Thyroid Autoimmunity, Infertility and Miscarriage

Abstract and Introduction

Abstract

Thyroid autoimmunity (TAI), infertility and miscarriage are currently issues of extreme interest that have attracted the attention of many investigators. Several papers have been published, focusing on women of childbearing age that include healthy women, women with recurrent miscarriage and those undergoing assisted conception. Most of these studies show a significant association between the presence of thyroid autoantibodies, infertility and a higher miscarriage rate. The underlying pathogenetic mechanisms, which might explain the association between TAI and infertility, remain speculative given the scarce information from animal models and from in vitro data addressing the potential effects of TAI on fertility. Adequate levels of circulating thyroid hormones are of primary importance for normal reproductive function and inadequate delivery of triiodothyronine to granulosa and stromal cells may disrupt normal female reproductive function. With regards to the association between TAI and miscarriage, a close relationship has been largely confirmed in recent studies. The aim of this review is to present the relevant information published so far in the literature regarding TAI and miscarriage in euthyroid female individuals.

Introduction

Autoimmune thyroid disorders are characterized by the presence of thyroid auto-antibodies (Abs), particularly thyroid peroxidase (TPO) autoAbs and anti-thyroglobulin (Tg) autoAbs. TPO is an enzyme responsible for iodination of tyrosine residues and coupling of iodinated residues to form thyroid hormones.^[1] Tg is a molecule produced by thyroid cells that is stored in the thyroid colloid. The primary function of Tg is the storage and synthesis of thyroid hormones. Thyroid autoAbs may be present in apparently healthy populations and are more frequently observed in women during their reproductive years.^[2]

Female causes account for 35% of infertility among couples. Assisted-reproduction technology encompasses in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). These techniques are often the ultimate options available to childless couples when all other treatments have proved unsuccessful. The live birth rate after one cycle of assisted-reproduction technology in women aged between 30 and 35 years is between 25 and 30%.^[3]

Thyroid autoimmunity (TAI) is the most common autoimmune disorder in women of reproductive age, with a prevalence varying between 5 and 15%. It is five- to ten-times more common in women than in men and can be present without thyroid dysfunction, thus remaining undiagnosed.^[3] The effects of estrogens in promoting autoimmunity, genetic factors and perhaps maternal microchimerism and chromosome X abnormalities, may potentially explain the high prevalence of TAI in women.

The relationship between autoimmune abnormalities and reproductive failure has been investigated extensively. Numerous studies have focused on TAI in infertile women. Interpretation of the available data is difficult for a variety of reasons, most notably because of the heterogeneity of the samples of women studied and the largely retrospective uncontrolled experimental design of the studies. Some variability among studies can be further explained by differences in sample size (generally small series), by differences in assays used to detect TAI and different geographical locations of the studies.^[3] Overall, however, the studies indicate an increased prevalence of TAI among women attending infertility clinics ( Table 1 ).

Pregnancy is associated with profound changes in thyroid function. The requirements for thyroid hormone increase, a process mediated by the direct thyrotropic effects of human chorionic gonadotropin (hCG), a rise in the binding capacity of serum (thyroxine binding globulin) and possibly alterations in the peripheral metabolism of thyroid hormones.^[4] Iodine excretion in the urine rises during pregnancy, accounting for the increase of thyroid volume in iodine-deficient areas.^[5] In early pregnancy, women with thyroid Abs have higher serum thyrotropin-stimulating hormone (TSH) levels compared with thyroid Ab-negative women, although the mean TSH levels may still fall within the normal range. These Ab-positive women are prone to develop subclinical or overt hypothyroidism during pregnancy^[6] owing to the reduced functional reserve of their thyroid, which is unable to compensate for the increased hormone requirement of pregnancy.^[7] As pregnancy progresses, a striking decrease in thyroid auto-Ab levels occurs, both in women with initially extremely elevated, and those with only modest elevations of, TPO Ab titers. At parturition, on average, TPO Ab titers are 60% lower than at the beginning of pregnancy.^[6]

Some diseases of the thyroid gland, such as hypothyroidism and hyperthyroidism, are associated with fetal loss.^[8,9] More recent studies have confirmed this association^[10,11] and linked TAI with recurrent abortions.^[12,13,14] The mechanism involved in the association between TAI and pregnancy loss is not clear. It is postulated that the presence of thyroid Abs reflects a generalized activation of the immune system and a heightened autoimmune state against the fetal–placental unit.^[14] It is known that immunological factors play an important role in the reproductive processes of fertilization, implantation and placental development.^[15] Women with thyroid Abs have abnormal T-cell function.^[16] Thyroid Abs may serve as peripheral markers for abnormal T-cell function, which may be responsible for pregnancy loss.^[17]

Overall, the association between the presence of thyroid Abs and recurrent pregnancy loss has been confirmed in several studies.

