The prevalence of hypothyroidism during pregnancy in Western countries is estimated to be 0.3-0.5% for overt hypothyroidism (OH) and 2-3% for subclinical hypothyroidism (SCH) [194, 197-199]. On a worldwide basis, the most important cause of maternal thyroid deficiency remains iodine deficiency, which is known to affect over 1.2 billion individuals [133]. When the iodine nutrition status is adequate, the main cause of hypothyroidism during pregnancy is chronic autoimmune thyroiditis. Thyroid auto-antibodies are found in 5-15% of normal women in the childbearing age and the prevalence rises to over 50% in pregnant women with an elevated serum TSH level (see Figure 14-13). Other causes of gestational hypothyroidism, much less frequent however, include the previous radical treatment of hyperthyroidism (using radioiodine ablation or surgery) or surgery for thyroid tumors.

The prevalence of elevated serum TSH in early gestational stages was investigated in two population-based studies of women without known hypothyroidism. In the first study (retrospective), serum TSH, free T4 and TPO-Ab were measured in 2,000 pregnant women [198]. Forty-nine women had an elevated serum TSH (2.5%) and 6 women also had a low serum free T4, yielding a 0.3% prevalence of undisclosed hypothyroidism. The design of this study did not permit the investigators to determine whether the women with an elevated TSH had a known prior 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 study (prospective), systematic screening in a cohort of 1,660 apparently healthy pregnant women showed that 2.2% of them had an elevated serum TSH [197]. Special mention should be made of recent studies showing that in pregnant women with diabetes mellitus type 1, thyroid dysfunction may even be more prevalent (27-45%), consisting mainly of SCH [200, 201].

Figure 13. A cohort of 10,857 women was screened for thyroid antibodies and serum TSH concentrations in the 2nd trimester of pregnancy. Two hundred and nine women were found with an elevated serum TSH (above 6 mU/L), corresponding to an overall 2% prevalence of hypothyroidism. The study also showed that in women with an elevated serum TSH, the frequency of having positive thyroid antibodies rose, from less than 10% in the controls, to 55% in women with a TSH between 6-10 mU/L, and to 80% in women with a serum TSH above 10 mU/L (from Allan, Ref 199).

A hypothalamic-hypophyseal origin of hypothyroidism is rare, and can include lymphocytic hypophysitis occurring during pregnancy or postpartum [202]. Other rare causes to consider in the differential diagnosis of hypothyroidism are those associated with the presence of TSH receptor ‘blocking’ antibodies. 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 thus cause intrauterine or transient neonatal hypothyroidism [149, 203-207].

Symptoms and signs may raise clinical suspicion of hypothyroidism during pregnancy (weight increase, sensitivity to cold, dry skin, etc.) but others may go unnoticed (asthenia, drowsiness, constipation, etc.). Because many women remain asymptomatic, particular attention is required from the obstetrical care providers for this condition to be diagnosed and to evaluate more systematically thyroid function when women attend the prenatal clinic for the first time. Only thyroid function tests confirm the diagnosis.

A serum TSH elevation suggests primary hypothyroidism and measurement of serum free T4 levels further distinguish between SCH and OH, depending on whether free T4 is normal or clearly below normal for gestational age. Determination of thyroid auto-antibodies titers, thyroperoxidase (TPO-Ab) and thyroglobulin (TG-Ab), confirms the autoimmune origin of the disorder [208-210].

A fascinating new topic in the field of autoimmunity and pregnancy is fetal microchimerism, that consists in the migration of fetal cells into maternal blood and the prolonged engraftment of fetal progenitor cells into maternal tissues. Several studies have recently confirmed that microchimerism occurs within the thyroid gland in women with Hashimoto’s and Graves’ disease. Although the functional consequences of persisting fetal microchimerism are not yet known and 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 [211-215]. It should however be noted that in two recent clinical studies, the authors failed to observe an association between previous pregnancy, parity and thyroid antibodies, hence arguing against a key pathogenic role of microchimerism as a trigger of chronic thyroid autoimmunity [216, 217].

Despite the known association between decreased fertility and hypothyroidism, the latter condition does not preclude the possibility to conceive. This is probably the main reason why, until a few years ago, hypothyroidism had been considered – wrongly – to be relatively rare during pregnancy [218-222]. In a recent study by Abalovich at al., 34% of hypothyroid women became pregnant without thyroxine treatment: 11% of them had OH and 89% SCH [223]. When hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for early and late obstetrical complications (see Table 14-6 and Table 14-7).

