|Year : 2018 | Volume
| Issue : 2 | Page : 241-245
Thyroid-stimulating hormone in pregnancy: are we in need of a lower cutoff value?
Mahmoud F Midan1, Khaled N Elfayoumy2, Walaa M El-Bassiony1, Ahmad A Al-Metwally1
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt
|Date of Submission||29-Apr-2018|
|Date of Acceptance||31-May-2018|
|Date of Web Publication||17-Aug-2018|
Dr. Khaled N Elfayoumy
Internal Medicine Department, New Damietta Faculty of Medicine, Al-Azhar University Hospital, Almegawra 6, New Damitta, 34517
Source of Support: None, Conflict of Interest: None
Background No consensus has been reached regarding the normal range of thyroid-stimulating hormone (TSH) in the first trimester of pregnancy.
Aim To determine the effect of TSH levels and thyroid peroxidase antibody (TPOAb) positivity on miscarriage outcome among Egyptian euthyroid women.
Materials and methods The study was a prospective case–control study conducted at Al-Azhar University Hospital in New Damietta. It included 80 newly-diagnosed pregnant euthyroid women: 40 women with unexplained recurrent miscarriage, assigned as group 1 (subdivided into two subgroups according to the presence of TPOAb), and a control; group of 40 randomly selected fertile pregnant women who had no history of miscarriage, assigned as group 2. Free T4, TSH, and TPOAb assays were performed at 8-week gestational age. We followed all cases periodically every 4 weeks and when necessary.
Results The study revealed significant higher frequency of positive TPOAb in group 1 than group 2 (P=0.045). During the study observation, miscarriage occurred more than two-fold higher in group 1 than group 2 (17.5 vs. 7.5%, respectively, P=0.176) but was significantly higher among TPOAb positive than TPOAb negative women within group 1 (54.5 vs. 3.4% respectively, P<0.001). Interestingly, 75% of cases who were positive for TPOAb and at the same time had a family history of autoimmune thyroid disease were aborted. In group 1, there was a positive correlation between TSH and TPOAb titer (P=025), and abortion occurred more frequently with TSH more than 2.5 mU/l (P=0.021).
Conclusion TPOAb is a useful marker for identifying the risk for miscarriage among Egyptian euthyroid women. The risk was augmented when TSH exceeded 2.5 mU/l in the first trimester of pregnancy, and in the presence of family history of autoimmune thyroid disease.
Keywords: euthyroid women, pregnancy, recurrent miscarriage, thyroid peroxidase antibody, thyroid-stimulating hormone
|How to cite this article:|
Midan MF, Elfayoumy KN, El-Bassiony WM, Al-Metwally AA. Thyroid-stimulating hormone in pregnancy: are we in need of a lower cutoff value?. Benha Med J 2018;35:241-5
|How to cite this URL:|
Midan MF, Elfayoumy KN, El-Bassiony WM, Al-Metwally AA. Thyroid-stimulating hormone in pregnancy: are we in need of a lower cutoff value?. Benha Med J [serial online] 2018 [cited 2018 Nov 19];35:241-5. Available from: http://www.bmfj.eg.net/text.asp?2018/35/2/241/239202
| Introduction|| |
Antithyroid antibodies are frequently encountered in childbearing-age women but, unfortunately associated with adverse pregnancy outcomes including recurrent miscarriage (RM) ,,. From the other view, at least one-fifth of women with spontaneous abortion are positive for antithyroid antibodies .
On the contrary, there is an association between thyroid-stimulating hormone (TSH) levels during early pregnancy and the risk of abortion . In addition, TSH levels have a positive correlation with thyroid perioxidase antibody (TPOAb) titers in euthyroid pregnant women . Therefore, the definition of normal TSH during pregnancy is changing, and no consensus has been achieved till now. Negro et al.  suggested 2.5 mIU/l to be the cutoff value for TSH during the first trimester of pregnancy. The American Thyroid Association, however, recommended antecedent evaluation of thyroid function and TPOAb status in different regions to determine this value .
Our region (Damietta) is a coastal area in northern Egypt where people used to take a lot of iodine-supplemented salt in addition to sea food. In spite of poor statistical data, we noticed increasing frequency of autoimmune thyroid disease (AITD) (Elfayoumy KN, unpublished observations).
