NIHR Signal Treating subclinical thyroid dysfunction in pregnancy probably has no benefit

Published on 8 August 2017

Testing for and then treating pregnant women with mild or “subclinical” underactive thyroid did not improve pregnancy outcomes, newborn baby outcomes, or the child’s IQ at three to five years.

A clearly underactive thyroid (clinical hypothyroidism) in pregnancy has been linked with various adverse outcomes for the mother and baby, including pre-eclampsia, preterm birth, congenital defects and neurodevelopmental delay. This needs treatment. However, there has been debate around the harms and benefits from treating only mildly abnormal blood test results in women who do not show signs of thyroid problems, subclinical hypothyroidism.

These two linked trials randomised 1,203 women with borderline abnormal levels of thyroid-related hormones (but not “clinical” or “overt” hypothyroidism) to receive thyroid replacement treatment, with levothyroxine, or placebo. Treatment had no benefits for mother or baby, including the main outcome of child IQ by three to five years of age.

This supports current UK practice, which does not routinely screen all pregnant women for subclinical thyroid dysfunction.

Treating subclinical thyroid dysfunction in pregnancy probably has no benefit

Share your views on the research.

Why was this study needed?

The thyroid gland produces hormones that help to regulate the body’s metabolism. Around 15 in every 1,000 women in the UK have an underactive thyroid though fewer women in pregnancy have the condition, about four in every 1,000 women. People with definite (clinical) low thyroid hormones can feel tired or depressed, gain weight and experience muscle aches, it can also lead to high cholesterol. In pregnancy there can also be harms to the unborn child including failure to develop normally and reduced intelligence. Therefore, clinical hypothyroidism during pregnancy is usually treated with levothyroxine, a drug that replaces thyroid hormone.

However, the exact risks associated with borderline blood levels, and the cut-off thyroid levels for treatment are not clear. There could even be harms from unnecessarily treating women with sub-clinical hypothyroidism. About 5% of women screened in pregnancy would be labelled as having sub-clinical hypothyroidism, depending on definitions.

What did this study do?

This study comprised two randomised controlled trials of women identified through antenatal clinic screening prior to 20 weeks of pregnancy. They were found to have only one abnormal of the two indicator hormones; both are abnormal in clinical hypothyroidism. The practicalities of screening meant that women were at 16 weeks gestation when they started treatment.

One trial included 677 women with “subclinical” hypothyroidism defined by normal thyroid hormone (thyroxine, T4) levels, but high thyroid stimulating hormone (TSH) levels of 4.00mU/L or greater. These women were randomised to either 100µg of levothyroxine or a placebo, with dose adjustment.

The other trial included 526 women with hypothyroxinemia, defined by low thyroxine (T4) levels (less than 0.86ng/dL) but normal TSH levels. They were randomised to either 50µg of levothyroxine or placebo, with dose adjustment.

The main outcome examined was the child’s IQ at three to five years, but several others were also measured.

What did it find?

  • Levothyroxine treatment during pregnancy had no significant effect on child IQ at age three to five years. In the high TSH trial the difference in IQ score was zero (95% confidence interval [CI] -3 to 2), and in the low T4 trial, -1 (95% CI -4 to 1).
  • Treatment also did not affect the child’s cognitive, motor, language, information processing ability or their behaviour up to five years of age.
  • Levothyroxine treatment had no effect on the frequency of any other adverse maternal or neonatal outcomes in either trial, such as pre-eclampsia, preterm birth, birth weight, neonatal intensive care admission, miscarriage or stillbirth.

What does current guidance say on this issue?

There is no UK guidance to screen for hypothyroidism from the National Screening Committee or in the NICE antenatal guideline. Nor is there guidance to treat sub-clinical hypothyroidism

NICE Clinical Knowledge Summaries outline various criteria for testing thyroid function for women who are pregnant or planning a pregnancy. This includes testing for those over 30 years of age, with thyroid swelling or symptoms of thyroid dysfunction, with a personal or family history of a thyroid condition, with diabetes, morbid obesity or an autoimmune condition, after head or neck radiotherapy, or after past miscarriage or preterm delivery.

What are the implications?

This large trial indicates that treating subclinical hypothyroidism or hypothyroxinemia does not affect pregnancy outcomes or newborn outcomes, or affect the child’s neurodevelopment up to five years of age. This agrees with the previous large UK CATS trial of screening that reported while this study was underway.

This suggests that there is no advantage to treating women in this subclinical and asymptomatic group, and therefore no benefit in screening. This aligns with current UK practice, which does not routinely screen all pregnant women for thyroid dysfunction.

The results do not apply to women with overt thyroid disorders or to those discovered in early pregnancy before 16 weeks. There could be a small benefit to the developing foetus if the problem were detected and treatment started very early in pregnancy, but this is unknown.

Citation and Funding

Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.

This trial was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the US National Institute of Neurological Disorders and Stroke.

Bibliography

BTF. Thyroid in Pregnancy - FAQs. Harrogate: British Thyroid Foundation; 2015.

CKS. Hypothyroidism: screening for hypothyroidism. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: assessment. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: levothyroxine. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: preconception or pregnant. London: National Institute for Health and Care Excellence; 2016.

NHS Choices. Underactive thyroid (hypothyroidism). London: Department of Health; 2015.

Why was this study needed?