As indicated in Table 14-6 & Table 14-7, both obstetrical and fetal complications have been shown to occur with an increased frequency in pregnant women with hypothyroidism. These complications are more frequent and more severe with OH than with SCH and, most importantly, adequate treatment with thyroid hormone greatly decreases the risk of a poorer obstetrical outcome [223, 224, 232-234]. In the study of Abalovich, it was clearly shown that it was not so much the diagnosis of OH versus SCH that mattered with regard to pregnancy outcome, but primarily the adequacy of thyroxine treatment [223]. When the treatment was not adequate, pregnancy ended with abortion in 60% and 71% of OH and SCH women respectively, with an increased prevalence of preterm deliveries. Conversely, in hypothyroid pregnant women receiving an adequate treatment, the frequency of abortions was minimal and in general pregnancies were carried to term without complications (see Figure 14-14). Concerning the risk of premature delivery in women with untreated hypothyroidism, a recent study confirmed that gravidas with high TSH levels had a greater than 3-fold increase in risk of very preterm delivery (<32 completed weeks) [235, 236].

Figure 14. The graphs compare the outcome of pregnancy in 27 women with hypothyroidism known before pregnancy who received an adequate thyroxine treatment during pregnancy (upper panel) with 24 women in whom thyroxine treatment was not adequately adjusted during gestation and hence remained hypothyroid (lower panel). Significantly more frequent abortions and preterm deliveries were observed in non adequately treated women, both with OH & SCH (from Abalovich, Ref 223).

There are no recommendations for universal screening for thyroid dysfunction in women before or during pregnancy. As the overall benefits of screening for thyroid dysfunction (primarily hypothyroidism) have not yet been universally justified by current evidence-based medicine, we recommend ‘aggressive’ case finding among the following groups of women who are at high risk, preferably already prior to pregnancy or in early gestation (see Table 14-8) [1].

Among possible screening algorithms, the following scheme has been proposed and is outlined in Figure 14-15.

Figure 15. An algorithm for systematic screening of thyroid autoimmunity and hypothyroidism during pregnancy, based on the determination of thyroid antibodies (Ab), serum TSH and free T4 concentrations during the first half of gestation. GA = gestational age; NL = normal limits; PP = postpartum (from Glinoer ; Ref 194).

The first step in the algorithm is to measure serum TSH and thyroid antibodies in early gestation. Because isolated hypothyroxinemia may occur in some women (without concomitant rise in serum TSH), it is reasonable to include systematically a free T4 determination [237, 238]. Ideally, both TG-Ab and TPO-Ab should be determined; however, if for economical reasons only one antibody can be measured, then it is preferable to measure TPO-Ab because it yields the best diagnostic score. When serum TSH is elevated or free T4 clearly below normal, and irrespective of the presence (or absence) of TAI, women should be considered to have thyroid underfunction and treated with thyroxine. The second step concerns women with TAI and normal thyroid function. We have proposed to base the medical response on serum TSH levels during early pregnancy. When serum TSH is <2.5 mU/L (most frequently associated with low antibodies titers and normal free T4 levels), thyroxine treatment is not systematically warranted, and serum TSH and free T4 should be monitored later during gestation. For women with TAI and a serum TSH that is still within the normal range in early gestation, but already slightly shifted to higher ‘normal’ values, i.e. between 2.5-4.0 mU/L (most frequently associated with higher antibody titers and low-normal free T4 levels), obstetric care providers should consider thyroxine treatment. It is important to keep in mind that serum TSH is down-regulated under the influence of peak hCG values in the 1st half of gestation, and also that the thyroid deficit tends to deteriorate as gestation progresses in TAI-positive women. Because the potential deleterious effects, for both mother and progeny, are not due to high serum TSH per se but to low free T4 concentrations, clinical judgment should be based on serum free T4. If low or low-normal for gestational age, thyroxine treatment is probably justified. In daily practice, when such a scheme is systematically applied, most - if not all - of the pregnancies followed are successful and uneventful [223, 239]. Even though more prospective studies are needed to assess the final clinical relevance of the proposed scheme, the recent study of Negro et al. provided strong arguments in favor of early thyroxine administration in women with AITD and normal thyroid function during early gestation [190]. From many indirect arguments, it is our personal belief that no harm can be done and that thyroxine treatment can only be beneficial, in such conditions, for both the patient and offspring. Finally, systematic screening for AITD during early pregnancy also allows to delineating women who are prone to developing thyroid dysfunction after parturition. Thus, even when no specific treatment is warranted during gestation, systematic screening is useful to clinicians for organizing the monitoring of potential postpartum thyroid dysfunction [ 75, 240, 241].

