Hypothyroidism complicates up to 3% of pregnancies, of which 0.3–0.5% is overt and 2.0–2.5% is subclinical hypothyroidism.[2,5] When iodine intake is sufficient, the most common cause of hypothyroidism during pregnancy is chronic autoimmune thyroiditis whereas a smaller proportion is due to iatrogenic causes including surgery to treat thyroid cancer or nodules or radioactive iodine ablation to treat hyperthyroidism. Pregnant women or women planning pregnancies are diagnosed with overt hypothyroidism when they have elevated TSH levels with low free T4 concentrations, preferably defined with pregnancy-specific reference intervals.[2,5] However, pregnant women with TSH over 10 mIU/l are always diagnosed with overt hypothyroidism, irrespective of free T4 concentrations.[2,5] Subclinical hypothyroidism is diagnosed when TSH is elevated but less than 10 mIU/l and fT4 concentrations are normal.[2,5]
Overt and subclinical hypothyroidism as well as increases in maternal TSH concentrations have been associated with increased risk of miscarriages/fetal losses,[13–20] hypertensive disorders of pregnancy,[18,21–24] placental abruptions,[22,25] preterm birth[19,20,25–28] and poor neurological development in the offspring.[20,29,30] Overt hypothyroidism has also been associated with maternal anemia and postpartum hemorrhage, and subclinical hypothyroidism with cesarean sections, gestational diabetes,[25,31] breech presentation,[32,33] infants being small for gestational age, fetal distress, neonates needing intensive care treatment[25,27] and respiratory distress syndrome. However, some studies have found no association between adverse perinatal outcomes and hypothyroidism.[34–39]
In a large cohorts, women with diagnosed hypothyroidism (without data on treatment) or treated hypothyroidism (without data on treatment adequacy) had higher risk of pregnancy complications such as preeclampsia,[40–42] gestational diabetes,[40,41] cesarean sections,[40,41] labor inductions,[40,41] preterm birth,[40,41] malformations, placental abruptions, intensive care unit admissions and neonatal complications including need for intensive care unit treatment, respiratory problems, sepsis, anemia and infants being both large or small for gestational age (depending on the race/ethnicity of the mother). Adequately treated hypothyroidism still appears to increase risk of cesarean sections[44,45] but is not associated with other adverse outcomes.
Due to the well-established associations between overt hypothyroidism and adverse pregnancy outcomes, overt hypothyroidism should be promptly treated to attempt to mitigate these known risks.[2,5] However, there is debate about whether to treat all women with subclinical hypothyroidism. Two different strategies are proposed: to treat everyone or to treat women with subclinical hypothyroidism and positive thyroid antibodies. Up to 40% of women with positive thyroid antibodies develop hypothyroidism during or immediately after pregnancy, but most studies evaluating the association between subclinical hypothyroidism and pregnancy outcomes have been cross-sectional and based on first trimester measures of thyroid function. Therefore, more information is needed to determine whether hypothyroidism detected in the first trimester will progress, which factors predict disease progression, and if some women switch from hypothyroidism to euthyroidism as pregnancy continues. In a study evaluating treatment for subclinical hypothyroidism, 44% of women with initially high TSH had normal thyroid function tests in a repeat sample taken 1 week later. An ongoing randomized placebo controlled trial of levothyroxine treatment for subclinical hypothyroidism during pregnancy with early pregnancy sampling and longitudinal follow-up will provide new information on the natural history of untreated subclinical hypothyroidism and indicate whether levothyroxine treatment is beneficial in reducing adverse outcomes.
Treatment of Hypothyroidism During Pregnancy
Levothyroxine is the treatment of choice for hypothyroidism with the goal of normalizing serum TSH concentrations, using the pregnancy-specific reference intervals. In pregnancy, treatment should be started with a dose as close to the final estimated dose as possible to minimize time with hypothyroidism.[20,47] Pregnancy increases levothyroxine requirements in the majority of women very early on among those diagnosed and treated for hypothyroidism before conception. Women with levothyroxine treatment should have preconception TSH levels less than 2.5 mIU/l to minimize the probability of hypothyroidism during pregnancy. However, even with adequate preconception management of hypothyroidism, up to 27% of women had elevated TSH concentrations in early pregnancy. Therefore, the current recommendation is for women to increase their levothyroxine dose by 25–30% upon missed periods. Interestingly, 50 and 17% women with prepregnancy TSH levels of 1.21–2.40 and 0.1–1.2 mIU/l, respectively, needed levothyroxine dose increases during pregnancy. This indicates that tighter hypothyroidisms control before pregnancy might reduce the risk of elevated TSH levels in pregnancy.
In one trial, hypothyroid women (irrespective of cause but with baseline TSH less than 5.0 mIU/l) were randomized to receive two or three extra levothyroxine tablets per week once pregnancy was confirmed, resulting in 29–43% increase in their medication. Under this strategy, 58–78% of women maintained euthyroidism throughout pregnancy. Those requiring dose reductions were more often athyreotic, had high prepregnancy levothyroxine doses (at least 100 μg/day) or prepregnancy TSH less than 1.5 mIU/l. Most women did not need additional levothyroxine dose increases under this treatment strategy.
