AUTOIMMUNE THYROID DISEASE AND PREGNANCY

Here is an intersting article from http://www.thyroidmanager.org/chapter14/Ch-14-3.htm
Miscarriage

The association between thyroid autoimmunity (TAI) and the risk of miscarriage has recently been examined in three comprehensive review articles. In the review by Poppe & Glinoer published in 2003, the available information from thirteen studies comparing the risk of a miscarriage with the presence (versus the absence) of TAI clearly led the authors to the conclusion that TAI (without overt thyroid dysfunction) was significantly associated with a 3-5-fold increase in overall miscarriage rate ¹²¹.Complete article:

AUTOIMMUNE THYROID DISEASE AND PREGNANCY

Effects of pregnancy on immune function

Many autoimmune diseases have been shown to be affected by pregnancy. In normal pregnancy, the maternal immune system undergoes major adjustments to allow the maintenance of what may be immunologically considered a foreign body (the developing fetus) with 50 % paternal genes. The alterations in maternal immune system which permit the successful implantation of the fetal allograft have not yet been definitively identified, but the factors leading to this immune tolerance seem likely to be partially responsible for the generalized improvement in autoimmune thyroid disease, which is so characteristic of the pregnant state. In normal pregnancy, along with the overall dampening of the immune system, maternal immune responses have been shown to shift dramatically, moving immune responses away from Th1 cell-mediated immunity and reducing antibody-production, hence leading to a pattern were both arms of immune responses are reduced ⁹⁸. Table 14-2 summarizes the main effects of pregnancy on lymphocyte subsets in patients with and without thyroid autoantibodies ^99-103. The precise mechanisms by which thyroid antibodies, as well as those against other tissues, are suppressed during pregnancy, and often exacerbate after delivery, remain obscure. Presumably, the rapid reduction in immune suppressor functions following delivery leads to the reestablishment and exacerbation of these conditions. The postpartum exacerbation of autoimmune thyroid disease is one of the most striking examples of this phenomenon. This pattern is especially well illustrated in patients with Hashimoto’s disease, in euthyroid patients with positive thyroid antibodies who develop postpartum thyroid dysfunction, and in those with Graves’ disease who frequently present exacerbations or recurrences of thyrotoxicosis following parturition ^104-114.

Table 14-2. Effects of Pregnancy on Lymphocyte Subsets in Patients with and Without Thyroid Autoantibodies.

Decreased CD4+ and increased CD8+ T cells in all patients. Increase in CD29+/CD45RA+ ratio (suppressor-inducer T cell function) during postpartum in all patients. Decrease in TPO-Ab and TG-Ab during pregnancy and a marked increase during postpartum. In patients who develop postpartum thyroid disease: thyroid antibodies are higher during and after pregnancy. there is an increased prevalence of HLA DR3+ antigens.

Thyroid autoimmunity and disorders of female reproduction

Infertility

Infertility is defined as the inability to conceive after one year of regular intercourse without contraception. The prevalence of infertility is estimated between 12 and 14% and has remained stable in recent years. Infertility evaluation usually identifies different causes, including male infertility (30%), female infertility (35%), the combination of both (20%), and finally unexplained or ‘idiopathic’ infertility (15%). Female causes of infertility comprise endometriosis, tubal disease and ovulatory dysfunction. Among negative prognostic factors influencing fertility, immunologic factors may play an important role in the reproduction processes of fertilization, implantation and early fetal development. Different investigations support the association between reproductive failure and abnormal immunological test results, including anti-phospholipid, anti-nuclear antibodies and organ specific autoimmuity, among which the presence of anti-thyroid antibodies ^115,115bis. With regard to thyroid dysfunction, clinical (or overt) hypothyroidism is clearly associated with female infertility and, in women of reproductive age, autoimmune thyroid disease (AITD) is undoubtedly the most common cause of hypothyroidism. The association between sublinical hypothyroidism (SCH) and infertility has been evaluated in different studies, but most of these are uncontrolled and retrospective (see recent review by Poppe and Velkeniers) ^115ter. The impact of AITD without thyroid dysfunction on female infertlilty is even much less clear and the clinical relevance of such possible association remains controversial. Recently, a series of studies by Poppe et al. in Brussels have shed new light on this issue ^116-118. In a controlled prospective study of 438 consecutive infertile couples, the authors showed that female infertility was significantly associated with AITD without thyroid dysfunction, with the strongest association found for women with endometriosis (Figure 14-10). In a follow up study of the infertile couples who benefitted from Assisted Reproductive Techniques, the authors showed that while the onset of gestation was not hampered by the presence of AITD, the final outcome of the induced pregnancies was significantly lower in women with AITD because of an increase in early pregnancy loss.

