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Indian Journal of Medical Sciences, Vol. 59, No. 2, February, 2005, pp. 57-63 Original Article Maternal thyroid hormonal status in preeclampsia Kumar Ashok, Ghosh B.K., Murthy N.S. Department of Obstetrics and Gynaecology, Maulana Azad Medical College, Associated Lok Nayak Hospital, New Delhi - 110 002 Code Number: ms05010 Abstract BACKGROUND: The physiological changes in the thyroid gland during pregnancy are well understood but only a few reports provide information about thyroid function in complicated pregnancies. KEYWORDS: Hypothyroidism, preeclampsia, pregnancy and thyroid hormones INTRODUCTION Preeclampsia and eclampsia are still an important cause of maternal and perinatal morbidity and mortality in the developing countries. Although pregnancy is usually associated with very mild hyperthyroxinemia, preeclamptic women have high incidence of hypothyroidism that might correlate with the severity of preeclampsia.[1],[2],[3] On the other hand, preeclampsia has also been observed in 16.7% of sub-clinical cases and 43.7% of overt cases of hypothyroidism during pregnancy.[4] The mechanism of hypothyroidism in preeclamptic women has not been identified but the changes in thyroid function during pregnancy are accounted for by high circulating estrogens.[5] There are controversies about the mechanism and clinical significance of low concentrations of thyroid hormones in preeclampsia, which are attributed to decreased plasma protein concentrations [2] and high levels of endothelin,[6] a potent vasoconstrictor produced by vascular endothelium after a vascular injury. The obstetricians are increasingly becoming aware of the potential or adverse effects of hypothyroidism on the outcome of pregnancy and have a high index of suspicion. The present study examines the thyroid hormonal levels in pregnant women with preeclampsia in the third trimester.MATERIALS AND METHODS The study period was from July 2001 to December 2002. Eighty-two pregnant women consecutively admitted with the diagnosis of preeclampsia in the third trimester were recruited for the study. The inclusion criteria were: (a) all consecutively diagnosed cases of preeclampsia, (b) no previous history of thyroid disease through pregnancy and the postpartum period and (c) no previous history of congenitally malformed baby.The study adopted a case-control approach. An equal number of age (±1 year) and gestation (±1 week)-matched healthy normotensive pregnant women in the third trimester attending the antenatal clinic during the study period, constituted the control group. The development of hypertension any time during antenatal follow-up excluded them from the control group. The exclusion criteria for both the groups were: (a) history of any metabolic disorder before or during the pregnancy, (b) history of intake of any medication that might affect thyroid function, (c) history of renal disease, and (d) history of hypertension. Women in both groups had singleton pregnancies and were residing in Delhi and nearby surrounding areas for at least 5 years. All subjects belonged to the low or middle-income group. Informed consent was given by each woman. The study was approved by the departmental review committee. In an Indian study, the mean TSH titers in preeclamptic pregnancy has been reported to be 3.8 + 0.53 mIU/ml while in normal pregnancy, it was 2.3 + 0.24 mIU/ml.[7] Based on it, the sample size for the study worked out to be approximately 25 subjects in each group to estimate the statistically significant difference in mean TSH values. To adjust for the confounding effects of the factors such as gestation at the time of diagnosis of preeclampsia and at delivery, and birth weight of the newborn, nearly 80 women with preeclampsia were required. Preeclampsia as defined by the National High Blood Pressure Education Program Working Group, was diagnosed in the hospital as a blood pressure of 140/90 mmHg or more on two or more occasions, 6 hours apart, after 20 weeks of gestation and the presence of proteinuria (which was diagnosed when a reading of 1+ or more, on the uristix, was found in repeated clean catch midstream urine sample) and / or edema.