Thyroid hormone profile in preeclampsia patients: a case control study

Abstract

Objective: Preeclamptic women are reported to have a higher incidence of thyroid dysfunction that correlates with the severity of preeclampsia. The aim of this study was to assess thyroid hormone profiles in in pregnant women with preeclampsia and gestational hypertension and the risk for thyroid dysfunction.

Methods: In this study, age-matched pregnant females in the second trimester of pregnancy, diagnosed with preeclampsia (PE), gestational hypertension (GH), as cases, and apparently healthy normotensive (NT) pregnant woman as controls were recruited. Blood samples were drawn for the assessment of thyroid hormone (TSH, FT3 and FT4) levels and thyroid dysfunction.

Results: Out of the total of 133 pregnant women recruited for this study, sub-clinical hypothyroidism was the only thyroid dysfunction common to all study groups, with a prevalence of 3.3% in both PE and NT groups, and 4.3% in the GH group. 1% of women in the PE group had sub-clinical hyperthyroidism, compared to 3.3% in the NT group. Although TSH and FT3 were elevated in normotensives, mean differences between the three groups were not statistically significant. However, mean FT4 levels in the GH group (12.99 ± 1.24) and PE group (12.33 ± 2.26), when compared to the control group (11.55 ± 1.94), were significantly higher (p < 0.05).

Conclusion: Undiagnosed subclinical hypothyroidism was found in all the categories of pregnant women studied, which if uncontrolled, could increase the risk of pregnancy-related complications, especially in pregnant women with preeclampsia and gestational hypertension.

Keywords:

• TSH
• FT3
• FT4
• Preeclampsia
• thyroid dysfunction
• gestational hypertension

Introduction

Preeclampsia (PE), is a pregnancy specific syndrome described as new-onset, or worsening of existing hypertension (blood pressure [BP] > 140/90 mm Hg), with significant proteinuria (> 300 mg/24 h) after 20 weeks of gestation and/or maternal end organ damage [1].

Hypertensive disorders in pregnancy (HDP), including preeclampsia remain an important cause of maternal and perinatal morbidity and mortality in low resource countries [2]. Preeclampsia is the most severe form of HDP, affecting approximately 3–8% of pregnant women [2,3]. In Ghana, preeclampsia prevalence is approximately 8% whilst gestational hypertension accounts for about 10% [4,5]. Although the preeclampsia presents with the classic symptoms of hypertension and proteinuria, the pathological process(es) leading to this syndrome, begin early in the first trimester. Currently, clinical prediction of preeclampsia and its outcome is poor and unreliable. Thyroid dysfunction constitutes one of the commonest endocrine disorders during pregnancy, after diabetes mellitus [6], and has been associated with preeclampsia. Changes in levels of T4 and T3 during pregnancy largely result from the effect of various factors, such as elevation of thyroid-binding globulin (TBG) due to stimulation from estrogen, and human chorionic gonadotropin (HCG), increased renal losses of iodine due to increased glomerular filtration rate, modifications in the peripheral metabolism of maternal thyroid hormones, and modifications in iodine transfer of placenta [7]. Since maternal T3 does not cross the placenta, the fetus is dependent on trans-placental transfer of maternal T4, especially during the first trimester of pregnancy [8]. Adverse fetal outcomes at all stages of pregnancy, including prematurity, low birth weight, increased neonatal respiratory distress, and fetal thyroid abnormalities, may justify screening for thyroid function in pregnancy. The mechanism of thyroid dysfunction in preeclampsia is unclear, but has largely been attributed to an imbalance of vasoactive factors and the ensuing oxidative stress at the uteroplacental implantation site [9,10]. Considering that pregnancy induced changes in thyroid function can present an obstetric challenge in low resource settings, and the lack of data on thyroid hormone status in Ghanaians with complicated pregnancies, this study was carried out to determine thyroid hormone status in women with preeclampsia, and gestational hypertension, and the occurrence of thyroid dysfunction.

