Uncontrolled thyrotoxicosis has been associated with reduced fertility, miscarriage, preeclampsia, pre
term birth, placental abruption, and fetal hyperthyroidism.

Introduction 

Thyroid dysfunction is common in women of reproductive age.1 Normal functioning of the thyroid gland is essential for successful conception and pregnancy. Detection of thyroid disorders prior to pregnancy is of utmost importance due to the adverse effects thyroid abnormalities have on conception and pregnancy.  

 

Uncontrolled thyrotoxicosis has been associated with reduced fertility, miscarriage, preeclampsia, pre 

term birth, placental abruption, and fetal hyperthyroidism.1,2,3 Overt hypothyroidism has also been linked to adverse outcomes including impaired fertility, miscarriage, hypertensive disorders of pregnancy, placental abruption, preterm delivery, and higher rates of neonatal intensive care unit admissions as well as lower intelligence scores (IQ) in the offspring.4  

 

Subclinical hyperthyroidism and subclinical hypothyroidism (SCH) are biochemical diagnoses defined by an abnormal serum thyroid stimulating hormone (TSH) accompanied by normal concentrations of circulating thyroid hormones.  They may represent the earliest stages of thyroid dysfunction and can progress to overt disease.5 SCH has been linked to adverse outcomes such as subfertility, miscarriage, pre-term birth, pre-eclampsia, gestational hypertension, and perinatal mortality.6 

 

Thyroid auto-immunity 

Thyroid autoimmunity (TAI) describes the presence of circulating anti-thyroid autoantibodies that are targeted against the thyroid, with or without thyroid dysfunction. Thyroid peroxidase antibodies (TPOAb) are the most common anti-thyroid autoantibody, they are present in approximately 10% of women.7 

 

The presence of TPO antibodies, even in women with a normal thyroid function, has been shown to be associated with an increase in adverse pregnancy outcomes, such as miscarriage and preterm birth.8,9 There have been several randomised studies investigating whether levothyroxine treatment can improve pregnancy outcomes in women positive for TPOAb. The largest trial on the subject (TABLET trial) found no improvement in live birth outcome at or beyond 34 weeks in those taking levothyroxine (LT4) compared with placebo.10 However, the study found that around 7% of women with TPOAb went on to develop subclinical or overt hypothyroidism, either before or during pregnancy.10  

Bullet point guidance 

General guidance 

  • All women should have thyroid function testing (TFT; free T4 and TSH) performed.11
  • Women should have a documented normal TFT within the preceding 12 months of conception.
  • Overt thyroid disease should be managed jointly with endocrinologists.
  • Population-, trimester-, and laboratory- specific reference ranges for serum TSH should be applied when defining SCH. If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of 4.0 mIU/L may be used.
  • Levothyroxine dose should be based on maternal weight.
  • For women already taking levothyroxine, an empirical dose increase should be initiated from point of conception. Women should be advised to start taking double dose on 2 days of the week and require regular TFT monitoring starting at 7-9 weeks gestation.12

Overt hypothyroidism (TSH high, free T4 low) and subclinical hypothyroidism (TSH high, free T4 normal) 

  • Women should commence levothyroxine at a weight-adjusted dose (see below).
  • Repeat thyroid function tests (TFTs) 4 weeks later.
  • Women should be advised not to become pregnant until TFTs in normal range with optimal pre-conception TSH of <2.5 mIU/L.

Overt hyperthyroidism (TSH low, free T4 high) 

  • Clinicians should discuss with Endocrinologist regarding initiation of anti-thyroid drugs, and refer for further management.
  • Women should be advised not to become pregnant until TFTs in normal range.

Subclinical hyperthyroidism (TSH low, free T4 normal) 

  • No known adverse effects associated with subclinical hyperthyroidism in pregnancy.
  • In women whose TSH level is <0.1 mIU/L, endocrinology referral is advised to establish cause.
  • In women whose TSH level is between 0.1 mIU/L and the lower limit of the assay reference range, women should be reassured and offered repeat TFTs in 3-6 months.