The main practical question is whether one should give the benefit of l-thyroxine treatment to infertile women who present positive thyroid autoantibodies with variable degrees of thyroid insufficiency. Overt thyroid dysfunction should obviously be treated before natural conception or an assisted fertilization procedure is planned. Since SCH has a negative impact on pregnancy outcome after assisted reproduction, thyroxine treatment is also advised. Evidence on the treatment of isolated autoimmune features, without thyroid dysfunction, is insufficiently documented to advise prompt action.

Figure 10. The relative risks for positive TPO-Ab in infertile couples. The study was carried out in Brussels, in 440 succesive couples consulting for primary sterility. Female causes of infertility were significantly associated with an increased frequency of thyroid autoimmunity, particularly women with endometriosis. (Reproduced by permission from Poppe et al., Thyroid 12; 997, 2002).

Another interesting development concerns the reproductive function in males in relation with thyroid alterations. In males, hyperthyroidism appears to cause alterations in spermatogenesis and fertility, and most of the studies conducted so far have shown that male patients with thyrotoxicosis have abnormalities in seminal parameters, mainly sperm motility. Furthermore, these abnormalities improve or normalize when patients return to euthyroidism. Concerning hypothyroidism in males, severe and prolonged thyroid insufficiency, particularly when the onset occurs in childhood, may impair reproductive function. Also, severe juvenile hypothyroidism may be associated with precocious puberty. Finally, it appears that, overall, patho-zoospermia and astheno-zoospermia are more prevalent in infertile males who present features of AITD ^{119,120, 120bis,120ter}.

Miscarriage

The association between thyroid autoimmunity (TAI) and the risk of miscarriage has recently been examined in three comprehensive review articles. In the review by Poppe & Glinoer published in 2003, the available information from thirteen studies comparing the risk of a miscarriage with the presence (versus the absence) of TAI clearly led the authors to the conclusion that TAI (without overt thyroid dysfunction) was significantly associated with a 3-5-fold increase in overall miscarriage rate ¹²¹. In the more recent review by Stagnaro-Green & Glinoer published in 2004, a more detailed classification was carried out by examining separately: a) the association between miscarriage and TAI (five studies); b) the association between recurrent miscarriage and TAI (seven studies); and finally c) the association between early pregnancy loss after in vitro fertilization and TAI (five studies). Overall, and with few exceptions, all studies documented a statistically significant relation between TAI and increased pregnancy loss ^{121 bis}. Finally, in the review by Prummel & Wiersinga published in 2004, a meta-analysis was performed of both case-controlled and longitudinal studies published since 1990, when the association between miscarriage and TAI was first described ^121ter. The results of the meta-analysis amply confirmed that this association was valid, with an overall odds ratio of 2.73.

Table 14-3 Miscarriages in women with positive thyroid antibodies
First author	Year	Country	Number of subjects	Positive thyroid antibodies	Miscarriage rate in		P value	Characteristics of selection of the study groups
					Ab pos.	Ab neg. (or control women)
Stagnaro-Green	1990	U. S. A.	552	19.6 %	17.0 % vs	8.4 %	= 0.011	unselected population study
Glinoer	1991	Belgium	726	6.2 %	13.3 % vs	3.3 %	< 0.005	unselected population study
Lejeune	1993	Belgium	363	6.3 %	22.0 % vs	5.0 %	< 0.005	unselected population, before 14 wks gestation
Pratt	1993	U. S. A.	42	31.0 %	67.0 % vs	33.0 %	n.a.	recurrent spontaneous abortions
Singh	1995	U. S. A.	487	22.0 %	32.0 % vs	16.0 %	= 0.002	pregnant with assisted reproductive techniques
Bussen	1995	Germany	66	17.0 %	36.0 % vs	7.0 %	< 0.03	recurrent spontaneous abortions
Iijima	1997	Japan	1179	10.6 %	10.4 % vs	5.5 % <	0.05	unselected population study
Esplin	1998	U. S. A.	149	33.0 %	29.0 % vs	37.0 % >	0.05	recurrent pregnancy loss
Kutteh	1999	U. S. A.	900	20.8 %	22.5 % vs	14.5 %	= 0.01	two or more consecutive abortions
Muller	1999	Netherlands	173	14.0 %	33.0 % vs	19.0 %	= 0.29	pregnant with assisted reproductive techniques
Bussen	2000	Germany	48	30.6 %	54.2 % vs	8.3 %	= 0.002	failure to conceive after 3 cycles of IVF
Dendrinos	2000	Greece	45	32.5 %	37.0 % vs	13.0 %	< 0.05	recurrent spontaneous abortions
Bagis	2001	Turkey	876	12.3 %	50.0 % vs	14.1 %	< 0.0001	unselected population study