Materials and methods

Study design and recruitment of participants

This case-control study was conducted over a 12-month period, from July 2019 to June 2020 at the Maternity Unit of the Korle-Bu Teaching Hospital (KBTH), the leading national referral Center in Ghana. Inclusion criteria consisted of pregnant women diagnosed with preeclampsia and gestational hypertension. In this study, preeclampsia was defined as the occurrence of new onset hypertension (blood pressure ≥140/90 mm Hg), measured on two occasions, four hours apart, arising after 20 weeks’ gestation and or proteinuria, evidence of maternal acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia, and/or fetal growth restriction. Proteinuria was defined as ≥1+ by urine dipstick analysis. Gestational hypertension was defined as new onset of hypertension (blood pressure ≥140/90 mm Hg), arising after 20 weeks of gestation with no proteinuria or maternal target organ dysfunction (1). Controls were healthy normotensive pregnant women, matched for age, socio-demographic status, and gestational age, without any chronic disorders or previous hypertension in pregnancy. Women were excluded from the cases and controls if they had twins, or had previous history of thyroid disease during pregnancy or the postpartum period, renal disease, diabetes and any other endocrinopathies, liver disease, or were on medication that would affect thyroid function. After signing an informed consent, the socio-demographic and medical history were taken from the cases and controls using a standard questionnaire.

TSH, FT3 and FT4 estimation

Participants consented by endorsing a written consent form before samples were collected. A 5 ml venous fasting blood sample was collected from each participant, and dispensed into different sample tubes. Samples were processed for sera and stored at −80 °C until ready to be used. ELISA assay kits for TSH, FT3 and FT4 were purchased from Centronic GMbH (Kleinfeld, Germany). The manufacturer’s protocol was followed for all tests and absorbance read with GloMax® Discover Microplate Reader GM3000 (Promega Corporation Madison, USA). All study participants were categorized into various thyroid dysfunction groups based on results.

Ethical consideration

Institutional ethics approval was given by the Ethical and Protocol Review Committee of the College of Health Sciences (CHS), University of Ghana, with approval number SBAHS-MLS./10563848/SA/2018/2019.

Statistical analysis

Statistical analysis was performed using GraphPad Prism version 8.0.2. Continuous variables were presented as mean and standard deviation (mean ± SD). Student t-test was used to compare two mean values and ANOVA for three or more values. Categorical data including hypertension prevalence and thyroid dysfunction were presented in percentages. p-value less than 0.05 was considered statistically significant.

Results

General characteristics of the study population are presented in Table 1. Differences in age and gestational age between the groups were not statistically significant (p > 0.05). Body mass index (BMI) was significantly raised in the PE patients and gestational hypertensives (GH) than the normotensive individuals (p < 0.0001). PE patients that showed parity greater than 2, and gravidity greater than 3 were more than the respective proportions of the normotensives. Participants diagnosed with gestational hypertension showed gravidity greater than 3. Table 2 shows the clinical parameters of the participants. Systolic and diastolic blood pressures, as well as heart rate, were significantly higher in PE and gestational hypertension subjects than in the normotensive group (p < 0.0001). However, the mean differences of these haemodynamic parameters between the PE and GH groups were not statistically significant (p > 0.05). Thyroid hormone profiles of the study participants is presented in Table 3. Multiple comparison analysis of TSH and FT3 levels between PE, GH participants and normotensive pregnant women showed that these levels were not significantly different (p > 0.05). The GH participants had significantly higher elevated FT4 levels, when compared to the normotensive pregnant women group (p < 0.05). Prevalence of thyroid dysfunction among the participants is shown in Table 4. The vast majority of women were euthyroid. The most commonly observed thyroid dysfunction in all the study groups was sub- clinical hypothyroidism, with prevalence of 3.3%, for % PE and normotensive group, and 4.3% for the GH group. 10% of PE participants had sub-clinical hyperthyroidism.

Table 1. General characteristics of study participants.

Variables	Preeclampsia (N = 52)	Gestational hypertension (GH) (N = 23)	Normotensives (N = 58)
Age (yrs)	33.19 ± 5.61	34.17 ± 5.84	32.08 ± 2.58
Gest. age (wks)	29.15 ± 6.86	31.43 ± 5.41	28.17 ± 6.51
BMI (Kg/m2)	32.62 ± 6.43*	36.42 ± 6.96***	29.58 ± 4.19
Parity n (%)
0	15 (28.8)	3 (13.0)	16 (27.6)
1	13 (25.0)	3 (13.0)	23 (39.7)
2	13 (25.0)	7 (30.4)	13 (22.4)
> 2	11 (21.2)	10 (43.5)	6 (10.3)
Gravidity: n (%)
1	6 (11.5)	1 (4.3)	21 (36.2)
2	13 (25.0)	4 (17.4)	14 (24.1)
3	12 (23.1)	4 (17.4)	6 (10.3)
> 3	21 (40.4)	18 (78.3)	17 (29.3)

