The relationship between maternal thyroid volume, TSH levels, and Healthy Eating Index scores in BMI-matched pregnant women with hyperemesis gravidarum

Abstract Objective The aim is to investigate the relationship between thyroid volume measurement and healthy nutrition questionnaire scoring in pregnant women diagnosed with hyperemesis gravidarum (HEG). Methods One hundred and fifty pregnant women with a BMI of 15–25 kg/m2 and between the ages of 17 and 42 who were diagnosed with HEG at 11–14 weeks of gestation were included in the study. Patients with a history of any disease, drug use, and previously diagnosed eating disorders were excluded. All patients were subjected to the Healthy Eating Index (HEI) questionnaire. The cutoff value for HEI score was determined as 80 points. Patients were evaluated in two groups: group 1 (HEI <80 score) and group 2 (HEI ≥80 score). Complete urine analysis including ketonuria, and thyroid function tests including TSH, T3, and T4 levels were performed for all patients. In addition, the thyroid gland volume of every patient was measured by the same radiologist. Results Increased thyroid gland volume was significantly associated with lower TSH levels (p = .02) and lower HEI scores (p < .001). On the other hand, it was not significantly associated with ketonuria (p = .47), and parity status (p = .82). Conclusions In our study, we found that there may be an increase in thyroid volume in pregnant women with HEG with lower TSH levels and eating scores. Thyroid volume may predict the patients with probable eating disorders and further studies on thyroid volume in patients with HEG may contribute to the literature.


Introduction
Approximately, two-thirds of hyperemesis gravidarum (HEG) patients do not have clinical symptoms of hyperthyroidism, but biochemical hyperthyroidism (low thyroid stimulating hormone (TSH) and increased free T4 levels) is observed [1].Also, it was presented that in patients with HEG, thyroid function tests improve with regression of hyperemesis [1].Together with HEG, hyperthyroidism is one of the important reasons for severe vomiting in pregnancy.
The thyroid gland volume does not have a significant difference between pregnant women when compared to non-pregnant women [2].However, several factors such as nutritional habits [3,4], body mass [5,6] and body mass index (BMI) [7], and/or sex hormones [8] were priorly reported to be related with thyroid volume.Also, it was reported that nutritional habits such as the intake of foods rich in thiocyanate, iodinepoor diet, low levels of selenium, vitamin A insufficiency, iron deficiency, and low intake of proteins are in association with goiter [9][10][11][12][13].Starting with the point of view, we thought that there may be an association between thyroid gland volume and the nutritional status of the pregnant patient in the case of HEG.
In this study, we wanted to investigate the relationship between thyroid gland volume with blood TSH level and nutritional quality by using a Healthy Eating Index (HEI) questionnaire scoring in BMI-matched pregnant women with HEG.

Materials and methods
This prospective cohort study was conducted at Batman Training and Research Hospital under the principles of the Declaration of Helsinki.The study was approved by the local hospital ethics committee (document number 2020-6, also applicated as a clinical trial: clinical trial number NCT04528186 (USA)).An informed consent form was obtained from all participants.All participants were outpatients who applied to the obstetrics clinic at Batman Training and Research Hospital.The study included patients who were diagnosed with HEG (number: 150) and they were all subjected to Healthy Index Scoring between 11 and 14th gestational week.
Patients with intractable vomiting leading to weight loss and volume depletion, resulting in ketonuria and/or ketonemia were diagnosed as HEG and included in the study.Inclusion criteria were the age between 18 and 42 years, BMI of 15-25 kg/m 2 , and diagnosis of HEG before 14th gestational week.A history of thyroid disorders, gastrointestinal disorders or gastrointestinal system surgery, any chronic disease, drug/multivitamin (e.g.folic acid) use, cancer, and habitual abortus, and those with multiple pregnancies, priorly diagnosed eating disorders before pregnancy were determined as exclusion criteria.
The HEI is a practical questionnaire developed by the US Department of Agriculture and updated over the years.It evaluates the conformity of food consumption with international guidelines and is a measure of diet quality.Scoring is made according to 13 sections in the questionnaire and the total score is evaluated out of 100.If the score is >80, we have good diet quality; 50-80 means diet quality will be improved; and 50 is classified as poor diet quality [14].After obtaining informed consent from the patients, the HEI questionnaire was administered to all patients face-to-face by the nutritionist [14,15].Patients were divided into two groups according to the HEI score.Those in group 1 have an HEI score of <80, and those in group 2 have an HEI score of 80.
The weight status of patients was determined as the change between the weight at the time of the first positive human chorionic gonadotropin (b-hCG) result to the HEI questionnaire.Weight gain or loss was recorded by the dietician.
Thyroid function tests (TSH, free T3, and free T4 levels) and urinary ketones were measured in morning tests on fasting of all patients.Normal value ranges for TSH, free T3, and free T4 were accepted as 0.35-5.5 mIU/L, 2.3-4.2ng/dL, and 0.89-1.76ng/dL, respectively.
The thyroid gland volume measurement was performed by the same radiologist (Dr.MC) with a standard technique with a color Doppler scanner and a portable ultrasound device with a Ge Logic S7 linear transducer.Thyroid volume was measured as the total volume of both lobes, excluding the thyroid isthmus [16].Each thyroid lobe was measured in the transverse longitudinal and axial planes in millimeters, and the total volume was calculated.

Statistical analysis
Statistical analyses were performed by using the statistical software package SPSS version 22.0 (SPSS, Inc., Chicago, IL).Patient data including age, gravidity, parity, BMI, and weight gain until the beginning of pregnancy to questionnaire time were also recorded.The data were expressed as median and range for the continuous variables.Binary variables were reported as counts and percentages.Independent samples t-test and Chisquared test were used to evaluate the association between thyroid gland volume and other parameters.The level of statistical significance was set at p < .05.