Isolated hypothyroxinaemia (TSH normal, free T4 low) 

  • If detected before conception, Endocrinology referral should be made as this could signal pituitary dysfunction.
  • If detected in pregnancy, no further action is required.

Starting levothyroxine 

  • Levothyroxine should be prescribed in a weight-adjusted manner as follows:
  • <50 kg: commence 50 mcg once daily (OD)
  • 50-75 kg: commence 75 mcg OD
  • >75 kg: commence 100 mcg OD.
  • TFTs should be rechecked 4 weeks after levothyroxine initiation.
  • TSH levels should be <2.5 mIU/L preconception, or within trimester-specific reference ranges if pregnant.

Management of pregnant women who are on levothyroxine preconception 

  • Women should be advised to start taking double their preconception dose of levothyroxine on 2 days of the week (e.g., Saturdays/Sundays). 
  • TFTs should be checked from 7 weeks’ gestation and antenatal Endocrinology clinic referral should be made by community midwife.

Side effects of levothyroxine: angina pectoris, anxiety, arrhythmias, arthralgia, diarrhoea, dyspnoea, fever, flushing, headache, hyperhidrosis, insomnia, irregular menstruation, malaise, muscle spasms or weakness, oedema, palpitations, skin reactions, thyrotoxic crisis, tremor, vomiting and weight loss.13 

Contra-indications to levothyroxine: thyrotoxicosis. 

 

Thyroid autoimmunity 

  • Women should be advised that there is no benefit from levothyroxine treatment in improving pregnancy outcomes for TPOAb positive women who have a normal thyroid function. 
  • Knowing TPOAb status allows for stratification of women who will require thyroid function monitoring during pregnancy. The options of performing TPOAb testing for women with RPL versus routine early pregnancy TFT testing are both acceptable strategies, until clinical and cost-effectiveness analyses are available. 
  • If a woman is known to be TPOAb positive, measurement of serum TSH concentration should be taken at 7-9 weeks and then in each subsequent trimester (16-18 weeks and 28-30 weeks), due to the risk of progression to subclinical and overt hypothyroidism. 
  • Further studies are required to determine the role of selenium or steroids in improving pregnancy outcomes for euthyroid TPOAb-positive women. 

References 

  1. Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 2021; 397(10285): 1658-67.
  2. Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999 Jul;9(7):727–33.
  3. Earl R, Crowther CA, Middleton P. Interventions for preventing and treating hyperthyroidism in pregnancy. Cochrane Database of Systematic Reviews 2010;(9):CD008633.  
  4. Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Thyroid dysfunction and pregnancy outcomes. Iranian Journal of Reproductive Medicine 2015 Jul;13(7):387–96.
  5. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Journal of the American Medical Association 2004 Jan 14;291(2):228–38.
  6. van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JAM, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Human Reproduction Update. 2011 Oct;17(5):605–19.
  7. Dhillon-Smith RK, Tobias A, Smith PP, Middleton LJ, Sunner KK, Baker K, et al. The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility. Journal of Clinical Endocrinology and Metabolism. 2020 Aug 1;105(8).
  8. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011;342:d2616.
  9. Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, Taylor PN, Meima M, Chen L, et al. Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis. Journal of the American Medical Association. 2019 20;322(7):632–41.
  10. Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. New England Journal of Medicine. 2019 04;380(14):1316–25.
  11. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Human Reproduction Open [Internet]. 2018 Feb 1 [cited 2018 Apr 30];2018(2). Available from: https://academic.oup.com/hropen/article/2018/2/hoy004/4963604
  12. Yassa L, Marqusee E, Fawcett R, Alexander EK. Thyroid hormone early adjustment in pregnancy (the THERAPY trial). Journal of Clinical Endocrinology and Metabolism. 2010;95(7):3234-41.
  13. Joint Formulary Committee (2021). British National Formulary. Available at: bnf.nice.org.uk.