Table 14-3 shows the information provided by the analysis of 13 studies carried out over the last decade in three continents. Over 5500 women were investigated, both as study cases and controls. The prevalence of TAI varied widely, from 6 % in Brussels to 33 % in Salt Lake City. Altogether the main results (except in two studies) concurred to establish that TAI was significantly associated with an increased rate of miscarriage. Finding an association does not imply a causal relationship, and it should be stressed that the etiology of pregnancy loss in women with TAI remains largely unknown. Three working hypotheses have been proposed. The first hypothesis holds that pregnancy loss is not directly related to the presence of circulating thyroid antibodies. In this view, TAI only constitutes a marker of an underlying (yet to be defined) more generalized autoimmune imbalance that, in turn, could explain a greater rejection rate of the fetal graft. The second hypothesis holds that despite apparent euthyroidism, the presence of TAI could be associated with a subtle deficiency in thyroid hormone concentrations or with a lesser ability of the thyroid gland to adapt adequately to the necessary changes associated with the pregnant state, because of the reduced reserve characteristic of chronic thyroiditis. A third hypothesis, recently put forward by us and others, holds that TAI could act by delaying the occurrence of pregnancies, because of its association with subfertility. In this view, TAI positive women would tend to become pregnant at an older age (on average 3-4 years later), and older women are more prone to pregnancy loss. These hypotheses are not in contradiction with one another, and it remains plausible that the increased risk of pregnancy loss associated with TAI is multifactorial, eventually resulting from a combination of several independently deleterious factors ^122-130.

Can medical intervention be proposed to help improve pregnancy success?

If increased pregnancy loss is due to an underlying generalized immune dysregulation, and if the presence of thyroid antibodies merely represent an indirect marker of the immune condition, then there is no proven medical intervention that can presently be proposed. It is worth mentioning that a in a few isolated cases, short-term steroid administration or injections of immunoglobulins have been employed, with variable success, to modulate the immune response in women with recurrent abortions. Also, if mild thyroid underfunction does play a significant role, then this would constitute a good argument for systematically screening women (either before conception, when they express the desire of being pregnant or as soon as a pregnancy is ongoing) for the presence of TAI and/or mild thyroid insufficiency, in order to give these patients the potential benefit of L-thyroxine treatment. Todate, only one such prospective trial was reported, with promising results ^129,131. In this study, women with TAI and a past history of recurrent early miscarriages were given thyroid hormone treatment, both before and during pregnancy. The results showed a significant reduction in the rate of spontaneous abortion: 81% of women who received thyroid hormone ended with live births, compared with only 55% in the women who were given immunoglobulin injections. Obviously, conclusions must be considered with caution and balanced with the small number of patients investigated and also the fact that there was no strict randomisation. However, despite its limitations, this study constitutes the first therapeutic intervention trial showing a positive effect of thyroid hormone administration in women who were habitual aborters. If delayed conception plays a significant role to decrease fertility in women with TAI, then this could constitute an argument for systematically screening infertile women for the presence of mild thyroid underfunction associated with TAI, particularly when seeking medical advice for in vitro fertilization procedures. Such an approach was recently used in Finland ¹³². The study showed a high prevalence of women with elevated serum TSH levels, an association between oligo-amenorrhea and abnormally elevated serum TSH, and an overall improvement in the success rate of induced pregnancies after thyroxine administration. Finally, women with TAI could be advised to plan for a pregnancy at a younger age, although this type of medical advice is more easily said than applicable in practice.

Effects of pregnancy on thyroid function in women with thyroid autoantibodies

Table 14-4 summarizes the various types of autoimmune thyroid disease which can be expected in the pregnant and postpartum population. These are also discussed in greater detail below and postpartum thyroiditis is reviewed in Chapters 8 and 13. The prevalence of TAI in the pregnant population is comparable to that found in the general female population with a similar age range, that is between 6 and 10% ^133,134. In first trimester patients with gestational diabetes mellitus, the prevalence of thyroid autoantibodies is even higher (20-25%) ^135,136. Taken together, the high frequency of thyroid antibodies, increased miscarriage risks, risks of developing hypothyroidism with the progression of gestation, and finally the observation that postpartum thyroiditis occurs in a significant fraction of these individuals have led physicians to recommend that all pregnant patients be screened for the presence of TPO antibodies during the first trimester of pregnancy (see below) ¹³⁴.

