Antithyroid Autoantibodies in Unexplained Recurrent Abortion

Abstract

Objective :To determine whether thyroid auto-antibodies (Thyroglobulin and Thyroid peroxidas antibodies) could be used as a marker for detection of abortion in cases with unexplained recurrent abortion.

Design: Clinical study.

Setting: Al-Hussein University Hospital and Kafr El-Zyat District Hospital

Patients: Fifty healthy euthyroid pregnant women with history of unexplained recurrent (>=3 recurrent abortion) abortion during the first trimester.

Interventions: Follow-up of all patients till 20^th week of pregnancy. None of the patients received any medication. Serum tested for thyroid autoantibodies (TG-AB, Tpo-AB), thyroid function (FT3, FT4, TSH). Ultrasound scan of thyroid gland were performed for all patients during the first trimester.

Main Outcome: Positive cases for thyroid autoantibodies (TG-Ab,TPO-Ab) and number of abortions.

Results Out of 50 cases 18 (36%) were positive for either one or both antibodies. 14 (77.7%)were positive for TG-Ab. 9 (50% ) were positive for TPO-Ab.and 5 (27.7%) were positive for both antibodies.

Abortion rate among antibody positive patients was 66.67% (12 out of 18) while abortion rate among antibody negative patients was 15.63% (5 out of 32), this is statistically significant p<0.001.

Tpo-Ab positivity was found to have the best specificity (93.94%) and the best positive predictive value (77.78%) while TG-Ab positivity showed the best sensitivity (58.82%) and best negative predictive value (80.56%).

Combination of both antibodies as predictor of abortion showed a sensitivity of 70.59%, specificity of 81.82%, positive predictive value of 66.67% and negative predictive value of 84.38%.

The study showed also a significant association between antibody positivity and maternal age, number of previous abortions and volume of thyroid gland.

Conclusion: Thyroid autoantibodies can serve as a useful marker for cases with unexplained recurrent abortion.

Introduction

Spontaneous abortion is the most common complication of pregnancy with the majority of loss occurring prior to the first missed menses.

Recurrent abortion is defined as the occurrence of three or more consecutive spontaneous abortions prior to 20^th week of gestation, it occurs in 0.5 to 1 % (1).

The cause of recurrent abortion is unexplained in up to 60% of studied couples (2).

Because the acceptance of the fetal allograft within the uterus remains one of the major physiologic response to pregnancy, the immune system has long been thought to be responsible for many miscarriages (3). In particular, the Lupus anticoagulant has been associated with an increased abortion rate, even in women who did not present with systemic lupus erythmatosus (4). Furthermore, recent studies have shown the presence of numerous autoantibodies in women who are habitual aborters (5,6).

The relationship of autoimmune thyroid disease to pregnancy has been the object of considerable interest with the recognition of the postpartum thyroid disease syndrome (7,8). Thyroid autoantobodies have been shown to be a useful markers in predicting women at risk for clinical miscarriage (9,10).

Thyroid peroxidase (Tpo) is a glycoprotein with molecular weight of 100-107KD present on the thyroid cell surface and is important antigenic target in autoimmune thyroid disease. It is responsible for the Iodination of tyrosine residues on thyroglobulin (TG) and the intramolecular coupling reaction of Iodinated tyrosins leading to the formation of thyroxine (T4) and triiodiothyronine (T3).

Thyroglobuline (TG) is a large glycoprotein dimer (each subunit is 330KD) which is synthesized and secreted by the cell membrane. It is Iodinated on tyrosin residues by thyroid peroxidase. Basal production of thyroid hormones results from pinocytosis of Iodinated TG and hydrolysis by lysosomal enzymes. Post-translation modifications, together with the degree of TG Iodination, are important determinate of the immunogenicity of the TG molecule (10).

The aim of this work is to test the value of measuring thyroid antibodies,TG-Ab, andTpo-A, as predictor of abortion in those women with history of recurrent unexplained recurrent abortion.

