Importance of Universal screening for thyroid disorders in first trimester of pregnancy

Table of Contents

DISCUSSION

This prospective screening of thyroid function in a cohort of unselected pregnant women shows that high-risk women (with a personal or family history of thyroid disorders or a personal history of other autoimmune diseases) have more significant (P < 0.001) increased risk of hypothyroidism (subclinical or overt) during early pregnancy. However, testing only the high-risk pregnant women, as the consensus guidelines recommend[8], would miss about one- of women with hypothyroidism. Subclinical hypothyroidism during early pregnancy is common, affecting about 2.5% pregnant women.[9,10] Therefore with the growing evidence for an association between maternal subclinical hypothyroidism and adverse pregnancy outcomes but lack of intervention trials showing beneficial effect of thyroxine (T4) in preventing these adverse outcomes, the controversy between targeted high-risk case finding and universal screening continues.[11,12,13] The consensus guidelines recommend the use of T4 in pregnant women with subclinical hypothyroidism, justified on the basis of potential benefit to risk ratio.[8] Our study shows that, without universal screening, a significant number of such pregnant women with thyroid dysfunction will not be picked up. Several factors affect thyroid function tests during various stages of pregnancy. Free thyroxine (FT4) increases with suppression of TSH in response to placental human chorionic gonadotrophin during the first trimester, whereas FT4 tends to decrease in late gestation.[14] This is likely to be the cause for the high prevalence of suppressed TSH in this cohort. Furthermore increased serum thyroid-binding globulin and decreased albumin during pregnancy result in assay-dependent variations in FT4 levels.[15] These observations have led to the call for using trimester and assay-specific reference ranges for thyroid function tests in pregnancy.[16,17] If the trimester specific reference range is used, 9.8% pregnant women in this cohort will be considered to have hypothyroidism. Whereas there will be less of a controversy to use the trimester-specific reference range in titrating the dose of T4 in pregnant women on T4 replacement, further studies are needed to determine the threshold level of TSH at which initiation of T4 replacement should be considered. Clinical studies have confirmed that the increased requirement for T4 (or exogenous LT4) occurs as early as 4-6 weeks of pregnancy.[18] Such requirements gradually increase through 16-20 weeks of pregnancy, and thereafter plateau until time of delivery. These data provide the basis for recommending adjustments to thyroid hormone in affected women once pregnant and for the timing of follow-up intervals for TSH in treated patients.

The levothyroxine (LT4) adjustment, when necessary, should be made as soon as possible after pregnancy is confirmed to reduce the probability of hypothyroidism. Normalization of TSH levels throughout gestation is the goal. A prospective, randomized study has recently provided evidence in support of one dose adjustment strategy for women receiving LT4 who are newly pregnant.[19] For women who are euthyroid while receiving once-daily dosing of LT4 (regardless of amount), a recommendation to increase by two additional tablets weekly (nine tablets per week instead of seven tablets per week; 29% increase) can effectively prevent maternal hypothyroidism during the first trimester and mimic gestational physiology. This augmented dose should occur immediately after a missed menstrual cycle or suspected pregnancy occurs. Confirmatory biochemical testing should also occur simultaneously. A separate option is to increase the dosage of daily LT4 by approximately 25-30%.

There is also an uncertainty regarding the most appropriate initial screening test for thyroid dysfunction in pregnancy. The consensus guidelines recommend using TSH as the initial test[6], whereas others have stressed the importance of testing FT4 by highlighting the fact that FT4 (and FT3) is responsible for thyroid hormone action and that maternal hypothyroxinemia (normal TSH but low FT4) is associated with neuropsychological deficit in the offspring.[18] In our study, 9.8% of pregnant women had hypothyroxemia. The cause of maternal hypothyroxemia is not fully understood, but iodine deficiency is thought to be a major factor although urinary iodine was not analyzed in the present cohort, a previous study in this same population has shown that 7 and 40% pregnant women have urinary iodine excretion of less than 50 g/L (suggestive of dietary iodine deficiency) and 50-100 g/L (suggestive of borderline iodine deficiency).

Nearly one-quarter of hypothyroid women on T4 replacement in this study had raised TSH at their first antenatal visit. Given the fact that the fetus relies entirely on maternal thyroid hormones for its development until about 13 week of gestation, it is critical to ensure adequate T4 replacement in pregnant women during the first trimester. Hypothyroid pregnant women on T4 require an increased dose from as early as the fifth week of gestation to maintain optimum T4 replacement. Some recommend a 30% increase in the T4 dose as soon as the pregnancy is confirmed, with further dose adjustments based on TSH measurements. In addition, through education of all hypothyroid women in the reproductive age, every attempt should be made to ensure an adequate T4 replacement before a planned pregnancy.