Results
A total of 150 patients were evaluated in two groups in the study.The median age of the patients was 26 years (minimum 17, maximum 42) and one-third of the patients were nulliparous (43 pregnant) (Table 1).Weight gain was observed in most of the patients  2).Ketonuria was present in 72 (48%) of the patients (Table 3).TSH levels were in normal ranges in 113 patients (75.3%) (Table 3).TSH levels were found to be low in 47.2% (n ¼ 37) of the patients included in the study.A receiver operating characteristic (ROC) curve was used to assess the discriminative role of thyroid gland volume on HEI and the area under the curve (AUC) was found to be significant and the best cutoff was 4600 mm 3 (specificity 84.0% and sensitivity 70.6%, p < .001).Thyroid gland volume was greater than 4600 mm 3 in 31.8%(n ¼ 27) of these (Table 3).
Increased thyroid gland volume was not significantly associated with ketonuria (p ¼ .47).Moreover, it was not associated with parity status (p ¼ .82).Increased thyroid gland volume was significantly associated with lower TSH levels (p ¼ .02)and lower HEI scores (p < .001)(Table 3).

Discussion
In our study, we investigated if there is an association between thyroid volume and HEI in patients with HEG and we found that there may be an increase in thyroid volume in pregnant women with HEG with lower TSH levels and eating scores.Moreover, according to our knowledge, this is the first study to investigate such an association.
Nausea and vomiting are common in early pregnancy and affect 79-89% of pregnant women [17,18].Symptoms regress after the first trimester in 60% of patients [19].Dehydration, alkalosis due to loss of HCl, acidosis due to starvation, hypokalemia and weight loss (5%), or severe nausea and vomiting with a loss of more than 3 kg are generally considered the severe results of hyperemesis in pregnant women.Severe symptoms occur in 0.3-3% of pregnancies [20].There is a spectrum of abnormal thyroid dysfunctions that result from pregnancy.In the first and early second trimesters of pregnancy, b-hCG levels increase rapidly in early pregnancy and peak during the tenth week of pregnancy [2] and play an important role in the deterioration of thyroid functions, with its weak thyrotropic activity.This point may be supported by the increase in hyperemesis rates in twin pregnancies as a result of a faster increase in b-hCG levels.Goodwin et al. [16] reported that 66% of patients with HEG have biochemical hyperthyroidism and the cause of the hyperthyroidism may be related to hyperemesis itself.
Besides the functional changes, the size of the thyroid gland and hormone production increase during pregnancy [21].There are several factors that are associated with thyroid volume.The most common is low iodine intake resulting an increase in volume and a decrease in TSH levels [16,21,22].This point may have a role in our results because low iodine intake may be one of the outputs in patients with low HEI scores.Iodine level is not routinely evaluated thus we could  not discuss such an association in this study.Another probable factor for increased thyroid volume is the high body mass/BMI [7].We determined a range of BMI to avoid the effect of obesity and conducted this study in BMI-matched patients.Nutritional habits may also be related to thyroid volume.Similar with iodine, low selenium, low vitamin A, iron deficiency, and low intake of proteins [9][10][11][12][13] may be the results of low HEI scores.This may also be one of the points that may support our hypothesis.Mechanisms triggering food intake by thyroid hormones have not been fully elucidated yet [3,23,24].Food intake is regulated by neuropeptides that respond to peripheral satiety signals, such as leptin, ghrelin, and adiponectin.It is assumed that leptin signals the brain for satiety and increases thermogenesis.In thyrotoxicosis, experiments with animal models have shown that leptin levels decrease and increase hyperphagia [25,26].Another mechanism may be related to an increase in TSH values due to HEI resulting in thyroid volume increase.Oppositely patients with larger thyroid volume have lower TSH levels in our study and also the most remarkable association was between HEI scores and thyroid volume.
The data in our study showed that thyroid volume increases as the HEI score decreases, and among the mechanisms to support this theory, the leptin level may be increased secondary to iodothyronine deiodinase enzyme activity in peripheral tissues.The mechanism that supports our hypothesis is that low leptin levels, which have also been shown in animal models, decrease TRH expression and suppress TSH independently of circulating free thyroid hormone levels [27].In our study, in our patients with thyroid volume measurement above the cutoff value; free T4 was normal and TSH was significantly low.Although TSH and serum T4 levels are usually normal within 24-48 h of fasting, which we know theoretically, the free T3 level decreases [28].As we know in theory, our data are compatible with free T4 and free T3 values, but the fact that our TSH levels are significantly low suggests that a different mechanism is involved in the background.For this reason, we think that further research is needed.
As the strength of our work, thyroid volume measurements are made by a single radiologist.Our study and control groups are homogeneous, and healthy nutrition index evaluations are made to all patients face-to-face by the same dietitian.Also, to our knowledge, this is the first study evaluating the relationship between nutritional status and thyroid volume in HEG patients.Limitations of the study were considered as the lack of serum iodine and thyroglobulin measurements, lack of evaluation of thyroid volumes after the nutrition improved, and lack of thyroid volume/HEI relationship between the 6th and 11th gestational weeks.

Conclusions
In our study, we found that there may be an increase in thyroid volume in pregnant women with HEG with lower TSH levels and eating scores.Thyroid volume may predict the patients with probable eating disorders and further studies on thyroid volume in patients with HEG may contribute to the literature.

Table 2 .
The patient characteristics and thyroid values according to the HEI scores.

Table 3 .
The association between thyroid volume and other parameters.