Table 14-4. Autoimmune Thyroid Disease During Pregnancy and the Postpartum Period

Primary hypothyroidism Thyroid destruction (Hashimoto’s disease) Circulating TSH-receptor-blocking antibody Asymptomatic (euthyroid) autoimmune disease Increased risk of developing subclinical hypothyroidism during pregnancy Increased risk of spontaneous miscarriage Postpartum thyroid disease (PPTD) Hyperthyroidism Hypothyroidism Combinations Graves’ Disease Pre-existing Gestational exacerbation and remission Postpartum exacerbation

A decade ago, a prospective longitudinal study was carried out in 1660 consecutive healthy pregnancies to evaluate the changes in thyroid function occurring in pregnant women who had thyroid antibodies, but were euthyroid during early gestation ¹³⁷. Closely monitored during gestation and without administration of thyroid treatment or iodine supplements, the study showed that despite the expected decrease thyroid antibody titers during gestation, thyroid function showed a gradual deterioration toward subclinical hypothyroidism in a significant fraction of women with TAI (Figure 14-11).

Figure 11a. Individual patterns of changes in thyroperoxidase antibody titers (TPO-Ab) in women with autoimmune thyroid disease. During pregnancy, there was a marked reduction in antibody titers, by approximately 50-60% on average (solid lines represent the asymptomatic euthyroid women, and dotted lines the women with known hypothyroid hypothyroidism). (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Figure 11b. Among the women with positive thyroid antibodies, a progressively increasing fraction develop biochemical hypothyroidism, with 10% having basal TSH >3 mU/L in the first trimester, 20% in second and third trimesters, and finally 40% at the time of delivery. (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Figure 11c. Mean serum free T4 concentrations (3 days after delivery) in women with and without thyroid immunity. In the antibody positive group, not only was mean free T4 level significantly lower than in the control group, but in addition, the mean serum free T4 was at the lower limit of normal. (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Already in the first trimester, serum TSH (albeit within the normal range) was significantly shifted to higher values than in TAI-negative pregnant controls. Thereafter, serum TSH remained higher throughout gestation and, at parturition, 40% of TAI-positive women had a serum TSH >3 mU/L, with almost one-half of them exceeding 4 mU/L. Thus, TAI-positive women were able to maintain a normal thyroid function in the early stages of gestation, due to sustained thyrotropic stimulation. At delivery, however, their serum free T4 was significantly reduced, compared with the controls, and their mean serum free T4 was at the lower limit of the normal range. The 30% average reduction in serum free T4 indicated that almost one-half of TAI-positive women had free T4 values in the hypothyroid range at the end of pregnancy, hence confirming that these women have a reduced functional thyroid reserve associated with TAI. At the individual level, it was possible to predict the risk of progression to hypothyroidism, based on serum TSH levels and TPO-Ab titers: when serum TSH was >2.0 mU/L and/or TPO-Ab titers >1250 U/mL before 20 weeks, these markers were indicative of the propensity to develop hypothyroidism before the end of pregnancy. These observations are important, since they provide clinicians with simple tools to identify, during early gestational stages, those women who carry the highest risk. As a consequence, thyroid function can be closely monitored, and preventive treatment with L-thyroxine administered, to avoid the potential deleterious effects of hypothyroxinemia on both maternal and fetal outcomes.

Main “Take Home” Messages (rapid reading)

PRIMARY HYPOTHYROIDISM

Clinical epidemiology

The most common cause of primary hypothyroidism in women of reproductive age is chronic autoimmune thyroiditis, unless there is iodine deficiency or hypothyroidism that results from previous radical treatment for hyperthyroidism using radioiodine or surgery. Chronic autoimmune thyroiditis occurs in both the goitrous and atrophic forms of the disease (see Chapter 8). Between 1 and 2% of women who become pregnant already receive thyroxine therapy for hypothyroidism. In two population-based studies of women without known hypothyroidism, the prevalence of an elevated serum TSH concentration was systematically investigated in the early part of gestation. In the first retrospective study ¹³⁸, serum TSH, free T4 and TPO-Ab were measured in 2000 pregnant women (Table 14-5). Among these women, 49 had an elevated TSH (2.5% of the cohort) and 6 also had a low free T4, hence yielding a prevalence of undisclosed overt hypothyroidism of 0.3%. Some 58% of the women with an elevated TSH tested positive for TPO-Ab, compared with only 11% in euthyroid controls. The design of this study did not permit the investigators to determine whether women with an elevated TSH had a known thyroid condition (in which case they could have been taking an inappropriately low thyroxine dosage or, alternatively, excessive doses of antithyroid drugs). In the second prospective population study in Europe ¹³⁷, the systematic screening of a cohort of 1660 apparently healthy pregnant women showed that 2.2% of them had an elevated serum TSH. Thus, similar prevalences of undisclosed hypothyroidism were found, indicating that overall between 2-4% of women entering pregnancy may present hypothyroidism to various degrees, from subclinical to overt disease. Special mention should be made of a recent study showing that in pregnant women with diabetes mellitus type 1, thyroid dysfunction may even be more prevalent (27-45%), consisting mainly of subclinical hypothyroidism ^139,139bis.