The administration of thyroxine is the treatment of choice for maternal hypothyroidism, if the iodine nutrition status is adequate. Hypothyroid pregnant women require larger thyroxine replacement doses than do nonpregnant patients, and women who already take thyroxine before pregnancy usually need to increase their daily dosage by 30-50%, on average, above preconception dosage. Several reasons explain the incremented thyroid hormone requirements: the rapid rise in TBG levels resulting from the physiological rise in estrogen concentrations, the increased distribution volume of thyroid hormones (vascular, hepatic, fetal-placental unit), and finally the increased placental transport and metabolism of maternal T4 [60, 208, 209, 242].

Thyroxine treatment should be initiated with a dose of 100-150 μg/day or titrated according to body weight. In non pregnant women, the full replacement thyroxine dose is 1.7-2.0 μg/kg bw/day. During pregnancy, because of the increased requirements, the full replacement thyroxine dose should be increased to 2.0-2.4 g/kg bw/day [60-62, 209, 242, 243]. In a newly diagnosed hypothyroid patient, a full replacement thyroxine dose should be instituted immediately, assuming there are no abnormalities in cardiac function. In initially severe hypothyroidism, therapy may be initiated by giving for the first few days a thyroxine dose corresponding to two times the estimated final replacement daily dose, in order to normalize more rapidly the extra-thyroidal thyroxine pool. In women who already take thyroxine before conception, the need to adjust the preconception daily dosage may become manifest as early as by 4 to 6 weeks gestation, hence justifying the early adaptation of thyroid hormone replacement to ensure that maternal euthyroidism is maintained during the first months of pregnancy. An alternative (recommended by some thyroidologists) is to anticipate the expected increase in serum TSH by raising the thyroxine dose already before conception or as soon as pregnancy has been confirmed. Among the possible preventive strategies to avoid the risk of maternal hypothyroidism during early gestational stages, it can be recommended to adjust the preconception thyroxine dose with the aim to maintain serum TSH near the low-normal range [244, 245]. It is important to note that 25% of hypothyroid women who are able to maintain a normal serum TSH level in the first trimester, and 35% of those who maintain a normal serum TSH level until the second trimester without increasing their daily dosage, will still require an increment in thyroxine replacement during late gestation to remain euthyroid [209, 229, 246]. If the pregnancy is planned, the patient should have thyroid function tests soon after the missed menstrual period. If serum TSH is not increased at that time, the test should be repeated at 8-12 weeks and 20 weeks, as the increase in hormone requirements may not become apparent until later during gestation.

The magnitude of thyroxine increment during pregnancy depends primarily on the etiology of hypothyroidism, namely the presence or absence of residual functional thyroid tissue. Women without residual functional thyroid tissue (after radioiodine ablation, total thyroidectomy, or due to congenital agenesis of the gland) require a greater increment in thyroxine dosage than women with Hashimoto’s thyroiditis, who usually have some residual thyroid tissue. As a simple rule of thumb, it has been suggested that the increment in thyroxine can be based on the initial degree of TSH elevation. For women with a serum TSH between 5-10 mU/L, the average increment in thyroxine dosage is 25-50 μg/day; for those with a serum TSH between 10-20 mU/L, 50-75 μg/day; and for those with a serum TSH >20 mU/L, 75-100 μg/day [209]. Serum free T4 and TSH levels should be measured within one month after the initiation of treatment. The overall aim is to achieve and maintain normal free T4 and TSH levels throughout pregnancy. Ideally, thyroxine treatment should be titrated to reach a serum TSH value <2.5 mU/L (see Table 14-9). As already discussed, because it is sometimes difficult to correctly interpret the results of free T4 and TSH measurements in the context of pregnancy, it is useful to optimize the monitoring of treatment during pregnancy by establishing laboratory-specific reference ranges for serum free T4 and trimester-specific reference ranges for serum TSH. Once parameters of thyroid function have been normalized by treatment, they should be monitored every 6-8 weeks. If they remain abnormal, thyroxine dosage should be adjusted and tests repeated after 30 days, and so on until normalization. After parturition, most patients need to decrease thyroxine dosage, over a period of ~4 weeks postpartum. It should also be remembered that women with thyroid autoimmunity features are at risk of developing postpartum thyroiditis, a syndrome that may justify differences in the pre- and post-pregnancy thyroxine requirements. It is therefore important to continue monitor thyroid function tests for at least during six months after the delivery [247].