A Practical Approach to Hypothyroidism and Pregnancy
1V O’Dwyer, 1,2M Hatunic
1National Maternity Hospital, Holles Street, Dublin
2Mater Misericordiae University Hospital, Eccles Street, Dublin 7
The prevalence of hypothyroidism during pregnancy is estimated to be 0.3–0.5% for overt hypothyroidism and 2–3% for subclinical hypothyroidism (SCH)1. Thyroid hormone is critical for fetal brain development2. In the first trimester of pregnancy the fetus is completely dependent on the mother for the production of thyroid hormone. The fetus then starts to produce its own thyroid hormones from 16-20 weeks of pregnancy, but it still requires the mother to ingest adequate amounts of iodine to aid production of thyroxine. The World Health Organization recommends iodine intake of 250 micrograms/day during pregnancy to maintain adequate thyroid hormone production which is present in most western diets without supplementation.
Untreated hypothyroidism is associated with pregnancy complications such as spontaneous miscarriage, maternal anaemia, pre-eclampsia, small-for-gestational-age babies, preterm birth and postpartum haemorrhage3,4. Levothyroxine requirements in pregnancy frequently increase by 25-30 percent, and in some women levothyroxine requirements may increase by 50 percent. Hypothyroid women who are newly pregnant should pre-emptively increase their levothyroxine dose by approximately 30 percent and notify their clinician. Women with hypothyroidism should have Thyroid Stimulating Hormone (TSH) and thyroxine (free T4) checked once they have a positive pregnancy test. Thyroid function tests (TFTs) should be checked approximately every 4-6 weeks until the TSH becomes normal. Trimester specific ranges should be used for normal TSH. In the first trimester, TSH should be between 0.1-2.5mIU/l, in the second trimester 0.3-3.0mIU/l and third trimester 0.3-3.0mIU/l. If TSH is raised but <10mIU/L, increase the dose of levothyroxine by 25-50mcg and check TFTs four weeks later. A TSH level >10mIU/L should prompt referral to an endocrinologist. Free T4 should be kept between 10 and 21 pmol/L throughout pregnancy. Antenatal vitamin supplements that contain iron and calcium can impair the absorption of thyroid hormone from the gastrointestinal tract, therefore women should not take these at the same time of day and should be encouraged to take thyroxin one hour before food or two hours after food. Postpartum, the woman can go back to her pre-pregnancy dose of levothyroxine. TFTs should then be checked at the 6 week postnatal appointment.
In recent years, there has been a change in management of euthyroid women with infertility whose TSH is above the first trimester level of normal but below the upper limit of normal for a non-pregnant women. An increased risk of fetal loss, perinatal mortality, and large-for-gestational-age infants has been reported in euthyroid women with high serum thyroid peroxidase (TPO) antibody concentrations. Women with TSH levels between 2.5 mIU/L and 4.0 mIU/L and positive thyroid peroxidase TPO antibodies benefit from levothyroxine supplementation. This improves fertility rates, especially in unexplained infertility, and reduce miscarriage rates5. Up to 18% of pregnant women can have TPO antibodies. However, there is insufficient evidence to support treatment in this group to improve perinatal outcomes including fetal neurodevelopment. Treatment is not indicated for women with TSH between 2.5 mIU/L and 4.0 mIU/L who do not have TPO antibodies.
Subclinical hypothyroidism (SCH) is defined as a serum (TSH) level above the upper limit of normal (>4mIU/L) despite normal levels of serum-free T46. It affects between 3-8% of the population, and may progress to clinical hypothyroidism. It has been suggested that SCH may be associated with adverse maternal and fetal outcomes. A Dublin study of 904 low-risk primigravidas found that SCH and isolated maternal hypothyroxinaemia was associated with an increased risk of placental abruption7. Another Dublin study found that children of mothers who had unrecognised SCH during pregnancy had significantly lower IQ scores, using the Wechsler Intelligence Scale for Children IV assessment, at age 7-8 compared with controls. However, the numbers in this study were small8. A systematic review and meta-analysis found that SCH during pregnancy was associated with multiple adverse maternal and neonatal outcomes but the value of levothyroxine therapy in preventing these adverse outcomes was uncertain9.
