|Year : 2017 | Volume
| Issue : 2 | Page : 68-73
Thyroid hormone status in preeclampsia patients: A case–control study
Nineetha Muraleedharan1, Jessy Sumangala Janardhanan2
1 Department of Biochemistry, SUT Academy of Medical Sciences, Thiruvananthapuram, Kerala, India
2 Department of Biochemistry, Government Medical College, Thrissur, Kerala, India
|Date of Web Publication||7-Aug-2017|
Mayookham, T.C.9/2040(2), Sasthamangalam P.O., Thiruvananthapuram - 695 010, Kerala
Source of Support: None, Conflict of Interest: None
Context: Preeclampsia (PE) is a common complication of pregnancy associated with high morbidity. Antiangiogenic factors are raised in PE, which may affect thyroid secretion. Aims: The aim of this study was to determine the association between thyroid hormonal status in PE and the severity of PE and also any correlation between albumin levels and thyroid status. Materials and Methods: Cases include forty women between 30 and 38 weeks of gestation with PE. Forty healthy normotensive pregnant women in third trimester constituted the control group. Thyroid profile (free triiodothyronine [FT3], triiodothyronine [T3], free thyroxine [FT4], thyroxine [T4], and thyroid stimulating hormone [TSH]) was measured by enzyme-linked immunosorbent assay technique. Analysis and Results: Mean, median, standard deviation for quantitative variables were compared by Student's t-test. Percentage values were compared using Chi-square test. ANOVA tests and post hoc analysis were done. Odds ratio was used to assess risk for hypothyroidism. TSH was significantly high in PE (3.76 ± 1.55) than controls (2.30 ± 0.94 mIU/L). Mean FT3 in PE was 2.12 ± 0.55 and in controls was 2.43 ± 0.47 pg/ml. FT4 in cases was 1.16 ± 0.24 and in controls was 1.33 ± 0.27 ng/dL, suggestive of hypothyroidism. The mean serum albumin was significantly lesser (3.11 ± 0.39 g/dL) in PE. Conclusion: Preeclamptics had 11 times, severe preeclamptics 31.5 times while mild preeclamptics had five times more risk for hypothyroidism. Risks for hypothyroidism increase with the severity of PE.
Keywords: Free thyroxine, free triiodothyronine, hypothyroidism, preeclampsia, thyroid-stimulating hormone, thyroxine, triiodothyronine
|How to cite this article:|
Muraleedharan N, Janardhanan JS. Thyroid hormone status in preeclampsia patients: A case–control study. Muller J Med Sci Res 2017;8:68-73
|How to cite this URL:|
Muraleedharan N, Janardhanan JS. Thyroid hormone status in preeclampsia patients: A case–control study. Muller J Med Sci Res [serial online] 2017 [cited 2018 Mar 23];8:68-73. Available from: http://www.mjmsr.net/text.asp?2017/8/2/68/212415
| Introduction|| |
Preeclampsia (PE) is a common complication of pregnancy associated with increased morbidity and mortality in mother and fetus. Its incidence in India is 1.5%. Even though pregnancy is usually associated with mild hyperthyroxinemia,, recently Basbug et al., Sardana et al., and Kumar et al. have detected a high incidence of biochemical hypothyroidism in PE.
Although the actual cause is unclear, various hypotheses link this decrease in thyroid hormones with a decrease in plasma protein or an increase in antiangiogenic factors,,, associated with PE. Hypothyroidism in PE can cause morbidities in mother and growth retardation, intrauterine death, or congenital hypothyroidism in the fetus. Whether these outcomes are affected by maternal thyroid status in the initial or in the late gestation are unclear.
Previous studies have tested either free or total hormones, but the results have been controversial. Qublan et al. and Khadem et al. have even reported negative results. Hence, the present study aims to test the complete thyroid profile in PE patients and normal pregnant ladies to find out how the severity of PE could influence the thyroid hormone levels. Similar previous study has not been done so far in Kerala.
| Materials and Methods|| |
This is a case–control study involving a total sample size of eighty, wherein forty are cases and forty are controls. Cases include pregnant women with PE as defined by blood pressure ≥ 140/90 mmHg and minimal proteinuria in a pregnant women after 20th week of gestation. The controls include normal pregnant women without PE. This study was done at Department of Biochemistry and the Department of Obstetrics and Gynaecology of Medical College, Thiruvananthapuram, during a period of 1 year.
