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. The work up of infertile women usually identifies different causal factors, including male infertility (30%), female infertility (35%), the combination of both (20%), and finally unexplained or ‘idiopathic’ infertility (15%). Major known female causes of infertility comprise endometriosis, tubal disease and ovulation dysfunction. Among the factors that may negatively influence normal fertility, immunologic factors are known to play an important role in the reproduction processes of fertilization, implantation and the early development of an embryo. Different investigations support the association between reproductive failure and abnormal immunological test results, including anti-phospholipid, anti-nuclear antibodies and organ specific autoimmunity, among which the presence of antithyroid antibodies [155, 156].

With regard to thyroid dysfunction, clinical hypothyroidism is clearly associated with female infertility and, in women in the reproductive age, autoimmune thyroid disease (AITD) is undoubtedly the most common cause of hypothyroidism. The association between subclinical hypothyroidism (SCH) and infertility has been evaluated in different studies, but most of the latter are retrospective and uncontrolled [157]. The impact of AITD on infertility in women without thyroid dysfunction is even much less clear and the clinical relevance of such possible association remains controversial. Recent studies by Poppe et al. have shed new light on these issues [158-161]. In a controlled prospective study of 438 consecutive infertile couples, female infertility was significantly associated with AITD without thyroid dysfunction, with the strongest association found in women with endometriosis. In a follow-up study of infertile couples who benefited from Assisted Reproductive Techniques (ART), the authors showed that medically-assisted conception and onset of gestation were not hampered by AITD, but a successful outcome of the ongoing pregnancies was significantly reduced in women with AITD, due to greater early pregnancy loss (see Figure 14-11).

The main practical question is whether one should give the benefit of thyroxine administration to infertile women who have positive thyroid antibodies with variable degrees of thyroid insufficiency. Obviously, overt thyroid dysfunction should be treated before conception or planned ART. Since SCH has a negative impact on the outcome of pregnancy after ART, thyroxine treatment should also be advised. Evidence on the treatment of isolated autoimmune features, but without thyroid dysfunction, was insufficiently documented until recently to advise prompt action (see later section on medical interventions).

Another interesting development concerns reproductive function in males with thyroid alterations. In males, hyperthyroidism causes alterations in spermatogenesis and fertility, and most studies conducted so far showed that male hyperthyroid patients have abnormalities in seminal parameters, mainly sperm motility. These abnormalities tend to improve and normalize when the patients become euthyroid. Concerning hypothyroidism in males, severe and prolonged thyroid insufficiency may impair reproductive function, particularly when its onset occurs in childhood. Severe juvenile hypothyroidism may also be associated with precocious puberty. Finally, patho-zoospermia and astheno-zoospermia seem more prevalent in infertile males who present features of AITD [162-164].

Thirty-one percent of all pregnancies end in miscarriage. Generally, women who experience a single pregnancy loss do not routinely undergo an evaluation for the cause of miscarriage. Women who experience recurrent miscarriages (i.e. 0.3%-5% of women), which is defined as three or more spontaneous miscarriages without an intervening live birth, should thoroughly be evaluated for an underlying etiology (such as infections, auto-immune disorders, exposure to drugs, etc.) [165-167].

An association between AITD and miscarriage was first reported in 1990-91 [168, 169]. Since then, a large body of literature has evaluated the relationship between AITD and miscarriage in various populations of pregnant women. The topic has recently been reviewed in 3 comprehensive articles (see Table 14-4). In a review by Poppe & Glinoer (2003), available information from 13 studies that compared the risk of miscarriage with the presence (versus the absence) of AITD led the authors to conclude that AITD without overt thyroid dysfunction was significantly associated with a 3-5-fold increase in the overall miscarriage rate [170]. In a more recent review by Stagnaro-Green & Glinoer (2004), a classification was attempted by examining separately the association between AITD and miscarriage (5 studies), AITD and recurrent miscarriage (7 studies), and finally AITD and early pregnancy loss after ART (5 studies). Overall, and with only few exceptions, all studies documented a statistically significant relationship between thyroid autoimmunity and an increased risk of pregnancy loss [171]. Finally, Prummel & Wiersinga (2004) published a meta-analysis of both the case-controlled and longitudinal studies published since 1990, after the association between miscarriage and AITD was first described [172]. The results of the meta-analysis amply confirmed that the association does exist, with an overall increased relative risk of miscarriage of 2.73 in women with AITD.

Finding an association does not imply a causal relationship and the etiology of increased pregnancy loss in women with AITD remains largely unknown. Three working hypotheses have been proposed. The first hypothesis holds that the pregnancy loss is not directly related to the presence of circulating thyroid antibodies and, in this view, AITD would only represent a marker of an underlying - yet to be defined - more generalized auto-immune imbalance that, in turn, could explain a greater rejection rate of the fetal graft. The second hypothesis holds that despite apparent euthyroidism, AITD could be associated with a subtle deficiency in thyroid hormone concentrations or with a lesser ability to adapt adequately to the changes associated with the pregnant state, because of a reduced functional reserve characteristic of the thyroid gland in chronic thyroiditis. The third hypothesis holds that AITD could act by delaying the occurrence of a conception, because of its known association with infertility. In this view, thyroid antibody-positive women could tend to become pregnant only at an older age (3-4 years older, on the average), and older women are more prone to pregnancy loss. These hypotheses are not mutually exclusive and it remains plausible that the increased risk of pregnancy loss associated with TAI is multi-factorial, eventually resulting from a combination of several independently deleterious factors [173-179].