[8] Ten ml venous blood sample was taken from the cubital vein of (i) preeclamptic women, after the diagnosis was made but before the initiation of the antihypertensive treatment, and before the delivery and (ii) each control subject as mentioned above. All samples were sent to the laboratory with different code numbers, which were deciphered at the time of the analysis of data by the third author. Sera was separated and stored at -20oC until assayed. Free T3 (triiodothyronine), free T4 (thyroxine) and TSH (thyroid-stimulating hormone) were measured using radioimmunoassay (Clinical Assays GammaCoat FreeT3, T4, RIA kit, IRMA kit - DiaSorin, USA ). All women were followed up through their antenatal, intrapartum and postpartum period. They were especially observed for the development of the symptoms and signs of hypothyroidism. The data was tabulated and analyzed. All the quantitative parameters were expressed as mean with standard deviation (mean + SD) in both groups. To test for the differences in the mean values between the two groups for various quantitative parameters, Student′s t-test was applied when the data followed the normal approximation. If the data was skewed, nonparametric (Mann-Whitney) test was applied. Differences in the proportions between different categorical variables (mode of delivery, dichotomous levels of TSH < 5 mIU/ml and > 5 mIU/ml) were tested through Chi-square test of significance. Statistical significance was considered as P<0.05. To quantify the association between TSH and preeclampsia, odds ratio along with 95% CI (confidence interval) were estimated for TSH levels. To understand the relationship between two quantitatively measured variables, simple correlation coefficient was estimated and tested for its significance using ′t′ test. RESULTS A total of 164 pregnant women were recruited in this case-control study. Of these, 82 women with the diagnosis of preeclampsia in the third trimester constituted the study group.The mean (± SD) age of the study group and control group was 28.4 ± 6.24 years and 27.5 ± 5.91 years respectively and there was no statistically significant difference between the two groups (P>0.05). The mean (± SD) gestational age at the time of taking the blood sample for thyroid hormonal levels was 34.3 ± 2.92 weeks in the study group and 35.1 ± 2.86 weeks in the control group. This corresponded with the time of diagnosing the preeclampsia in the study group. The difference between the two groups was not statistically significant (P=0.06). The preeclamptic women delivered at an earlier period of gestation (37.3 ± 1.17 weeks) as compared to the normotensive women (38.1 ± 1.12 weeks) (P<0.001; degree of freedom 162; mean difference ′-0.85′; 95% CI ′-1.20 to -0.50′). The mean birth weight (± SD) of the newborns in the study group was 2.5 ± 0.45 kg (kilogram) and 2.8 ± 0.41 kg in the control group (P<0.001; degree of freedom 162; mean difference ′-0.29′; 95% CI ′-0.43 to -0.16′). There were statistically significant differences between the two groups concerning gestational age and birth weight of the newborns. Seventy women belonging to the study group (85.4%) and 72 of the control group (87.8%) had vaginal mode of delivery. There was no difference in the mode of delivery between the two groups (P = 0.82). All babies were discharged alive and healthy from the hospital. At no time during the follow-up, did any of the study women have symptoms and clinical signs of hypothyroidism. The values of free T3, free T4 and TSH in the two groups are shown in [Table - 1]. The mean values of thyroid hormones were within the normal laboratory reference ranges in both the groups. The mean FT3 and FT4 titers were not significantly different in the two groups ( FT3: P = 0.24; FT4 : P = 0.25). The mean TSH value was significantly higher in the preeclamptic women than that of controls (P < 0.001; degree of freedom 162; mean difference 2.08; 95% CI 1.17 to 2.98). The values of TSH corresponding to the first quartile in the study group and in controls were 1.75 and 1.04 while those corresponding to the third quartile were 7.16 and 3.47 respectively. The inter-quartile range for the study and control group was 5.91 and 2.44 respectively. Out of 82 pregnant women in each group, 33 (40.2%) women in the preeclamptic study group and 10 (12.2%) in the control group had abnormal TSH titers (> 5 mIU/ml). Thirty-three (76.7%) of the 43 pregnant women with abnormal TSH titers, had the diagnosis of preeclampsia whereas only 49 (40.5%) of the 121 pregnant women with normal TSH titers, had preeclampsia in the third trimester [Table - 2]. This difference between the two groups is found to be statistically significant (p < 0.001;degree of freedom 1; 95% CI 2.06 to 11.65). The odds ratio corresponding to TSH levels > 5 mIU/ml in the study group compared to the control group, was 4.85 (95% confidence interval 2.19-10.74). Thus, TSH was found to be a strong associating factor for the occurrence of preeclampsia. When correlation coefficients were computed between the thyroid hormonal levels and gestation at the time of diagnosis of preeclampsia, gestational age at the time of delivery of newborns and birth weight of newborns respectively, no statistically significant correlation could be elicited either in the study group or in the control group [Table - 3]. Hence, no adjustments were made with these confounding factors for eliciting the association between preeclampsia and TSH levels. DISCUSSION A recent report of 27 women with severe preeclampsia from Jordan found that there was no significant difference in the levels of FT4, FT3 and TSH between the preeclamptic patients and healthy controls in the various gestational age subgroups.