Patients were classified as severe PE according to the diagnostic criteria for severe PE as given in review of literature., The rest of cases were classified as having mild PE. Participants with elevated thyroid-stimulating hormone (TSH) (>3.5 mIU/L) with FT4 within expected limits (0.8–2 ng/dL) were classified as having subclinical hypothyroidism in this study.,, Those having elevated TSH with low FT4 were classified as overt hypothyroidism.
All preeclamptics without previous history of any thyroid disease or congenitally malformed baby were included in the study. Those having any history of metabolic disorders and on medication that affects thyroid function, hypertension, renal disease were excluded from the study. Equal number of healthy normotensive pregnant women in third trimester attending the antenatal clinic during the study period constituted the control group.
This study was conducted after getting the clearance from the Ethical Committee (IEC no: January 30, 2012). The details of patients were recorded in pro forma after getting their informed consent. In addition, details of symptoms suggesting severe PE (headache with visual disturbances, epigastric pain, etc.,) were noted. Abnormal laboratory results such as those in liver or renal function tests were also recorded.
Five millilitre of venous blood sample was taken from the median cubital vein. Blood was collected in polypropylene tubes. Specimens were centrifuged at 3000 rpm for 10 min to obtain serum. The isolated serum was stored at −20°C until use. All the chemicals and reagents used in the study were of analytical grade. Thyroid profile (free triiodothyronine [FT3], triiodothyronine [T3], free thyroxine [FT4], thyroxine [T4], and TSH) was measured using enzyme-linked immunosorbent assay (ELISA) AccuBind ELISA test kit as per guidelines and read in ELx 800MS, ERBA MICROSCAN ELISA machine. Serum albumin was measured by chemical method using fully automated ERBA XL 360 analyzer.
| Results|| |
Statistical analysis was performed using SPSS version 16 (SPSS Inc., Chicago, 2007). This study is of the case–control type, in which forty cases of PE and forty controls of normal pregnant women have participated. The mean and standard deviation for quantitative variables were calculated for the study population. Difference in percentage values was compared using Chi-square test or Fisher's t-test. Difference in the group means of quantitative variables was compared by Student's t-test. ANOVA tests were done to compare study parameters between severe PE, mild PE, and normal controls. Odds ratio (OR) was used to calculate risk for hypothyroidism among cases. Pearson's correlation coefficient was obtained to study correlation between thyroid hormonal values and albumin in cases. A P < 0.05 is considered to be statistically significant.
When we compared means of different variables between cases and controls [Table 1], the mean age of PE patients was 24.98 ± 2.8 and that of normal pregnant women was 24.5 ± 3 years. Mean gestational age of cases is 34.5 ± 2.6 and that of controls is 35.5 ± 2.5 weeks. There is no significant difference in age and gestational age between cases and controls. On comparing difference in parity, 26 out of 40 cases (PE patients) or 65% were primigravida and 23 out of 40 controls (normal pregnant) or 57.5% were primigravida. Rest were multigravida. This difference in parity was not significant (P = 0.491), according to Chi-square test. Hence, cases and control groups were comparable.
|Table 1: Comparison of means of general characteristics and different variables|
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Mean T3 (ng/mL) of cases is 1.28 ± 0.36 which is significantly lower than that of controls (1.62 ± 0.21) [Table 1]. Mean T4 (mg/dL) of cases is 11.59 ± 2.59 which is lower than controls (13.63 ± 1.92) (significance was not assessed for T4 since there was a wide gap between minimum and maximum values). Mean TSH (mIU/L) of cases (3.76 ± 1.55) was significantly higher than controls (2.3 ± 0.94). Mean FT3 (pg/mL) of cases (2.12 ± 0.55) was significantly lower than controls (2.43 ± 0.47). Mean FT4 (ng/dL) of cases (1.16 ± 0.24) was significantly lower than controls (1.33 ± 0.27). Mean serum albumin (g/dL) levels were significantly lower in cases (3.11 ± 0.39) than controls (3.7 ± 0.14).