Routine screening for SCH in pregnancy is not recommended by the American College of Obstetricians. The Controlled Antenatal Thyroid Study (CATS) did not show a cognitive benefit in offspring to mothers treated with thyroxine in pregnancy who had SCH or hypothyroxaemia when compared with controls. This was a large randomised controlled trial of pregnant women who were screened for either isolated high TSH or isolated low free thyroxine level. Children of treated women with either diagnosis were compared with children of controls. Treatment had no effect on mean offspring IQ at age 3 years. A recently published randomised controlled trial in New England Journal of Medicine (NEJM) was conducted to examine perinatal outcomes in women with subclinical hypothroidism 11. Subclinical hypothyroidism was defined as TSH level ≥4.0mIU and normal free T4 or hypothyroxaemia defined as normal TSH level and free T4 <0.86ng/dl. All women had a singleton pregnancy and were enrolled before 20 weeks gestation. The women were either treated with levothyroxine or placebo. Of the 677 women randomised in the subclinical hypothyroidism group, there was no difference between adverse perinatal and neonatal outcomes between the treatment and placebo group. Of the 526 randomised in the hypothyroxaemia group there was also no difference between adverse perinatal and neonatal outcomes between the treatment and placebo group. Developmental and behavioural outcomes were assessed in both groups up to 5 years of age and again there was no difference between the treatment and placebo groups10. The recent guidelines of the American Thyroid Association recommend early initiation of low-dose levothyroxine therapy for subclinical hypothyroidism as it may be of benefit and it is inexpensive, and is unlikely to be harmful12.
The benefits of treating overt hypothyroidism are clear. It remains uncertain as to whether treating subclinical hypothyroidism improves maternal and fetal outcomes including neurodevelopmental outcomes in childhood.
Dr. Vicky O’Dwyer, Maternal Medicine Fellow, National Maternity Hospital, Holles Street, Dublin
Phone number: 016373100
1. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, and Stagnaro-Green A. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol & Metab. 2007; 92 (Supplement):S1–S47.
2. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, Mitchell ML.Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41–46.
3. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol. 1988 Jul; 72(1):108-12.
4. Sheehan PM, Nankervis A, Araujo Júnior E, Da Silva Costa F. Maternal Thyroid Disease and Preterm Birth: Systematic Review and Meta-Analysis, J Clin Endocrinol Metab. 2015; 100: 4325-31.
5. Springer D, Jiskra J, Limanova Z, Zima T, Potlukova E.Thyroid in pregnancy: From physiology to screening. Crit Rev Clin Lab Sci. 2017; 54: 102-116.
6. Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260-265
7. Breathnach FM, Donnelly J, Cooley SM, Geary M, Malone FD. Subclinical hypothyroidism as a risk factor for placental abruption: evidence from a low-risk primigravid population. Aust N Z J Obstet Gynaecol. 2013; 53: 553-60.
8. Murphy NC, Diviney MM, Donnelly JC, Cooley SM, Kirkham CH, Foran AM, Breathnach FM, Malone FD, Geary MP. The effect of maternal subclinical hypothyroidism on IQ in 7- to 8-year-old children: A case-control review. Aust N Z J Obstet Gynaecol. 2015; 55: 459-63.
9. Maraka S, Ospina NM, O’Keeffe DT, Espinosa De Ycaza AE, Gionfriddo MR, Erwin PJ, Coddington CC 3rd, Stan MN, Murad MH, Montori VM. Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis. Thyroid. 2016; 26: 580-90.
10. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall’Amico D, Parkes AB, Joomun M, Wald NJ. Antenatal thyroid screening and childhood cognitive function. N Engl J Med 2012; 366: 493-501.
11. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr, Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP.Treatment of subclinical hypothyroidism or hypothyroxaemia in pregnancy. N Engl J Med 2017; 376: 815-25.
12. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman WA, Laurberg P, Lazarus JH, Mandel SJ, Peeters RP, Sullivan S. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27:315-389.