[9]In the present study, only mean TSH is significantly increased in preeclamptic patients at the time of diagnosis as compared to control subjects. Free T3 and free T4 were comparable in both the groups. Our findings supported the reports that preeclamptic women had higher incidence of biochemical hypothyroidism compared with normotensive pregnant women.[1],[2],[3],[6] The mechanism of it in these preeclamptic women is not well understood. Mild alteration in the thyroid hormones might occur due to non-thyroidal illness acting as a stress factor as well as due to decreased plasma albumin concentrations in these patients.[10],[11] Serum total T3 (TT3) and TT4 were decreased significantly and TSH was increased significantly in preeclamptic women in their third trimester.[1],[2],[3],[6],[12] Higher levels of FT4 and TT4 along with lower levels of TT3 and FT3 were observed in toxemic patients compared to normal pregnant women.[13] The titers of FT3 are reported to be significantly related to the decreased plasma albumin concentration in preeclamptic women.[2] It has been suggested that reduced serum concentrations of thyroid hormones in toxemia may be due to the loss of protein and protein-bound hormones in the urine.[3] Modest decreases in thyroid hormones with concomitant increases in TSH levels in maternal serum correlated with severity of preeclampsia or eclampsia and high levels of endothelin.[6] The endothelial cell dysfunction plays an important role in the pathogenesis of preeclampsia. Nitric oxide, a vasodilator released from the endothelial cells, regulates secretion of thyroid hormones by modulating regional blood flow. Animal studies showed that the release of nitric oxide is altered in hypothyroidism.[13] Reduced serum concentrations of thyroxine binding globulin (TBG), T3 and T4 may also be explained by the faulty estrogen production due to placental dysfunction in preeclamptic women.[2] FT4 concentration is not related to plasma albumin. The decrease in thyroid hormones with concomitant increase in TSH titers has been found to be correlated with the severity of preeclampsia.[1],[2],[12] The finding of normal T3 and T4 titers in our study may be due to the fact that the blood sample was taken just at the time of diagnosis of preeclampsia. It is possible that low titers of T3 and T4 along with high TSH titers would be observed at a later stage of preeclampsia (i.e. with severe disease and low plasma albumin levels). TT4, TT3, serum albumin and thyroid antibodies were not measured in these study women. It is unlikely that preeclamptic patients had autoimmune hypothyroidism because the abnormal TSH titers were not very high and all of them were normal when examined 6 weeks postpartum. It has also been observed that preeclamptic and eclamptic women with higher TSH levels along with lower thyroid hormones were more likely to have small for gestation newborns.[1],[2],[3] TT4 and TT3 concentrations in preeclamptic and eclamptic women correlated positively with the birth weight of their infants.[3],[6] Lao et al observed a negative correlation between the birth weight of the infants and TSH levels in preeclamptic patients.[2] We could not find any correlation between the birth weight of the newborn and maternal FT3, FT4 and TSH levels. The difference in the number of pregnant women of the two groups, having high TSH titers was also significant. More number of preeclamptic women had abnormally high TSH levels at the time of diagnosis when compared with normotensive pregnant women. A statistically significant higher number of cases with preeclampsia (76.7%) were also observed in pregnant women with abnormally high levels of TSH. Diseases of the thyroid gland itself are a predisposing factor for the development of preeclampsia.[14] If the titers of TSH are above 5 mIU/ml, then there is 4.8 times higher risk of the development of preeclampsia. This high-risk potential marker of preeclampsia needs further investigation because of the small number of subjects in this study. A multi-centric study may answer the association and mechanism of thyroid abnormality in preeclamptic women in terms of the geographical variation. Therefore, identification of thyroid abnormalities and appropriate measures might affect the occurrence and severity of the morbidity and mortality associated with preeclampsia. References
Copyright 2005 - Indian Journal of Medical Sciences The following images related to this document are available:Photo images[ms05010t1.jpg] [ms05010t2.jpg] [ms05010t3.jpg] |
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![[Table - 2]](/showimage?ms/photo/ms05010t2.jpg){kind=link}
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