The thyroid gland produces hormones that help to regulate the body’s metabolism. Around 15 in every 1,000 women in the UK have an underactive thyroid though fewer women in pregnancy have the condition, about four in every 1,000 women. People with definite (clinical) low thyroid hormones can feel tired or depressed, gain weight and experience muscle aches, it can also lead to high cholesterol. In pregnancy there can also be harms to the unborn child including failure to develop normally and reduced intelligence. Therefore, clinical hypothyroidism during pregnancy is usually treated with levothyroxine, a drug that replaces thyroid hormone.

However, the exact risks associated with borderline blood levels, and the cut-off thyroid levels for treatment are not clear. There could even be harms from unnecessarily treating women with sub-clinical hypothyroidism. About 5% of women screened in pregnancy would be labelled as having sub-clinical hypothyroidism, depending on definitions.

What did this study do?

This study comprised two randomised controlled trials of women identified through antenatal clinic screening prior to 20 weeks of pregnancy. They were found to have only one abnormal of the two indicator hormones; both are abnormal in clinical hypothyroidism. The practicalities of screening meant that women were at 16 weeks gestation when they started treatment.

One trial included 677 women with “subclinical” hypothyroidism defined by normal thyroid hormone (thyroxine, T4) levels, but high thyroid stimulating hormone (TSH) levels of 4.00mU/L or greater. These women were randomised to either 100µg of levothyroxine or a placebo, with dose adjustment.

The other trial included 526 women with hypothyroxinemia, defined by low thyroxine (T4) levels (less than 0.86ng/dL) but normal TSH levels. They were randomised to either 50µg of levothyroxine or placebo, with dose adjustment.

The main outcome examined was the child’s IQ at three to five years, but several others were also measured.

What did it find?

  • Levothyroxine treatment during pregnancy had no significant effect on child IQ at age three to five years. In the high TSH trial the difference in IQ score was zero (95% confidence interval [CI] -3 to 2), and in the low T4 trial, -1 (95% CI -4 to 1).
  • Treatment also did not affect the child’s cognitive, motor, language, information processing ability or their behaviour up to five years of age.
  • Levothyroxine treatment had no effect on the frequency of any other adverse maternal or neonatal outcomes in either trial, such as pre-eclampsia, preterm birth, birth weight, neonatal intensive care admission, miscarriage or stillbirth.

What does current guidance say on this issue?

There is no UK guidance to screen for hypothyroidism from the National Screening Committee or in the NICE antenatal guideline. Nor is there guidance to treat sub-clinical hypothyroidism

NICE Clinical Knowledge Summaries outline various criteria for testing thyroid function for women who are pregnant or planning a pregnancy. This includes testing for those over 30 years of age, with thyroid swelling or symptoms of thyroid dysfunction, with a personal or family history of a thyroid condition, with diabetes, morbid obesity or an autoimmune condition, after head or neck radiotherapy, or after past miscarriage or preterm delivery.

What are the implications?

This large trial indicates that treating subclinical hypothyroidism or hypothyroxinemia does not affect pregnancy outcomes or newborn outcomes, or affect the child’s neurodevelopment up to five years of age. This agrees with the previous large UK CATS trial of screening that reported while this study was underway.

This suggests that there is no advantage to treating women in this subclinical and asymptomatic group, and therefore no benefit in screening. This aligns with current UK practice, which does not routinely screen all pregnant women for thyroid dysfunction.

The results do not apply to women with overt thyroid disorders or to those discovered in early pregnancy before 16 weeks. There could be a small benefit to the developing foetus if the problem were detected and treatment started very early in pregnancy, but this is unknown.

Citation and Funding

Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.

This trial was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the US National Institute of Neurological Disorders and Stroke.

Bibliography

BTF. Thyroid in Pregnancy - FAQs. Harrogate: British Thyroid Foundation; 2015.

CKS. Hypothyroidism: screening for hypothyroidism. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: assessment. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: levothyroxine. London: National Institute for Health and Care Excellence; 2016.

CKS. Hypothyroidism: preconception or pregnant. London: National Institute for Health and Care Excellence; 2016.

NHS Choices. Underactive thyroid (hypothyroidism). London: Department of Health; 2015.

Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy

Published on 2 March 2017

Casey, B. M.,Thom, E. A.,Peaceman, A. M.,Varner, M. W.,Sorokin, Y.,Hirtz, D. G.,Reddy, U. M.,Wapner, R. J.,Thorp, J. M., Jr.,Saade, G.,Tita, A. T.,Rouse, D. J.,Sibai, B.,Iams, J. D.,Mercer, B. M.,Tolosa, J.,Caritis, S. N.,VanDorsten, J. P.

N Engl J Med Volume 376 , 2017

Background Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children. Methods We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4 level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years. Results A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups. Conclusions Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297 .).

Expert commentary

A baby’s development can be affected if its mother has reduced thyroid function in pregnancy. It is not clear at what level of thyroid function treatment is needed. This makes doctors and pregnant women anxious, and there is a risk of overtreatment to avoid possible harm.

This study helps to reassure doctors and pregnant women that treatment of minor changes in thyroid blood tests during pregnancy is not needed. However, the study does not include treatment in very early pregnancy where benefits remain unknown.

Dr Kate Wiles, NIHR Doctoral Research Fellow, Women's Health Academic Centre, King's Health Partners, St. Thomas' Hospital