In this study, we showed that serum ADAMTS-1 levels were significantly increased in HEG patients compared with the healthy pregnant control group. There was a significant and positive correlation with urine ketone levels and a significant negative correlation with serum TSH levels. Our study is the first to evaluate ADAMTS-1 levels in HEG patients and their associations with other biochemical parameters.
Liu et al. [
13] stated in their study that not only hCG but also many different cytokines are secreted from trophoblasts in chorionic villi, and hCG alone may not be responsible for nausea and vomiting. For example, in a study by Fejzo M.S et al. [
14] it was found that the GDF-15 gene encodes a TGF-β superfamily member, which is expressed at high levels in the trophoblast cells of the placenta, and this protein, which has high levels in maternal blood especially in the first two trimesters, acts to facilitate placentation and suppress pro-inflammatory production of cytokines in order to suppress the continuation of pregnancy. In addition to this role, in the same study, it was shown that GDF 15 activates hypothalamic neurons and regulates body weight and appetite by affecting the nausea-vomiting center in the area postrema. In a study conducted by Kuno et al. [
11] and Lerner L et al. [
15], which included the same model of cachexia, they showed that overproduction of GDF-15 in cancer patients was the main cause of cancer anorexia and cachexia, and it led to the symptoms of chronic nausea and vomiting in HEG.They also found that ADAMTS-1 and GDF-15 together may be associated with cancer cachexia. Thus, in the future it will be interesting to determine whether ADAMTS-1 increases GDF15 levels or vise versa. It has been shown in various studies that the presence of ADAMTS-1 is needed for a healthy implantation, placentation, and continuation of pregnancy [
10,
16,
17]. In a large population-based cohort study, it was reported that the incidence of small-for-gestational age (SGA) increased in women with HEG [
18]. It has been claimed that this may be secondary to placentation abnormality and stated that this possibility is stronger in the presence of HEG and early-onset preeclampsia, especially in the second trimester [
18]. In the literature, there is no study investigating the relationship between ADAMTS-1 levels and HEG, but there was a study investigating its levels in preeclampsia patients. In this study by Kalem et al. [
9], the ADAMTS-1 levels in the blood of preeclamptic patients were lower, and the levels in the placental tissue were higher than in the control group. In our study, we found ADAMTS-1 levels to be significantly higher in HEG patients than in the control group. Based on this, crosstalk between trophoblasts and the extracellular matrix might be correlated with ADAMTS-1 levels rather than trophoblast invasion in HEG. It is well known that ADAMTS-1 functions as a VEGF antagonist [
19]. VEGF, on the other hand, is a vascular permeability factor that plays a role in angiogenesis, which is produced in the maternal fetal unit at high levels and secreted into the maternal blood during pregnancy. Schreurs et al. [
20] showed that VEGF had the feature of increasing the blood–brain barrier. In a different study, Miyata et al. [
21] showed that the blood–brain barrier, which is more permeable than other parts of the brain as formed by fenestrated capillaries, could become more permeable with VEGF, especially in circumventricular organs such as the area postrema, which includes the nausea and vomiting center inside. Despite the relationship mentioned above, we could not find any study investigating VEGF levels in patients with HEG. Therefore, based on the above studies, we thought that ADAMTS-1 levels, which are high in HEG patients, might be secreted from the placenta as a compensation mechanism to regulate the increased permeability in the nausea-vomiting center. In a small number of studies on ADAMTS-1, it has been shown that by regulating the blood–brain barrier, it enables neurons to adapt to the new situation [
22]. Although higher levels of ADAMTS-1 as an VEGF antagonist, would hypothetically result in decreased permeability which should decrease nausea and vomiting, ADAMTS-1 antagonizes VEGF to regulate trophoblastic invasion at the receptor level in the placenta. Considering that the VEGF receptor types in placental and neural tissues are different, it is possible that ADAMTS-1 may not be effective on VEGF receptors in the brain, or GDF-15 or some other growth factors and or cytokines may reduce the activity of ADAMTS-1 [
10,
23].
It is well known that ketone bodies are a fuel for the brain as an alternative to glucose in long periods of fasting and have the ability to cross the blood–brain barrier [
24]. Studies have shown that starvation ketosis could be observed in long-term nausea and vomiting seen in HEG, and this might be harmful to the maternal and fetal neuronal system [
25]. ADAMTS-1 might have a function, such as protecting the blood–brain barrier from the negative effects of ketone bodies, because ADAMTS-1 is an antagonist of VEGF, which increases the blood–brain barrier. Although most studies could not find a relationship between ketonuria and HEG severity, we detected a significant degree of ketonuria in our HEG group compared to the control group, and we observed a positive correlation between ketonuria and ADAMTS-1 levels [
26]. In a different study that investigated the relation between ketonuria and HEG, Soysal et al. [
27] claimed that ketonuria in HEG was determined by the inflammatory response in pregnancy rather than HEG itself. Similar to that study, we found that inflammatory markers such as PDW, PCT, and MPV were higher in the HEG group compared with the control group.
One of the main weaknesses of this study is that GDF 15 levels were not measured. Another weakness is that we did not measure VEGF levels as there was no standardized value in the first trimester of pregnancy. The well-matched features of the patients and the fact that they were free from the effects of BMI and age showed that the results and comparisons were reliable.