Four out of 40 cases (10%) had low T3 while none of the controls had low T3 [Table 2] . Normal ranges that were followed in our lab during the study are provided in [Appendix 1]. Rest of the people among both groups had T3 within normal range (0.8–2 ng/mL). This difference was not significant according to Fisher's t-test (P = 0.116). Seventy-five percent of preeclamptics and 33% of normal pregnant have T4 values in the expected range (4.4–12.8 mg/dl). This difference was significant according to Chi-square test (P < 0.001) [Table 2]. High TSH (>3.5 mIU/L) was seen in majority of preeclamptics (55%) while 45% had TSH within normal range (0.1–3.5 mIU/L). However, 90% of controls had normal TSH. This difference was significant when Chi-square test was done (P < 0.001). PE patients were found to have 11 times greater risk for hypothyroidism (OR = 11.0, 95% confidence interval [CI] =3.292–36.751). 7.5% of PE patients had FT3 < 1.4 pg/mL. However, majority of cases (92.5%) and all of the controls had FT3 in the normal range. Fisher's test showed that the difference is not significant (P = 0.24). Five percent of PE patients and 2.5% of normal pregnant controls had FT4 < 0.8 ng/dL. However, majority of cases (95%) and controls (97.5%) had FT4 in normal range (0.8–2 ng/dL). The difference was not significant according to Chi-square test. 85% of the cases while none of the controls had albumin below 3.5 g/dl. Fisher's exact test showed a significant difference in percentage distribution of albumin among the two groups.
Forty cases were divided into severe PE (18) and mild PE (22) patients based on severity assessment criteria, [Table 3]. ANOVA was done to compare variables among three groups (severe PE, mild PE, and normal pregnant controls). Thyroid hormones were lower among severe PE compared to mild PE and normal pregnant ladies. This difference in T3, T4, FT3, and FT4 was significant according to ANOVA (P < 0.001 for T3, P = 0.001 for T4, P = 0.023 for FT3 and P = 0.006 for FT4). TSH of severe PE was higher than that of mild PE and normal pregnant. This difference in TSH was significant (P < 0.001). Serum albumin was lower in severe PE, compared to the other groups. There was significant difference among three groups (P < 0.001).
|Table 3: Comparison of means of different variables between mild preeclampsia, severe preeclampsia, and controls|
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Post hoc analysis/paired comparison [Table 4] showed significant lowering of T3 (P < 0.001) and T4 values (P = 0.002) of both severe and mild cases compared to normal pregnant. However, between severe and mild cases, there was no significant difference in T3 (P = 0.705) or T4 (P = 0.832). There was a significant decrease in FT3 (P = 0.01) and FT4 (P < 0.01) of severe cases when compared to controls. There was no significant difference in FT3 (P = 0.42) or FT4 (P = 0.129) between severe and mild cases or between mild cases and normal pregnant (FT3 [P = 0.067] and FT4 [P = 0.1]).
|Table 4: Post hoc analysis/paired comparison of different variables between severe preeclampsia, mild preeclampsia, and controls|
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Severe cases had higher TSH than mild cases and controls and the difference was statistically significant (P = 0.019 and 0.001, respectively). Even mild cases had significantly higher TSH than controls (P < 0.01).
When albumin was tested, the severe group did not have significantly decreased albumin compared to mild preeclamptics, (P = 0.06). However, both severe and mild preeclamptics had significantly lower values (P < 0.01) than normal pregnant ladies.
Out of 18 severe preeclamptic patients, 14 (78%) have hypothyroidism [Table 5]. Out of normal pregnant, 90% have TSH within normal limits. Chi-square test was done and the difference between % values was statistically significant (P < 0.01).
|Table 5: Association between preeclampsia and thyroid-stimulating hormone|
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Out of 22 mild preeclamptic patients, 8 (36%) have hypothyroidism. Chi-square test was done and the difference between % values is statistically significant (P < 0.05). The OR (risk ratio) for hypothyroidism among severe preeclamptics was 31.5 (95% CI = 6.909-143.619) and among mild PE was 5.143 (95% CI = 1.334–19.832), when compared to normal pregnant women [Table 5].
There is negative correlation of TSH with albumin [Table 6] and [Graph 1]. Positive correlation was seen only for FT4 with albumin. There is no statistical significance for the correlation between TFT and serum albumin among forty cases.
|Table 6: Correlation between serum albumin and thyroid profile of the study population|
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| Discussion|| |
In PE, there is an increase in antiangiogenic factors that decrease nitric oxide production. This in turn decreases thyroid capillary flow which could lead to hypothyroidism. In support of this hypothesis, we found a lower mean T3, T4, FT3, FT4 in PE. This decrease was significant except that of T4 (significance could not be assessed since there was a wide gap between minimum and maximum values). The percentage of preeclamptics with low thyroid hormones was not significantly high.