 
Patients and Method

Fifty healthy pregnant women during the first trimester with history of unexplained recurrent abortion were selected from the outpatient clinic at Al-Hussein University Hospital and Kafr El-Zyat District Hospital. All patients were previously proved to have no medical problems, clinically all were euthyroid. Toxoplasmosis, Cytomegalovirus, Lupus anticoagulants and VDRL were all negative. They had no explanation for their recurrent abortion.

All selected women were subjected to the following investigations:

• Thyroglobulin antibodies (TG-Ab) and thyroperoxidase (Tpo-Ab) by ELISA Technique (Hermann Biermann Gmbh, Diagnostica, Germany) (12)
• Free tetraiodothyronin (FT4), Free triiodothyronin (FT3), and thyroid stimulating hormone (TSH) by RIA Technique (Diagnostic Products Corporation DPC,USA) (13)

All patients had thyroid scan by ultrasound. Follow-up for all patients till 20^th week of gestation was done. Cases with abortion were reported and the status of thyroid antibody positivity was evaluated. Data expressed as mean ±SD were analyzed using Chi square test, Student t-test and Fisher's exact test when appropriate.

Sensitivity, specificity, positive predictive value and negative predictive value were used for evaluation of thyroid autoantibodies positivity as predictors of abortion (14).

 
Results

Positivity for TG-Ab was determined at serum level of 250 IU/ml, and for Tpo-Ab positivity at 125 IU/ml.

Out of 50 pregnant women during the first trimester 18 (36%) were positive for either one or both antibodies.

Among the antibody positive cases 14 (77.7%) were positive for TG-Ab, with mean levels (± SD) of 1447± 469 IU/ml, 9 (50%) cases were positive for Tpo-Ab with mean levels ( ±SD) of 215 ±62.5 IU/ml, and 5 (27.7%) were positive for both antibodies.

Thyroid function tests were within normal in both antibody positive and antibody negative patients with no significant difference between them with regard to FT4, FT3, and TSH. There was significant differences between volume of thyroid gland in antibody positive and antibody negative patients (23.88± 3.05ml vs 19.34± 4.49) respectively.

Out of 18 cases with antibody positivity 12 (66.6%) cases had spontaneous abortion while 5 cases (15.6%) out of 32 women with antibody negative tests were aborted. The difference between number of abortions was highly significant p<0.001. (table 1).

With regard to TG-Ab positivity 10 (77.7%) women were aborted and 4 (28.5%) continued pregnancy passed 20^th week. The mean (± SD) levels of TG-Ab were significantly higher in aborters (1782± 489 vs 1277.345 IU/ml) p<0.001.

The association between TG-Ab positivity and abortion was significant, p<0.001, sensitivity was 58.82%, specificity was 87.88%, positive predictive value was 71.43% and negative predictive value was 80.56%. (table 2)

With regard to Tpo-Ab positivity 7 (77.7%) out of 9 cases aborted and 2 (22.3%) continued pregnancy. The difference was significant p<0.001. The mean (± SD) for aborters was significantly higher than non aborters ( 164.82 ±20.4 vs 133.39 ±22.2 IU/ml) p<0.001.

Sensitivity of Tpo-Ab in prediction of abortion was 41.18%%, specificity was 93.94%, positive predictive value was 77.78% and negative predictive value was 75.61%. (table 3)

When positivity for both antibodies used as predictor for abortion the sensitivity was 70.59%, specificity was 81.82%, positive predictive value was 66.6% and negative predictive value was 84.38%.

The study showed a significant differences in mean age of cases with antibody positive and antibody negative with those with antibody positive tests having older age (33.1±4.7 years vs 29± 4.3 years) p<o.o1 (table 1).

Also there was significance difference between the number of previous abortion in antibody positive and antibody negative cases (5.06± 1.68 vs 3.84± 1.19)p<0.05. (table 1).

The study showed also a significant difference between thyroid volume in cases with antibody positive and antibody negative (23.88 3.05ml vs 19.34 4.49 ml) p<0.001. (table 1). There was no association between antibody positivity and time of abortion.