Several studies have examined whether the miscarriage rate was higher in infertility patients who underwent ART, according to the presence or absence of thyroid autoimmunity. Four studies (2 prospective, 2 retrospective), showed a 2- to 3-fold difference in the miscarriage rate in thyroid antibody-positive versus antibody-negative patients, while in two other studies (1 prospective, 1 retrospective) no difference was found [159, 173, 180-183]. The largest of these series, although retrospective, failed to demonstrate an adverse effect on the miscarriage rate in antibody-positive versus antibody-negative women undergoing ART [183]. The prevalence of thyroid autoimmunity, in women undergoing ART, was examined in 4 studies and found to range between 14% and 22%, which was not statistically different from the prevalence of antibodies in women not undergoing ART [159, 181, 182, 184]. Pregnancy rates have also been examined in women with or without thyroid autoimmunity undergoing ART and results were conflicting. In the two largest studies, Poppe et al. and Muller et al. found no difference in overall pregnancy rates (see also Figure 14-11) [159, 173]. However, in other studies, pregnancy rates were found to be lower by ~1.5- to 2-fold in thyroid antibody-positive women, compared with those without antibodies [180, 185]. In summary, the literature on pregnancy loss in women with thyroid autoimmunity who undergo ART is mixed. The methods of ART were not consistent between the series nor were the causes of infertility controlled for among the various studies. Given that the majority of the studies did find a relationship, there is at least a suggestion that such a relationship does exist, but without sufficient clear evidence for us to draw a definitive conclusion.

If an increased pregnancy loss was due to an underlying generalized immune dysregulation and the presence of thyroid antibodies merely represented an indirect marker of this immune condition, then medical intervention could be proposed using immuno-modulatory drugs. Alternatively, if underlying mild thyroid underfunction played a role, this would constitute a good argument to systematically screen women for the presence of TAI and/or mild thyroid insufficiency (either before conception, when they express the desire of being pregnant or as soon as a pregnancy has started) and give them the potential benefit of thyroxine treatment.

To date, five studies have investigated whether a medical intervention could benefit women with thyroid autoimmunity and recurrent pregnancy loss (3 with immuno-modulatory drugs and 2 with thyroxine administration). In a study by Kiprov et al., 35 TAI-positive women were treated with intravenous injections of immunoglobulin (IVIG) prior to conception and during the first 8 months of gestation: 85% of these women had a successful pregnancy (the study did not comprise a control group) [186]. In a study by Sher et al., 82 TAI-positive (but anti-phospholipid antibody-negative) pregnant women were treated either with heparin/aspirin (n = 37) or heparin/aspirin combined with IVIG (N = 45). The outcome of pregnancy was successful in 51% of women in the combined therapy group, compared to only 27% in the other group [187]. In a study by Stricker et al., 47 women (among whom 53% were TAI-positive) were treated with IVIG before pregnancy. Among the women who accepted to receive the treatment, two thirds of them became pregnant and almost all of these (>90%) carried pregnancy successfully to term [188]. In a study by Vaquero et al., 27 TAI-positive women with two first trimester miscarriages were subdivided into 11 TAI-positive women who received IVIG during pregnancy and 16 TAI-positive women who received thyroxine, starting before and continued during pregnancy. The pregnancy success rate was 81% in the thyroxine-treated group compared with 55% in the IVIG group [189]. Despite inherent limitations in the last study (small number of cases and absence of randomization), the Vaquero study was the first therapeutic intervention trial showing a positive effect of thyroid hormone administration in women who were recurrent aborters [178].

As mentioned earlier, Negro et al. reported in 2005 the results of thyroxine administration in TAI-positive euthyroid infertile women undergoing ART, and showed a reduction in the miscarriage rate to 33%, compared with 52% in untreated controls. The study, however, failed to reach statistical significance, perhaps because of the small number of cases [181]. The same group of authors recently published the results of a fascinating intervention trial with thyroxine administration [190]. They carried out a randomized trial in 984 unselected women who had been screened for the presence of TPO-Ab and thyroid function tests at the first obstetrical visit. One hundred and fifteen euthyroid women were TPO-Ab positive, and were subdivided into two groups: one group (A) included TPO-Ab positive women who were treated with thyroxine, while the second TPO-Ab positive group of women (B) did not receive thyroxine. The third group (C) consisted of all the other euthyroid (and TPO-Ab negative) women, who served as the controls. Study’s outcome parameters included spontaneous pregnancy loss and preterm delivery (<37 weeks gestation). The miscarriage rate was significantly higher in group B than in both groups A and C (13.8% versus 3.5% & 2.4%, respectively). Similarly, the preterm delivery rate was significantly higher in group B than in both groups A and C (22.4% versus 7% & 8.2%, respectively). Thus, with early thyroxine administration in women with thyroid autoimmunity features and a normal thyroid function at the onset of pregnancy, these authors were able to show for the first time in a randomized trial a 75% reduction in the miscarriage rate and a 69% reduction in the risk of premature delivery [191].

If delayed conception plays a significant role to explain decreased fertility in women with AITD, this would certainly constitute an argument for systematically screening infertile women for the presence of mild thyroid underfunction frequently associated with thyroid autoantibodies, particularly when these women seek medical advice before in vitro fertilization procedures. Such an approach was used in Finland [192]. A study by Arojoki et al. showed a high prevalence of women with elevated serum TSH levels, an association between oligo-amenorrhea and abnormally elevated serum TSH values and an overall improvement in the success rate of induced pregnancies after thyroxine administration. Finally, women with AITD 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.

To conclude this section, although a clear association exists between the presence of thyroid autoimmunity and pregnancy loss, systematic screening can not be universally recommended at present time, at least until adequately designed therapeutic trials will demonstrate beyond doubt a clear reduction in miscarriage rate with thyroxine treatment. This being said, more and more data point to the growing interest of screening as well as early thyroxine administration before/during pregnancy, and many centers, in Europe and elsewhere, already routinely screen women with infertility and/or miscarriage for the presence of thyroid autoimmunity and dysfunction.