Basbug et al. reported a significant decrease in both total and free thyroid hormones. Tolino et al. and Sardana et al. found a significant decrease in T3. Tolino et al. and Lao et al. found a significant decrease in T4 in preeclamptic women. Significantly reduced FT4 in preeclamptics was reported by Lao et al. and Raoofi et al. Kumar et al. tested FT3 and FT4 only, but they were within the expected range. Qublan et al., Khadem et al., and Gulaboglu et al. did not get a significant decrease.
The mean TSH level in PE patients was significantly higher than normal pregnant. There was a significant percentage of cases (55%) with high TSH. We have found that PE patients have 11 times greater risk for hypothyroidism. Kumar et al. also reported significantly increased TSH. Levine et al. found TSH levels 2.42 times above baseline compared with a 1.48 times increase in controls. Qublan et al., Khadem et al., and Raoofi et al. did not find any significant result.
It was found that severe cases of PE had significantly lower T3, T4, fT3, and fT4 than normal pregnant ladies, but not when compared to mild cases. Sardana et al. also did not find a significant reduction in T3 and T4 between severe and mild cases. There was a significant decrease in T3 and T4 values even in mild cases of PE (but lowering of fT3 and fT4 was insignificant).
TSH was significantly higher in severe cases when compared to mild cases as well as normal pregnant. TSH was significantly higher even in mild cases when compared to normal pregnant. Lao et al. did not find a significant reduction in preeclamptics, but severe preeclamptics had significantly reduced TSH than mild preeclamptics. Tolino et al. and Lao et al. also found that TSH was increased significantly in severe compared to mild PE. Sardana et al. also reported similar result.
Thus, TSH could be used to predict the severity of PE. The T4 and T3 concentrations also reflect PE severity. Kumar et al. found positive relation between increase in TSH and severity of PE.
The mean albumin levels among PE patients were significantly lower than controls. 85% of preeclamptics had low albumin and this was significant. Both severe and mild preeclamptics had significantly lower albumin than the normal pregnant ladies, but the decrease in albumin in severe was insignificant compared to mild preeclamptics. However, Sardana et al. found significantly decreased albumin in severe preeclamptics compared to mild cases. Margarson et al. says that decrease in serum albumin in PE is correlated with the severity of the disease.
Among severe preeclamptics, a total of 78% had hypothyroidism. Among mild preeclamptic patients, a total of 36% had hypothyroidism. Severe preeclamptic patients had 31.5 times risk for hypothyroidism when compared to normal pregnant women. There was five times more risk for hypothyroidism among mild PE when compared to normal pregnant. However, as mentioned earlier, if one considers all preeclamptics together (severe and mild), they had 11 times greater risk than normal pregnant. Bankowska et al. observed thyroid dysfunction in 78% of pregnant women with PE. Kumar et al. found the OR in preeclamptic women as 4.85 (he had used cut off value of TSH as 5 instead of 3.5 mIU/mL).
Correlation studies were done between thyroid profile and serum albumin. A decrease in FT4 and increase in TSH correlated with a decrease in albumin, which was not statistically significant. Rest of the thyroid hormones did not have positive correlation with albumin. Sardana et al. observed that serum albumin levels showed a positive correlation with total thyroid hormones (but free hormones were not studied) and a negative correlation with TSH levels in PE. Lao et al. did not get correlation between TSH and albumin but observed that the thyroid hormones, with the exception of FT4, were correlated with the plasma albumin concentration in preeclamptic women.
The limitations of this study are that it does not follow-up the PE patients postdelivery to see if thyroid hormones return to normal nonpregnant levels or if the newborns are affected. In future, large-scale prospective studies or randomized control trials could describe the role of antiangiogenic factors in PE.
Thyroid profile could be checked in third trimester in preclampsia patients. The availability of low-cost thyroxine may reduce the associated morbidity in both mother and baby.
We are thankful for the general support given by Dr. M. Saboora Beegum as the HOD of Biochemistry, at the time of conducting this study.