The aim of this study was to investigate the relationship between TPOAb and TSH concentrations in the early pregnancy, and to determine their effect on the miscarriage outcome among euthyroid Egyptian women who had experienced RM.
| Materials and methods|| |
All procedures were in accordance with the standards of the 1964 Helsinki Declaration and its later amendments of ethical standards. All women gave written informed consent for utilization of their data.
The study was a prospective case–control study. It included 80 newly diagnosed pregnant women of two groups:
Group 1 included 40 women with unexplained RM attended the outpatient clinic of Al-Azhar University Hospital in New Damietta between December 2015 and September 2016, and met the inclusion and exclusion criteria of the study. They were subdivided into two subgroups: group 1a included 11 cases with positive TPOAb, and group 1b included the other 29 cases with negative TPOAb. Cases in group 1 were also stratified as having TSH ≥2.5 mU/l or <2.5 mU/l.
Group 2 included 40 randomly selected healthy fertile women who did not have a history of miscarriage, as a control group.
Women with thyroid dysfunctions or under treatment of chronic diseases were excluded from the study. Those with history of induced abortion, or having cervical incompetence or any other uterine pathology were also excluded. Finally, patients having chromosomal anomalies or having any autoimmune diseases, or positive for anticardiolipin antibody or lupus anticoagulant, were excluded too.
All cases had normal TSH and FT4 concentrations. The upper reference limit used for TSH was 4.0 mU/l. RM was defined as two or more consecutive spontaneous abortions.
Recruited women were integrated before 8-week gestation, and followed every 4 weeks. Clinical pregnancy was confirmed by the presence of a gestational sac and fetal heart beat at 8-week gestation. Obstetric ultrasonography was repeated at 18 week, then once monthly till 28 week. None of the women received adjuvant treatment, such as thyroid hormones, glucocorticoids, or anticoagulants during the study.
FT4, TSH, and TPOAb assays were performed at 8-week gestational age by a solid-phase, competitive chemiluminescent enzyme immunoassay on IMMULITE system (Siemens Medical Solutions Diagnostics Technical Services Department, Tarrytown, NY, USA).
Reference ranges for TSH and FT4 were 0.4–4.0 mIU/l and 10.3–23 pmol/l, respectively. Levels of TPOAb at least 35 UI/ml were considered positive.
Statistical analysis of data
The collected data were organized, tabulated, and statistically analyzed using statistical package for the social sciences (SPSS) version 19 (SPSS Inc., Chicago, Illinois, USA), running on IBM compatible computer. For quantitative data, mean and SD were calculated. For qualitative data, frequency and percent distributions were calculated. For comparison between categorical groups, Fisher’s exact test was used. Statistical significant difference was considered at P value less than 0.05.
| Results|| |
Background patient characteristics
The age, parity, and FT4 were nearly comparable between both the groups, with no statistically significant difference. However, BMI was significantly higher in group 1. Moreover, in that group, there were six (15%) cases with a family history of AITD of either Graves’ disease or Hashimoto thyroiditis. Conversely, women in group 2 had no family history suggestive of thyroid or other autoimmune diseases ([Table 1]). The mean frequency of RM in group 1 was 2.85±1.2.
The frequency of cases having positive TPOAb was more likely (P=0.045) among group 1 than controls. Moreover, TPOAb titer had significant difference (P<0.001) between the main groups. Mean TSH values were nonsignificantly higher in groups 1 (P=0.262) ([Table 1]). Meanwhile, TSH correlated positively with both TPOAb titer and the number of previous consecutive miscarriage in group 1 (r=0.324, P=0.025 and r=0.417, P=0.007, respectively) ([Figure 1]).
|Figure 1 Correlation between TPOAb titer and TSH level in group 1. TPOAb thyroid peroxidase; TSH, thyroid stimulating hormone.|
Click here to view
In relation to thyroid peroxidase antibody
Miscarriage outcome was more than double-fold higher (17.5 vs. 7.5%) among group 1 than group 2, but it did not reach significance (P=0.176). Interestingly, in the presence of positive TPOAb, it was nearly comparable (54.5 vs. 50%) ([Table 2]). In general, 80% of aborted women had TPOAb positivity, and specifically in group 1, miscarriage was significantly higher in subgroup 1a (P<001) ([Table 3]).
In relation to the presence of family history of autoimmune thyroid diseases
Of four cases having family history of AITD in subgroup 1a, three women were aborted. The other two cases (with the same history) in subgroup 1b, however, completed pregnancy safely ([Table 2] and [Table 3]).