Discussion

Predicting women suffering from recurrent abortion who are at risk for subsequent abortion remains a challenge. The early identification of such women may eventually provide the opportunity for intervention and prevention (7).

The incidence of antibody positivity was significantly higher in aborters than in nonaborters (66.6% vs 15.6%), so an association between thyroid autoantibodies and increased risk of spontaneous abortion can be suggested . The higher the levels of antithyroid autoantibodies the higher the abortion rate. (table 1) This association have been found to be highly significant in present study p<0.001. These findings are in agreement with previous reports who suggested such assumption (15,10,16,17).

Although Esplin et al (19) showed that no difference in positivity for antithyroid antibodies in nonpregnant women with and without history of recurrent abortion. Wilson et al (20) showed that thyroid peroxidase titers and avidity was significantly higher in women with recurrent abortion who later miscarried compared to women with recurrent abortion whose pregnancies continued and showed that the titer and avidity declined in those who continue to term. Also Roberts et al (21) showed that women with recurrent miscarriage had a higher incidence of thyroid antibodies suggesting an association between autoimmunity and recurrent miscarriage.

Several mechanisms have been suggested to explain the role of thyroid autoantibodies in recurrent abortion:

1-They may affect the maternal thyroid gland

In the present study there was no significant association between antibody positivity and abnormal thyroid function, which supports the study done by Lejeone et al (9).

2-They may cross the placenta and can affect the fetus where 40% of neonates born to mothers with elevated Tpo-Ab titers at birth. All newborn were euthyroid at birth and had normal TSH levels on the fifth day of life. However, the potential importance of the presence of elevated Tpo-Ab titers, passively transmitted from the mother remains to be clarified (15). They also can affect the maternal gestational tissues like antiphospholipid antibodies which causes decidual vascularity and placental insufficiency (22).

3-The thyroid autoantibodies may be the result rather than the cause of recurrent pregnancy loss. This can happen as a consequence of early immune interaction resulting in rejection of the fetus (18)

4-An interaction exists between thyrotopin-like hormones produced by human placenta (Human Chorionic Gonadotrophin and Human Chorionic Thyrotrophin) and the thyroid autoantibodies resulting in early pregnancy loss (17).

5-Increased risk of chromosomal abnormalities such as Down's syndrome, where thyroid autoantibodies have been considered a risk factor for meiotic non-dysjunction. However, no association between maternal thyroid autoantibodies and fetal chromosomal abnormality has been found (23).

6-Antithyroid antibodies reflect generalized activation of the immune system. Stagnaro-Green et al (18) suggested that the autoantibodies are secondary markers of autoimmune risk rather than specific causative factors. However, the role of thyroid autoantibody positivity as a causative factor of abortion, still need more explanation.

In the present study thyroid function was not different in antibody positive and antibody negative cases, although a possible influence of mild degree of thyroid insufficiency on incidence of abortion was suggested (18). It was reported that thyroid antibody positivity often has diminished functional thyroid reserve (15).

Table 1

 Antithyroid antibody positive and negative cases

N=number NS..not significant

Table 2

TG-AB positivity and number of abortions

Antibody

Number Aborted

Non-aborted number

10

4

Fisher's exact test P<0.001

Table 3

Tpo-Ab positivity and number of abortion 

Antibody

7

2

10

31

17

33

Fisher's exact test p<0.001

Table 4

TG-Ab and Tpo-Ab positivity and number of abortions

Number Aborted

Nonaborted number

12

6

5

27

17

33

P<0.001

References:

References

1. Alberman E. The epidemiology of repeated abortion. In: Early pregnancy loss mechanisms and treatment. Sharp F and Beard RW (eds) Royal Collage of Obstetrician and Gynecologist, London;1988:9-17

2. Stray-Pederson B and Stray-Pederson S. Etiological factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion, Am.J.Obstet.Gynecol. 1984;148:140-146.

3. Davies LE; Lucas MJ; Ilankins GDV; Roark ML and Cummingham FG. Thyrotoxicosis complicating pregnancy. Am.J.Obstet.Gynecol.1989;160:63-70.