Table 14-5. Prevalence of abnormally elevated TSH in 2000 consecutive women at 15 to 18 weeks of gestation*
	N	TSH(mU/L)	Free T4 (pmol/L)	TPO- antibody (% positive)
Total screened	2000	2.1	–	–
Elevated TSH ( >6 mU/L)	49	10	11.5	58
Controls	99	2.3	13.4	11
* adapted from Klein et al. (Ref. N° 138)

A much rarer cause of hypothyroidism is that associated with the presence of TSH receptor blocking antibodies during pregnancy ^109,140-144. In such patients, hypothyroidism is presumably caused by interference in TSH-TSH receptor interactions. Even though extremely uncommon, the clinical significance of this problem in the pregnant state is that blocking antibodies may be transferred to the fetus and cause intrauterine or transient neonatal hypothyroidism ^142,143.

A fascinating new topic in the field of autoimmunity and pregnancy is that of fetal microchimerism, that is the migration of fetal cells into maternal blood and the prolonged engrafment of fetal progenitor cells into maternal tissues. Recent studies have confirmed that microchimerism occurs within the thyroid gland in women with Hashimoto’s and Graves’ diseases. Although the functional consequences of persisting fetal microchimerism are not yet known and are only beginning to be explored, fetal cells engrafted into maternal tissues may possibly play a role in the etiology of autoimmune thyroid diseases, and perhaps also in the modulation of autoimmunity during pregnancy ^{145-147,147bis}.

Effect of hypothyroidism on pregnancy outcome

As already alluded to, hypothyroidism has until recently been – wrongly – considered to be relatively rare during pregnancy, presumably because of the increased infertility and miscarriage rates associated with hypothyroidism ^148-152. Nowadays, this view has changed. Several studies have shown that when hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for obstetric and fetal complications. The main obstetric complications that have been described in association with hypothyroidism are listed in Table 14-6.

Table 14-6 Obstetrical complications associated with hypothyroidism during pregnancy
MOTHER	frequency	% *	Hypo	First author (year)
Anemia	increased	31 %	( OH ) **	Davis (1988)
Postpartum hemorrhage	increased	4 %	( SCH ) **	Leung (1993)
	increased	19 %	( OH )	Davis (1988)
Cardiac dysfunction	increased	n. a.	( OH )	Davis (1988)
Preclampsia	increased	15 %	( SCH )	Leung (1993)
	increased	22 %	( OH )	Leung (1993)
	increased	44 %	( OH )	Davis (1988)
	increased	n. a.	( OH )	Mizgala (1991)
Placental abruption	increased	19 %	( OH )	Davis (1988)
FETUS	frequency	%	Hypo	First author (year)
Fetal distress in labour	increased	14 %	( OH )	Wasserstrum (1995)
Prematurity/Low birth weight	increased	31 %	( OH )	Davis (1988)
	increased	9 %	( SCH )	Leung (1993)
	increased	22 %	( OH )	Leung (1993)
	increased	13 %	( OH )	Abalovich (2002)
Congenital malformations	increased	4 %	( OH )	Leung (1993)
	increased	6 %	( OH )	Abalovich (2002)
Fetal death	increased	4 %	( OH )	Leung (1993)
	increased	12 %	( OH )	Davis (1988)
	increased	3 %	( OH )	Abalovich (2002)
	increased	8 %	( OH )	Allan (2000)
Perinatal death	increased	9-20 %	( OH )	Montoro (1981)
	increased	3 %	( OH )	Allan (2000)
Foot-notes: the percentages listed were taken (or recalculated) from the studies shown as references. ** SCH = subclinical hypothyroidism; OH = overt hypothyroidism; n.a. = non appropriate. Adapted from Poppe & Glinoer (Reference N° 121)