In relation to thyroid-stimulating hormone values
In group 1, of the 16 cases having TSH values more than 2.5 m IU/l, five of them were aborted (P=0.021).
| Discussion|| |
Thyroid antibodies are detected in more than 15% of ‘healthy’ women . Nevertheless, there are questions regarding the clinical significance of low levels of TPOAb, and whether the term healthy is still convenient and right. Over the past two decades, there is rise in knowledge relating TPOAb to the increased incidence of abortion and infertility, and TPOAb titer was shown to correlate positively with TSH levels in the euthyroid women ,,,. Therefore, the normative range for TSH values in the first trimester of pregnancy remains an area of controversy.
Our results revealed significantly higher frequency of TPOAb among women with RM (group 1) with respect to that found in the control group (P=0.045). Moreover, TPOAb ‘titer’ was significantly higher among the first group (P<0.001).
On following our cases throughout their current pregnancies, we recorded the prevalence of TPOAb to be 80% among the women aborted during the observation in both groups. On comparing the main groups, the number of abortions was nonsignificantly higher among group 1 than group 2 (17.5 vs. 7.5% respectively, P=0.176). In the presence of TPOAb, however, abortion outcome was nearly comparable (54.5 vs. 50%, respectively). Meanwhile, and specifically in group 1, abortion outcome was significantly worse in TPOAb positive than TPOAb negative women (54.5 vs. 3.4, respectively, P<0.001).
The results of our observation are consistent with those reported by Stagnaro-Green et al.  and Zhong et al. , keeping in mind that the last author was following in-vitro fertilization and embryo transfer. Moreover, increased prevalence of TPOAb among women with history of RM has been widely demonstrated ,,,.
Nevertheless, there are some exceptions that did not find any significant associations between TPOAb positivity and RM; these exceptions came from the studies of Yan et al.  and Esplin et al. . The small number of patients with positive TPOAb in the former, whereas the extremely high prevalence of TPOAb positive controls of the latter may have affected their results.
Therefore, the association between TPOAb and miscarriage becomes more or less clear. The underlying mechanism, however, is not established yet. Matalon et al.  and Zhong et al.  suggested potential mild hypothyroidism in ATA positive women resulting in inadequate thyroid response to the increased demand during pregnancy.
More recent studies explained that women with ATA have increased migration of cytotoxic natural killer cells. Those cells directly target placental antigens, thus disturbing the immune and hormonal response of the uterus ,.
In the present study, 15% of patients (six cases) in group 1 had positive family history of AITD of either Graves’ or Hashimoto’s thyroiditis. Two-thirds of them had positive TPOAb. Interestingly, abortion outcome was high (50%) among those six women. All those women with abortion were positive for TPOAb. In other words, 75% of cases who were positive for TPOAb and at the same time had family history of AITD had abortion. Conversely, participants in the control group had no family history of AITD.
The association between positive family history of AITD and miscarriage among women in group 1 may have different explanations; first, the presence of family members with AITD could be potentially a predictor of upcoming thyroid disorders for their relatives. Second, both studied patients and their family members may share common genetic disorders or expose to the same environmental factors ,.
In present study, women aborted during observation had a mean TSH level of 2.75±1.03, P=0.059. In group 1, the mean TSH level was 2.92±1.07, and abortion occurred more frequently when TSH more than 2.5 mU/ml (P=0.021), and the latter had positive correlation with TPOAb titer (r=0.324, P=0.025).
Furthermore, TSH correlated also with the number of consecutive abortions in group 1 (r=0.417, P=0.007).
The adverse effect of TPOAb on pregnancy outcome is magnified by associated higher TSH values in euthyroid women ,,.
This link may be attributed to mild thyroid hypofunction mediated by TPOAb in pregnant women ,. So, TPOAb positive women may get benefit when treated with levothyroxine (LT4) in early pregnancy, even when biochemically euthyroid ,.
Now, the current question is, do we need a lower TSH cutoff level in newly pregnant Egyptian women with positive TPOAb? Can the positive family history of AITD affect our decision? In other words, can pregnancy outcome be improved by LT4 substitution in such cases?
Some authors recommend LT4 supplementation for euthyroid women with RM who are positive for TPOAb ,. Others, showed that empirical LT4 therapy for such cases did not improve the obstetrical outcome. We are not certain, however, if this controversy is related to population difference or environmental factors.