4. Knapp RG;and Miller MC. Defining normality using the predictive value method. In: Clinical Epidemiology and Biostatistics. National Medical Series., Mass Publishing Co.1992:53-60

5. Harris EN. Syndrome of the black Swan. Br.J Theumatol.71:421-427.

6. Laros RK and Sweet RL. Management of idiopathic thrombocytopenic purpura during pregnancy. Am.J.Obstet.Gynecol 1975;122:182-190.

7. Branch DW and Scott JR. Clinical implications of antiphospholipid antibodies: The Utah experience. In: Phospholipid-binding antibodies. Harris EN, Exner T., Hughes GRV and Asherson R. (ed Boca Raton. Fla:CRC press 1990.)

8. Dewolf F.; Carreras CO and Moermann P. Decidual vasculopathy and extensive placental infraction in a patients with repeated thromboembolic accidents, recurrent fetal loss and a lupus anticoagulant. Am.J.Obstet.Gynecol 1982;141:829-835.

9. Lejeune B; Grum JP; DeNayer P; Servais G. and Glinoer D. Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension. Br.J Obstet.Gynecol.1993;85:837.

10. Pratt DE; Karande V; Kaber Lein G and Gleicher N. The association of Antithyroid antibodies in euthyroid non pregnant women with recurrent first trimester abortion in the next pregnancy. Fertil. Steril. 1993;63:277-281.

11. Davis TE; Martin A; and Graves P. Human autoimmune thyroid disease: cellular and molecular aspects. Clin.Endocrin. and Metab. 1988;2(4):911-12.

12. Czarnocka B; Ruf J and Ferrand M. Purification of the human thyroid peroxides and its identification as the microsomal antigen involved in autoimmune thyroid disease. FEBS 1985;10

13. Biogos ST. Clinical use of serum TSH measurements in hyperestogenized states. Ligand Quarterly 1979;2:22-23.

14. Knapp RG and Miller MC. Defining normality using the predictive value method. In: Clinical Epidemiology and Biostatistics. National Medical Series., Mass Publishing Co.1992:53-60.

15. Glinor D; Soto MF and Bour Doux P. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussion,. J.Clin.Endocrinol.Metab. 1991;71:421-427.

16. Singh A; Danta ZN; Stones SC and Asch EH. Presence of thyroid antibodies in early reproductive failure. Biochemical versus clinical pregnancies. Fertil Steril.1995;63:277-81.

17. Stagnaro-Green A; Roman SH; Cobin RH and Davis TF. Detection of at-risk pregnancy by means of a highly sensitive assay for thyroid autoantibodies. JAMA 1990; 264:1422-23.

18. Esplin MS; Branch DW; Silver Rand Stagnaro-Green A. Thyroid autoantibodies are not associated with recurrent pregnancy loss. Am.J. Obstet.Gynecol.1998;179(6pt.1):1583-6

19. Wilson R, Lingh; MacLean MA; Mooney J; Kinnane D; Mckillop JH; Walker JJ . Thyroid antibody titer and avidity in patients with recurrent miscarriage. Fertil. Steril 1999; 71(3):558-61.

20. Roberts J; Jenkins C; Wilson R; Pearson C; Franklin IA; MacLean MA; McKillop JH; Walker JJ. Recurrent miscarriage is associated with increased number of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies. Eur.J Endocrinol 1996;134(1):84-6.

21. Branch DW and Scott JR. Autoimmunity and pregnancy loss. JAMA 1990;246:1453-54. Kennedy RL; Jones TEI; and Cuckle HS. Down’s syndrome and thyroid. Clin.Endocrinol. 1992;37:471-476.

22. Cowchock FS; Smith JB. Predictors for live birth after unexplained spontaneous abortions: correlation between immunologic tests, results, obstetric histories, and outcome of next pregnancy without treatment. Am.J.Obstet.Gynecol 1992;167(5):1208-12.

23. Quenby SM; Farquharson RG. Predicting recurring miscarriage: what is important? Obstet. Gynecol. 1993;82(1):132-8.