We also thank Dr. C. Nirmala, who was the HOD of Obstetrics and Gynaecology at the same period for her support to conduct the study among the patients admitted in the ward. We thank Mr. Jayakumar P who helped us with the statistical work for this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kalra VB, Aggarwal A, Sareen PM, Kalra R. Histopathological changes in placenta in toxemia of pregnancy. J Obstet Gynecol India 1985;35:86-90.
Glinoer D. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33.
Fantz CR, Dagogo-Jack S, Ladenson JH, Gronowski AM. Thyroid function during pregnancy. Clin Chem 1999;45:2250-8.
Basbug M, Aygen E, Tayyar M, Tutus A, Kaya E, Oktem O. Correlation between maternal thyroid function tests and endothelin in preeclampsia-eclampsia. Obstet Gynecol 1999;94:551-5.
Sardana D, Nanda S, Kharb S. Thyroid hormones in pregnancy and preeclampsia. J Turk Ger Gynecol Assoc 2009;10:168-71.
Kumar A, Ghosh BK, Murthy NS. Maternal thyroid hormonal status in preeclampsia. Indian J Med Sci 2005;59:57-63.
] [Full text]
Eiland E, Nzerue C, Faulkner M. Preeclampsia 2012. J Pregnancy 2012;2012:586578.
Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007;96:1788-95.
Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, et al
. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 2006;290:H560-76.
Levine RJ, Vatten LJ, Horowitz GL, Qian C, Romundstad PR, Yu KF, et al
. Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: Nested case-control and population based study. BMJ 2009;339:b4336.
Vargas F, Montes R, Sabio JM, García-Estañ J. Role of nitric oxide in the systemic circulation of conscious hyper- and hypothyroid rats. Gen Pharmacol 1994;25:887-91.
Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid 2000;10:871-87.
Idris I, Srinivasan R, Simm A, Page RC. Maternal hypothyroidism in early and late gestation: Effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf) 2005;63:560-5.
Qublan HS, Al-Kaisi IJ, Hindawi IM, Hiasat MS, Awamleh I, Hamaideh AH, et al
. Severe pre-eclampsia and maternal thyroid function. J Obstet Gynaecol 2003;23:244-6.
Khadem N, Ayatollahi H, Vahid Roodsari F, Ayati S, Dalili E, Shahabian M, et al
. Comparison of serum levels of tri-iodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) in preeclampsia and normal pregnancy. Iran J Reprod Med 2012;10:47-52.
ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002;77:67-75.
Wagner LK. Diagnosis and management of preeclampsia. Am Fam Physician 2004;70:2317-24.
Berek JS, Novak E. Berek and Novak's Gynaecology: Endocrine disorders . 15th
ed . Philadelphia: Lippincott Williams and Wilkins; 2012. p. 1114.
Fritz MA, Speroff L. In Clinical Gynecologic Endocrinology and Infertility: Reproduction and the Thyroid. 8th
ed. Philadelphia: Lippincott Williams and Wilkins; 2011. p. 905.
Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al
. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125.
Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, et al
. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;165:2460-6.
Tolino A, de Conciliis B, Montemagno U. Thyroid hormones in the human pregnancy. Acta Obstet Gynecol Scand 1985;64:557-9.
Lao TT, Chin RK, Swaminathan R. Thyroid function in pre-eclampsia. Br J Obstet Gynaecol 1988;95:880-3.
Lao TT, Chin RK, Swaminathan R, Lam YM. Maternal thyroid hormones and outcome of pre-eclamptic pregnancies. Br J Obstet Gynaecol 1990;97:71-4.
Raoofi Z, Jalilian A, Shabani Zanjani M, Parvar SP, Parvar SP. Comparison of thyroid hormone levels between normal and preeclamptic pregnancies. Med J Islam Repub Iran 2014;28:1.
Gulaboglu M, Borekci B, Halici Z. Placental tissue iodine level and blood magnesium concentration in pre-eclamptic and normal pregnancy. Int J Gynaecol Obstet 2007;98:100-4.
Margarson MP, Soni N. Serum albumin: Touchstone or totem? Anaesthesia 1998;53:789-803.
Bankowska EM, Pawlowska A, Leibschang J. Thyroid function in pregnant women with pregnancy induced hypertension. Ginekol Pol 2003;74:1044-8.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]