BMI = body mass index, Gest. age = gestational age, *Unemployed include students. *Preeclampsia = patients with blood pressure ≥ 140/90 mmHg and with urine protein. Gestational hypertension = pregnant women diagnosed with high blood pressure (pressure ≥ 140/90 mmHg) but no urine protein. Normotensives = Pregnant women with normal blood pressure and undetected urine protein. PE and GH are compared with the normotensives.

Table 2. Clinical characteristics of participants.

Variables	Preeclampsia (PE) (N = 52)	Gestational hypertension (GH) (N = 23)	Normotensives (NT) (N = 58)	p-value
SBP (mmHg)	152.21 ± 10.06***	148.34 ± 14.10***	116.71 ± 11.76	< 0.0001
DBP (mmHg)	97.48 ± 9.13***	95.17 ± 8.44***	72.67 ± 8.31	< 0.0001
Pulse (bpm)	92.46 ± 14.07***	93.17 ± 12.68***	80.01 ± 7.01	< 0.0001
Proteinuria: n (%)
+	45 (86.5)	–	–
++	7 (13.5)	–	–

SBP = systolic blood pressure, DBP = diastolic blood pressure. Result is presented as mean ± standard deviation. PE and GH are compared with the normotensives. +1 = urine protein of about 300 mg/24 h. *p < 0.05, **p < 0.01, ***p < 0.0001.

Table 3. Thyroid hormone profiles of study participants.

Variables	Preeclampsia (N = 30)	Gestational hypertension (N = 23)	Normotensives (N = 30)	p-value
TSH (μIU/ml)	2.58 ± 0.98	2.44 ± 1.18	2.79 ± 0.63	0.630
FT3 (pmpl//l)	4.07 ± 0.75	4.16 ± 0.45	4.21 ± 0.92	0.7676
FT4 (pmpl//l)	12.33 ± 2.26	12.99 ± 1.24*	11.55 ± 1.94	0.0272

N = sample size, TSH = thyroid stimulating hormone, FT3 = free triiodothyronine, FT4 = thyroxine. TSH normal range: 0.53–5.50 μIU/ml, FT3 normal range: 2.8–7.3 pmpl//l, FT4 normal range: 8.5–22.5 pmol/l. Result is presented as mean ± standard deviation. ^Δ Compared with other categories, mean difference is statistically significant. Kruskal–Wallis test was used to compare TSH values. *p < 0.05 was considered statistically significant.

Table 4. Thyroid dysfunction prevalence among study participants.

Thyroid dysfunction classification	Preeclampsia (N = 30)	Gestational hypertension (N = 23)	Normotensives (N = 30)
Sub-clinical hypothyroidism n (%)	1 (3.3)	1 (4.3)	1 (3.3)
Primary hypothyroidism n (%)	0 (0.0)	0 (0.0)	0 (0.0)
Sub-clinical hyperthyroidism n (%)	3 (10.0)	0 (0.0)	1 (3.3)
Primary hyperthyroidism n (%)	0 (0.0)	0 (0.0)	0 (0.0)

N = sample size, TSH normal range: 0.53–5.50 μIU/ml, FT3 normal range: 2.8–7.3 pmpl//l, FT4 normal range: 8.5–22.5 pmol/l. Sub-clinical hypothyroidism: when TSH is higher than 5.60 IU/ml, FT3 and FT4 within normal range. Primary hypothyroidism: when TSH is greater than 5.60 μIU/ml, FT3 and FT4 less than normal. Sub-clinical hyperthyroidism: when TSH is less than 0.53 μIU/ml, FT3 and FT4 within normal range. Primary hyperthyroidism: when TSH is less than 0.53 μIU/ml, FT3 and FT4 higher than normal.