The strength of the present study is in its retrospective plus prospective observations. Weakness of this study came from the homogeneity of the population from northern Egypt. Moreover, there were significant differences regarding age and weight of included women between groups.
| Conclusion|| |
TPOAb proved to be a useful marker for identifying the risk for miscarriage in Egyptian euthyroid women. The risk was augmented when TSH exceeds 2.5 mU/l in the first trimester of pregnancy, and in the presence of positive family history of AITD. Well-designed randomized trials are required to recommend the administration of empirical LT4 therapy for euthyroid women with TPOAb positivity, and TSH levels more than 2.5 mU/l.
The authors appreciate the help of Professor Tarek Emran; professor of Clinical Pathology, Al-Azhar University, New Damietta. They are also gratefully thank Dr Mohammad Aboelmaaty for his skillful assistance in statistical analysis.
Mahmoud F. Midan contributed for concept and design of the study, and critical revision of the manuscript. Khaled N. Elfayoumy contributed for interpretation and analysis of data and, drafting and critical revision of the manuscript. Walaa M. El-Bassiony contributed for acquisition and interpretation of data, and critical revision of the manuscript. Ahmad A. Al-Metwally contributed for acquisition of data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Stagnaro-Green A, Roman SH, Cobin RH, El-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264:1422–1425.
McElduff A, Morris J. Thyroid function tests and thyroid autoantibodies in an unselected population of women undergoing first trimester screening for aneuploidy. Aust N Z J Obstet Gynaecol 2008; 48:478–480.
Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004; 150:751–755.
Kutteh WH, Yetman DL, Carr AC, Beck LA, Scott RT Jr. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction. Fertil Steril. 1999; 71:843–848.
Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160:985–991.
Prummel MF, Wiersinga WM. Thyroid peroxidase autoantibodies in euthyroid subjects. Best Pract Res Clin Endocrinol Metab 2005; 19:1–15.
Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95:E44–E48
Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C et al.
Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017; 27:315–389.
Sinclair D. Analytical aspects of thyroid antibodies estimation. Autoimmunity 2008; 41:46–54.
Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003; 9:149–161.
Stagnaro-Green A. Optimal care of the pregnant woman with thyroid disease. J Clin Endocrinol Metab 2012; 97:2619–2622
Strieder TG, Prummel MF, Tijssen JG, Endert E, Wiersinga WM. Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxf) 2003; 59:396–401.
Zhong YP, Ying Y, Wu HT, Zhou CQ, Xu YW, Wang Q et al.
Relationship between antithyroid antibody and pregnancy outcome following in vitro fertilization and embryo transfer. Int J Med Sci. 2012; 9:121–125
Singh A, Dantas ZN, Stone SC, Asch RH. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. Fertil Steril 1995; 63:277–281.
Yan J, Sripada S, Saravelos SH, Chen ZJ, Egner W, Li TC. Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy. Fertili and Steril 2012; 98:378–382.
Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol 2011; 66:452–459.
Esplin MS, Branch DW, Silver R, Stagnaro-Green A. Thyroid autoantibodies are not associated with recurrent pregnancy loss. Am J Obstet Gynecol 1998; 179(Pt 1): 1583–1586
Matalon ST, Blank M, Ornoy A, Shoenfeld Y. The association between anti-thyroid antibodies and pregnancy loss. Am J Reprod Immunol 2001; 45:72–77.
Twig G, Shina A, Amital H, Shoenfeld Y. Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity. J Autoimmun 2012; 38:J275–J281.
Triggianese P, Perricone C, Conigliaro P, Chimenti MS, Perricone R, De Carolis C. Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure. Int J Immunopathol Pharmacol 2016; 29:65–75.
Manji N, Carr-Smith JD, Boelaert K, Allahabadia A, Armitage M, Chatterjee VK et al.
Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab 2006; 91:4873–4880.
Liu H, Shan Z, Li C, Mao J, Xie X, Wang W et al.
Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study. Thyroid 2014; 24:1642–1649.
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91:2587–2591.
Lepoutre T, Debiève F, Gruson D, Daumerie C. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Gynecol Obstet Invest 2012; 74:265–273.
Stagnaro-Green A, Glinoer D. Thyroid autoimmunity and the risk of miscarriage. Best Pract Res Clin Endocrinol Metab 2004;18: 167–181.
Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 2011; 9:d2616.
[Table 1], [Table 2], [Table 3]