The aim of this review is to present all relevant information published to date in the literature regarding TAI, infertility and miscarriage. It concentrates only on women with positive thyroid Abs and normal thyroid hormones. However, it must be noted that few patients in some of the studies have slightly elevated TSH levels. Currently, there is little doubt that women with even mild abnormalities in thyroid function, for example, subclinical hypothyroidism, should be treated with thyroxine.

Table 1. Published Studies Indicating the Percentage of Thyroid Antibody-positive Patients in a Cohort of Infertile Women Compared With Controls
Author	Year of publication	Number of individuals investigated	Results (%)	Statistical analysis	Ref.
Roussev et al.	1996	108p + 15c	65 vs 7	p = 0.0001	[18]
Geva et al.	1997	40p + 40c	20 vs 5	p < 0.05	[19]
Kutteh et al.	1999	688p (IVF) + 200c	19.2 vs 14.5	NS	[20]
Kaider et al.	1999	122p (IVF) + 100c	81 vs 10	p < 0.0004	[21]
Reimand et al.	2001	108p + 392c	40.7 vs 14.8	p < 0.001	[22]
Poppe et al.	2002	438p + 100c	18 vs 8	p < 0.05	[23]
Janssen et al.	2004	175p + 168c	26.9 vs 8.3	p < 0.001	[25]

Table 1. Published Studies Indicating the Percentage of Thyroid Antibody-positive Patients in a Cohort of Infertile Women Compared With Controls
Author	Year of publication	Number of individuals investigated	Results (%)	Statistical analysis	Ref.
Roussev et al.	1996	108p + 15c	65 vs 7	p = 0.0001	[18]
Geva et al.	1997	40p + 40c	20 vs 5	p < 0.05	[19]
Kutteh et al.	1999	688p (IVF) + 200c	19.2 vs 14.5	NS	[20]
Kaider et al.	1999	122p (IVF) + 100c	81 vs 10	p < 0.0004	[21]
Reimand et al.	2001	108p + 392c	40.7 vs 14.8	p < 0.001	[22]
Poppe et al.	2002	438p + 100c	18 vs 8	p < 0.05	[23]
Janssen et al.	2004	175p + 168c	26.9 vs 8.3	p < 0.001	[25]

Table 2. Studies Published in the English Literature Regarding the Relationship Between Thyroid Autoimmunity and Miscarriage
Author	Year of publication	Number of individuals investigated	Statistical correlation	Ref.
Stagnaro-Green et al.	1990	552	Positive	[14]
Glinoer et al.	1991	120	Positive	[32]
Lejeune et al.	1993	363	Positive	[33]
Pratt et al.	1993	45	No correlation	[34]
Pratt et al.	1993	42	Positive	[35]
Singh et al.	1995	487	No correlation	[12]
Bussen et al.	1995	66	Positive	[13]
Roussev et al.	1996	45	Positive	[18]
Roberts et al.	1996	53	Positive	[37]
Bussen et al.	1997	56	Positive	[36]
Iijima et al.	1997	1179	Positive	[38]
Esplin et al.	1998	149	No correlation	[39]
Kim et al.	1998	79	Positive	[48]
Kutteh et al.	1999	1588	Positive	[20]
Muller et al.	1999	173	No correlation	[41]
Dendrinos et al.	2000	45	Positive	[42]
Mecacci et al.	2000	138	Positive	[43]
Rushworth et al.	2000	870	No correlation	[44]
Bagis et al.	2001	876	Positive	[45]
Poppe et al.	2003	234	Positive	[24]
Sieiro Netto et al.	2004	534	Positive	[46]
Negro et al.	2006	984	Positive	[47]
Negro et al.	2007	416	No correlation	[49]

Table 2. Studies Published in the English Literature Regarding the Relationship Between Thyroid Autoimmunity and Miscarriage

Author

Year of publication

Number of individuals investigated

Statistical correlation

Ref.

Stagnaro-Green et al.

1990

552

Positive

[14]

Glinoer et al.

1991

120

Positive

[32]

Lejeune et al.

1993

363

Positive

[33]

Pratt et al.

1993

No correlation

[34]

Pratt et al.

1993

Positive

[35]

Singh et al.

1995

487

No correlation

[12]

Bussen et al.

1995

Positive

[13]

Roussev et al.

1996

Positive

[18]

Roberts et al.

1996

Positive

[37]

Bussen et al.

1997

Positive

[36]

Iijima et al.

1997

1179

Positive

[38]

Esplin et al.

1998

149

No correlation

[39]

Kim et al.

1998

Positive

[48]

Kutteh et al.

1999

1588

Positive

[20]

Muller et al.

1999

173

No correlation

[41]

Dendrinos et al.

2000

Positive

[42]

Mecacci et al.

2000

138

Positive

[43]

Rushworth et al.

2000

870

No correlation

[44]

Bagis et al.

2001

876

Positive

[45]

Poppe et al.

2003

234

Positive

[24]

Sieiro Netto et al.

2004

534

Positive

[46]

Negro et al.

2006

984

Positive

[47]

Negro et al.

2007

416

No correlation

[49]

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Thyroid Autoimmunity, Infertility and Miscarriage

Abstract and Introduction

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