Discussion

From our study, mean TSH and FT3 levels were highest in the normotensive group, but not statistically significant when compared to levels in the pre-eclampsia (PE) and gestational hypertension (GH) groups. Our results are at variance with other studies, which have demonstrated significantly higher serum TSH in preeclamptics, compared to normotensive mothers [11,12]. However, another study with severe preeclampsia patients reported no significant difference in the levels of FT4, FT3 and TSH between PE patients and healthy normotensives in various gestational age subgroups [14]. It is noteworthy to observe that most of such studies have predominantly been in Asian populations. Therefore, the observed differences could be due to population differences in serum TSH levels, which may arise from nutritional/dietary habits, and genetic differences, or inter-assay variability. Serum TSH values have been known to drop, as a result of altered thyrotrophic activity, induced by elevated circulating hCG concentrations, predominantly towards the end of the 1st trimester [13].

Therefore, reduction in serum TSH concentration during the first trimester in response to hCG elevation, which has been reported to occur in at least 20% of healthy pregnant women, may just be a transient lowering of TSH levels during gestation [15]. Mean FT4 was highest in the PE group, and significantly different from levels in the other groups. Some studies that have reported reduced serum FT4 in preeclampsia [13,14]. Yet still, other studies have observed no significant difference in serum levels of FT4 between PE and normotensive women [12,16]. We observed no significant difference in the mean levels of FT3 among the three study groups. This is in agreement with some studies, where no significant difference was found in serum FT3 levels between preeclamptic patients and healthy pregnant mothers [14,16]. Whereas most women in our study were euthyroid, the frequency of thyroid dysfunction in the PE study group was 3.3% and 10.0% for sub-clinical hypothyroidism and sub-clinical hyperthyroidism, respectively, whereas 4.3% of women with GH were classified as having sub-clinical hypothyroidism. Whilst the reasons for the relatively lower incidence of thyroid dysfunction are not exactly clear, it could be due to the small sample size for this study, among other factors such as ethnicity and environmental factors. Notwithstanding the debate over the clinical significance of subclinical thyroid dysfunction, it can have repercussions, such as progression to overt thyroid dysfunction. The potential cardiovascular risk in subclinical thyroid disease is an important factor that can affect decisions about the screening and treatment of patients [17].

Conclusion

Our findings show although majority of pregnant women were euthyroid, subclinical hypothyroidism and subclinical hyperthyroidism are likely to occur in preeclampsia, with subclinical hyperthyroidism, likely to occur more frequently. Furthermore, the incidence of biochemical subclinical hypothyroidism in preeclampsia may not necessarily be higher when compared to normotensive pregnant women.

Limitations of this study

1. Thyroid hormones were measured at the time of diagnosis but not at advanced stages of the disease/progression of pregnancy. The adoption of a single point evaluation of thyroid hormones was a limiting factor, as single point evaluation of thyroid hormones may give erroneous scenarios of thyroid dysfunction when the euthyroid state might exist.

2. Thyroid antibodies (TG-Ab and I PO-Ab) testing was not done due to limited funding. This could have led to inclusion of pregnant mothers with early thyroid disease in the control group despite rigorous screening.

3. The small sample size was a limiting factor.

What is already known about the subject?

1. The physiological changes in the thyroid gland during pregnancy are well understood but only a few reports have provided information about thyroid function in complicated pregnancies.

2. Many studied have compared of serum levels of Tri-iodothyronine (T3), Thyroxine (T4), and Thyroid-Stimulating Hormone (TSH) in only preeclampsia and normal pregnancy.

What does the study add?

This study evaluated thyroid hormonal profile in cases of preeclampsia and gestational hypertension in the first trimester of pregnancy. This study is the first preliminary report of alterations in thyroid function in cases of preeclampsia and gestational hypertension in a Ghanaian population.

Authors’ contributions

NAA, EAT, BAB and KAB conceived and designed the study. EAT and HA performed the experiments. KAB provided clinical support and supervision. Data were analyzed by EAT and NAA. NAA, EAT, KAB and BAB contributed reagents and materials. KAB and EAT contributed to writing the paper, with major contributions from NAA. All authors read and approved the final manuscript.

Consent for publication

All of the authors have read and approved the paper for publication.

Acknowledgements

The authors would like to acknowledge clinical and technical support received from staff of the Department of Medical Laboratory Sciences of the School of Biomedical and Allied Health Sciences, and the Departments of Medical Biochemistry and Obstetrics and Gynaecology, University of Ghana Medical School (UGMS), Korle-Bu.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

This work was funded by individual contributions from the authors.