The etiology of thyroid disease also affects the need of levothyroxine dose adjustments in pregnancy. Women with post-ablative or surgical hypothyroidism required higher dose increases than those with primary hypothyroidism or thyroid cancer, irrespective of good baseline management of hypothyroidism. In another study where women with subclinical, overt and post-ablative hypothyroidism were diagnosed and adequately treated before pregnancy, those with subclinical hypothyroidism required the highest absolute dose increases in levothyroxine. These studies would suggest that an individualized approach based on baseline TSH concentrations and etiology of hypothyroidism could be utilized when counseling women treated with levothyroxine who are planning pregnancy, as lower baseline TSH levels could potentially reduce risks of TSH elevation in early pregnancy. However, there are no large prospective studies evaluating the effectiveness of this strategy. Given that pregnant women are at increased risk of TSH elevations, tests for thyroid function should begin early in pregnancy, continuing every 4 weeks until mid-gestation and at least once between 26 and 32 weeks among those with levothyroxine treatment to ensure euthyroidism throughout pregnancy.[2,5] Monitoring thyroid function tests every 4 weeks during pregnancy detected over 90% of abnormal values in one study.
Similarly, the etiology and severity of hypothyroidism diagnosed during pregnancy affects the levothyroxine dose required to achieve and maintain euthyroid status. Newly diagnosed overt hypothyroidism in pregnancy required almost double the dose of levothyroxine compared with those treated for subclinical disease. Among women with subclinical hypothyroidism during pregnancy, those with baseline TSH up to 4.2 mIU/l required smaller levothyroxine doses (1 μg/kg/day) than those with baseline TSH 4.2–10 mIU/l (1.42 μg/kg/day) to achieve euthyroidism. When treating women with subclinical hypothyroidism with steady doses of levothyroxine based on their baseline TSH levels, 79, 82 and 90% of women with baseline TSH 2.5–5.0 mIU/l, 5.0–8.0 mIU/l and higher than 8.0 mIU/l, respectively, reached euthyroidism with respective levothyroxine doses of 50, 75 and 100 μg/day. Either weight-based starting dose or a steady starting dose based on the severity of newly diagnosed hypothyroidism determined by baseline TSH concentration seem to be appropriate in reaching euthyroidism.
Effectiveness of Levothyroxine Treatment. There are no prospective randomized controlled trials to study the effectiveness of levothyroxine treatment to prevent adverse outcomes among women with overt hypothyroidism, but as the association between overt hypothyroidism and adverse outcomes is well established, such a trial would be unethical. In a systematic review, treatment of clinical hypothyroidism was shown to reduce risk of miscarriage and preterm birth.
There is currently insufficient evidence to show clear benefits of treating subclinical hypothyroidism. In one trial randomizing women to case finding or universal screening for thyroid disease during pregnancy, 91.2% of all women with undiagnosed and untreated hypothyroidism had at least one adverse outcome, whereas the rate was 35% among those with diagnosed and treated hypothyroidism. The number of hypothyroid women needed to treat to prevent adverse outcomes was approximately 1.8. In a randomized trial, the infants of women with untreated thyroid hypofunction had similar intelligence quotient as those of women treated with levothyroxine. Among women undergoing assisted reproduction, levothyroxine treatment of subclinical hypothyroidism has been shown to reduce miscarriages in some but not all studies. An ongoing randomized placebo controlled trial, expected to be completed in 2015, will provide new evidence on treatment efficacy among women with subclinical hypothyroidism and show if treating maternal subclinical hypothyroidism is beneficial in preventing adverse intellectual outcomes in the offspring and have an effect on perinatal and neonatal outcomes.
Caveats of Levothyroxine Treatment During Pregnancy. Only about 62–82% of all ingested levothyroxine is absorbed, with concurrent ingestion of food, caffeine and iron and calcium supplements decreasing the absorption further. Levothyroxine should be ingested in the morning at least 60 min before eating. Additionally, there should be a 4- to 6-h gap between levothyroxine ingestion and administration of other medications that decrease levothyroxine absorption. This includes common dietary supplements such as iron and calcium in prenatal vitamins, which are routinely administered to nearly all pregnant women. In addition, several chronic conditions including coeliac disease, lactose intolerance and atrophic gastritis decrease absorption of levothyroxine if untreated. Compliance with medication as well as gastrointestinal conditions and medication interference should be evaluated in women with persistent hypothyroidism requiring higher than normal doses of levothyroxine.
Different levothyroxine products are not clinically interchangeable and there might be more than 12.5% difference in levothyroxine doses between products.[59,60] As levothyroxine has a narrow therapeutic range, such differences may be clinically meaningful and lead to deviations from euthyroidism when switching from one product to another.[59,60] Indeed, in a survey to physicians treating patients with levothyroxine, most reports of changes in thyroid function were after switching between levothyroxine products, often by the pharmacy without the physician's knowledge. For optimized therapy, patients are often advised to stay on the same brand of levothyroxine and warned that pharmacies may switch the brands without consultation. If products are switched, thyroid function tests should be performed to ensure euthyroidism. Staying under the same levothyroxine brand might be especially crucial in pregnancy where adverse effects of hypothyroidism are well established.
Treatment of Hypothyroidism During the Postpartum Period. Most women with hypothyroidism can reduce their dose of levothyroxine postpartum, with assessment of TSH levels 6 weeks following the dose reduction to ensure euthyroidism.[2,48,62] Women with positive thyroid antibodies are at higher risk of exacerbation of autoimmune thyroid dysfunction postpartum, and over 50% of women with Hashimoto's thyroiditis continued to require increased doses of levothyroxine in the postpartum period. Women with subclinical hypothyroidism during pregnancy may not require levothyroxine treatment during the postpartum period, unless postpartum thyroiditis ensues or the woman is planning to conceive again soon. These women are at high risk for thyroid dysfunction in their subsequent pregnancies and require adequate preconception consultation and management. They are also at higher risk of developing permanent thyroid disease later in life.
Expert Rev Endocrinol Metab. 2013;8(6):537-547. © 2013 Expert Reviews Ltd.