Low hCG Levels Can Indicate Preeclampsia Risk

Becky McCall

May 31, 2016

MUNICH — Additional measurement of human chorionic gonadotropin (hCG) levels in pregnant women with high-normal thyroid function can help determine which women are most at risk of preeclampsia, a new study indicates.

The analysis, which is the first to demonstrate this finding, highlights the importance of distinguishing women with physiologically high thyroid function caused by high levels of hCG, a hormone that rises naturally during pregnancy, from women with high thyroid function per se.

In relation to the latter group, Tim Korevaar, MD, study leader from Erasmus University Medical Center, Rotterdam, the Netherlands, said: "Identifying these women has implications for clinical risk management because they might benefit from further follow-up."

He presented the results at the European Congress of Endocrinology (ECE) 2016.

"Based on our study, we propose that by measuring hCG levels it is possible to distinguish patients with high-normal thyroid due to physiologically high hCG in pregnancy from those whose high-normal thyroid has a nonphysiological cause such as underlying hyperthyroidism pathology," he asserted.

Data were drawn from Generation R, a group of 5803 pregnant women who provided blood samples during their pregnancy between the years 2002 and 2006 and in whom measurements included thyroid- stimulating hormone (TSH), free thyroxine, and/or hCG levels available during early pregnancy (18 weeks or less). There were also data on preeclampsia outcomes.

"Classically, research on thyroid hormones focuses on early pregnancy because the fetus is dependent on the maternal transfer of thyroid hormones across the placenta during this period," explained Dr Korevaar, adding that "preeclampsia is a disease of placental dysfunction, and important developmental stages of placentation occur in early pregnancy and may be determined by thyroid hormones.

"Early pregnancy is also the time frame during which any intervention on a modifiable risk factor for preeclampsia could be effective," he added.

Women With Low hCG Nearly Four Times the Risk of Preeclampsia

Previous work by the same authors has shown that high free thyroxine during early pregnancy is associated with a twofold greater risk for preeclampsia, but there was no apparent association with low TSH.

However, the thyroid is stimulated by hCG during early pregnancy, and therefore Dr Korevaar and colleagues hypothesized that women with high-normal thyroid function due to high hCG levels would have a different risk of preeclampsia as compared with women with high-normal thyroid function and low hCG.

In the current study, the association of high-normal free thyroxine (fifth quintile) or low TSH with preeclampsia was analyzed, with adjustment for gestational and maternal age, smoking, education, ethnicity, parity, body mass index (BMI), and fetal gender.

In women in the highest free thyroxine quintile, with low hCG levels (<35,000 mIU/mL) the odds ratio of preeclampsia was between 3.44 to 4.64 compared with those women with a free thyroxine level from the middle quintile.

The combination of high-normal FT4 and hCG >20.00 was not associated with an increased risk of preeclampsia.

In pregnancy, TSH levels decrease as compared with a nonpregnancy state. "In women with very suppressed TSH (<0.1 mIU/L), we saw an increased risk of preeclampsia.…if they also had low levels of hCG. But this effect of low TSH is less pronounced than the effect of the high free thyroxine," said Dr Korevaar.

"It is clear from these data that the risk in the whole population we observed previously only comprised those women with high free thyroxine but low hCG levels," Dr Korevaar said.

It has also consistently been shown that women who are overweight or those experiencing their first pregnancy are at increased risk of preeclampsia. With this in mind, the group also stratified results for women with a BMI over 25 and also looked at nulliparous women.

"Among nulliparous women we saw effects similar to the whole cohort, but among those with high BMI we saw that in addition to their initial higher risk of preeclampsia, if we stratify for low hCG levels then they have an even higher risk level," Dr Korevaar explained.

"This is a big effect," he asserted. "The numbers were small, but these findings certainly point toward preeclampsia being a multifactorial disease in which high thyroid hormones are a risk factor."

He also pointed out that high BMI is also associated with lower thyroid function and lower hCG, so it is protective of high thyroid function.

"However, if you still develop a high thyroid function while you have a high BMI, despite the protective effect, it suggests that the high thyroid function is more likely related to thyroid-hormone overproduction. Plus, it seems that the combination of both risk factors has an additive effect on the risk of preeclampsia as compared with the separate effects."

For the TSH analyses, there were no synergistic effects with other risk factors (such as BMI or parity).

Test hCG Levels in the Clinic?

Dr Korevaar said that the study results indicate that, without measuring hCG, if a pregnant woman's free thyroxine level is high, it is unclear what is causing the effect.

"Is it high hCG levels or other factors alongside high hCG? We have found that approximately one-third of our population had [hCG] less than 35,000 mIU/mL, and so, during the first visit a pregnant woman makes to the clinic, there is roughly a one-third chance that the measurement of hCG can tell you something about the cause of the woman's high free thyroxine level. Otherwise, repeat testing may be necessary."

To place the findings into context, he pointed out that it is important to remember that the majority of women with high-normal thyroid function have high hCG levels.

"Our results confirm general opinion that this is normal physiology and these women do not require treatment, but clinicians should check that these high free T4 levels are transient. But it is also important to distinguish women with much higher risk, and they would benefit from more thorough blood measurements, including measurement of TSH-receptor–stimulating antibodies, and these women would require treatment, for example in the case of Graves' disease."

The session stimulated some discussion, and, commenting on the results, gynecologist Vanadin Seifert-Klauss, MD, from the Technical University of Munich, pointed out that it should be remembered that "hCG measurements between the 10th and 17th week of pregnancy have a very high variability, particularly twin gestations that have higher values than singletons."

She also noted that soluble fms-like tyrosine kinase (s-Flt1) is an established biomarker of preeclampsia risk, which is good to test during the second trimester.

And for the first trimester, algorithms have been established that have a 90% sensitivity for predicting preeclampsia, explained Dr Vanadin. "Any new test or marker combination in a specific subgroup would need to show a similar or better performance."

In response to the suggested use of s-Flt1, Dr Korevaar pointed out that prediction models can be improved by addition of new markers, in this case thyroid function and s-Flt1 and placental growth factor (PIGF).

"Although the design of our study does not allow us to infer causality, when replicated, these data could be used in clinical prediction models that utilize patient characteristics and biochemical markers, including s-Flt1 and PlGF, to predict the development of preeclampsia."

But he added that "the variation in hCG is what causes thyroid-hormone changes and thus this difference in stimulation is what we use to distinguish the subgroups discussed."

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European Congress of Endocrinology 2016; May 29, 2016; Munich, Germany. Abstract OC4.1

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