 4.01, NLR accurately predicted preeclampsia {AUC=0.568 (95% confidence interval 0.524–0.612), p=0.002} with sensitivity and specificity rates of 79.1% and 38.7% and positive and negative predictive values of 73.6% and 72.3%, respectively” (23).

Additionally, the study found that an elevated platelet-to-lymphocyte ratio was associated with an increased risk of severe preeclampsia (23).

However, a more recent review and meta-analysis concluded that the “diagnostic accuracy of NLR has unsatisfactory specificity but acceptable sensitivity for diagnosis of PE. Further large-scale prospective studies are required to validate the potential applicability of using NLR alone or in combination [with] other markers as PE diagnostic biomarkers and explore potential factors that may influence the accuracy of NLR for PE diagnosis (24).”

Thus, the NLR ratio may be a helpful screening tool for preeclampsia risk while requiring you to look for additional reasons why the NLR may be elevated.

For example, when the NLR is over 5.8, there is an increased risk of several adverse pregnancy outcomes, including miscarriage (25).

Additionally, elevated NLR in the first trimester is associated with an increased risk of gestational diabetes (26).

For clinicians who work with patients with autoimmunity, remember that long-term corticosteroid use can decrease lymphocyte counts and thus skew the NLR.

So, an elevated NLR may be purely consequential to medications. Nonetheless, any patient with an AI on corticosteroids who presents with an elevated NLR should be monitored by their healthcare team, and the NLR should cause neither alarm nor dismissiveness.

Lactate dehydrogenase (LDH)

Lactate dehydrogenase increases throughout pregnancy but is two times higher than healthy levels in preeclampsia. LDH and its isoenzymes are proposed as markers to screen for preeclampsia risk.

“Preeclampsia is characterised by disturbed trophoblastic migration of maternal spiral arteries leading to increased uteroplacental vascular resistance and dysfunction, resulting in reduced intervillous blood flow, oxygen and nutrient deprivation to the foetus [10] [11]. The central mechanism of preeclampsia revolves around placental under perfusion, associated hypoxia and cellular death, emphasizing the pivotal role of lactate dehydrogenase (LDH: an intracellular cytoplasmic enzyme of glucose metabolism, a key indicator of anaerobiosis and cell death) in the pathophysiology of preeclampsia” (27).

This study included samples collected after the 20th week of pregnancy. Thus, it isn’t clear whether LDH measured in the first half of pregnancy may be an early indicator of preeclampsia risk.

A study covered in a previous section found that LDH in early pregnancy was one of four markers correlated with increased risk of preeclampsia, with blood samples collected in early pregnancy, with a median of 13.4 weeks of gestation and a range of 7-18 weeks of gestation (4).

However, “When all … biomarkers were simultaneously included in multivariable analyses (Model 3), only increased UA, GGT, and ALP remained associated with increased BP,” so it isn’t clear whether measuring LDH before week 20 is particularly predictive of risk (4).

Thus, it might make the most sense to look at LDH as a preeclampsia marker in the second half of pregnancy rather than in the first, at least until further studies clarify the role of LDH in early pregnancy related to preeclampsia risk.

When is the best time to run preeclampsia blood tests?

Because blood chemistry changes by trimester, timing is essential for preeclampsia blood tests. Based on the above research and my clinical knowledge, I recommend the following timeline:

NLR (calculated based on CBC), UA, ALP, GGT, HCY: weeks 10-14

LDH: around mid-pregnancy, at or after week 20

Want to learn more?

If you’re interested in deeper dives into pregnancy, especially learning more about the best way to interpret blood work in pregnancy and postpartum, check out my self-paced masterclass, “What You Never Learned About Blood Work in Preconception, Pregnancy, & Postpartum.”

Sign up today to access the materials on our platform and start offering your patients the most accurate blood test analysis available!

Stay tuned for my next post, discussing preeclampsia blood pressure ranges.

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