Education Resource from the Society for Endocrinology
J Lazarus
Dept Medicine,University of Wales College of Medicine,Cardiff
Endocrine Nurses Training Course 9-11
September 2004
Wills Hall, Stoke Bishop, Bristol, BS9 1AE
Hyperthyroidism is found in 0.2% of all pregnancies. It is usually due to Graves’ disease and characterised by TSH receptor stimulating antibodies (TSHRAb) which usually decrease in titre through gestation. Maternal complications include miscarriage, placenta abruptio and preterm delivery. Congestive heart failure and thyroid storm may also occur and the risk of pre-eclampsia is significantly higher in women with poorly controlled hyperthyroidism. Also, if high titres of TSHRAb are present at 36 weeks gestation there is a high risk of neonatal thyrotoxicosis, which, while transient, may cause significant neonatal morbidity if unrecognised.
Hypothyroidism usually characterised by a high TSH level has been found to occur in around 2.5% of otherwise normal pregnancies. Again, untreated hypothyroidism may lead to obstetric complications such as preterm delivery as well as fetal loss. In addition important evidence has been presented during the last decade to show that the progeny of hypothyroxinaemic women have psychoneurological deficits. In a study by Haddow et al a group of 7 year old children born to mothers known to have a high TSH during pregnancy was compared to a control group whose mothers were known to have had normal TSH. The striking finding was that 19% of the former had an IQ < 85 compared to 5% of the control group, a highly significant difference. Similar data have been recorded in The Netherlands. In classical areas of iodine deficiency a range of psychological and neurological deficits in children have been described during the past century but in many of the mothers it is the maternal hypothyroxinaemia rather than high TSH that is the striking abnormality. In these areas maternal iodine intake is often substantially less than the 200µg per day currently recommended. Even in areas thought to be iodine sufficient there is evidence of substantial gestational iodine deficiency leading to low maternal circulating thyroxine concentrations. As maternal thyroxine is critical to fetal nervous system maturation even modest states of iodine deficiency could be deleterious.
Thyroid antibodies, particularly anti thyroid peroxidase antibody (AntiTPOAb), occur in 10% of women at 14 weeks gestation. A proportion of these will have subclinical hypothyroidism with a high TSH (see above) but most will be euthyroid. However, following delivery thyroid dysfunction will develop in 50% of TPOAb positive women as ascertained in early gestation clinically apparent as postpartum thyroiditis. In addition to the childhood neuropsychological problems relating to low thyroxine levels there is some evidence from a retrospective study that maternal antiTPOAb may result in intellectual impairment even when there is normal thyroid function. Postpartum Graves’ disease also develops in predisposed women although the prevalence of TSHRAb during gestation is much less than that of TPOAb.
The thyroid abnormalities during gestation described above suggest that screening for thyroid dysfunction in relation to pregnancy should be strongly considered. Detection of hyperthyroidism has been undertaken in Japan by testing for TSHRAb. However the current cost of this strategy relative to the incidence of the condition makes it impractical at least in the UK.
If screening for hypothyroidism during gestation is offered then treatment of hypothyroidism – even subclinical - with thyroxine should be instituted. What screening tests should be used? Serum free or total thyroxine have high sensitivity and specificity for diagnosis of hypothyroidism; so also has serum TSH. Preliminary data from an ongoing screening study suggests that utilising both parameters results in two abnormal pregnant populations namely about half with a low T4 and an equal number with a high TSH with very few having both a low T4 and a high TSH.
There is no correct screening service in the UK but interim measures can be proposed. Optimum iodine nutrition during pregnancy should be ensured; women with known thyroid disease should be identified in order to appraise them of the potential problems of low thyroid function during pregnancy; identification of women at increased risk for thyroid disease e.g. with Type 1 diabetes, or a positive family history of other autoimmune conditions.
The benefits of screening in this setting are the high incidence of thyroid failure in pregnancy, the high specificity of FT4 and TSH for detection of the thyroid failure and the (presumed) benefit of T4 therapy on fetal brain development. The disadvantages include inevitable maternal anxiety at the time of testing and during the childhood period.
The cost of such a programme must be appreciated. However, experience from the neonatal hypothyroid screening service (now routine in the UK) suggests that the costs of the reagents and administration may provide a value for money return.
This is characterised by the development of hyper / hypothyroidism or both around 13 to 19 weeks postpartum respectively. It occurs in 5-9% of women and is strongly associated with the presence of antiTPOAb. Of the 10% of women who are found to be antiTPOAb positive in early gestation 50% will develop postpartum thyroid dysfunction (PPTD). The condition is transient but 20-30% will develop permanent hypothyroidism. Long term follow up studies show that 50% of those whose thyroid function recovers after an episode of PPTD will become hypothyroid at 7 years compared to about 5% of antibody positive patients who were PPTD negative (i.e. euthyroid postpartum). In addition there is a higher rate of postpartum psychiatric symptomatology in all TPOAb positive women compared to controls. There is also considerable morbidity associated with the hypothyroid phase of PPTD. However, levothyroxine therapy results in a satisfactory clinical state. Although the sensitivity of TPOAb measured during early pregnancy is only 50% there is evidence that the gestational titre of antibody is also predictive of disease. Proponents of screening for PPTD justify it on the basis that it is relatively common, causes significant morbidity and can be diagnosed with freely available tests that are inexpensive. Effective treatment is available if required. Screening may also be pertinent in view of the high prevalence of long-term thyroid dysfunction in these women. However, there is a lack of consensus about the timing of screening or the screening test for PPTD prediction. TPOAb, free thyroxine or TSH have all been suggested as possible screening tools. Opponents of screening cite the lack of good prospective cost-benefit analyses to support their view. Targeted screening has been advocated, of individuals at the highest risk of developing PPTD, such as subjects with previous PPTD and type 1 diabetes mellitus. Nearly 70% of subjects who had PPTD had a recurrence in a subsequent pregnancy. Similarly, subjects with type 1 diabetes mellitus have a 25% prevalence of PPTD. The cost of testing is relatively high but new assay techniques will reduce this. The high incidence of the disease suggests that a significant reduction in postpartum morbidity will be derived from a screening strategy.
Allen WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Helmos RJ, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000;7:127-130
Amino N, Tada H, Hidaka Y, Crapo LM, Stagnaro-Green A: Therapeutic controversy. Screening for postpartum thyroiditis. J Clin Endocrinol Metab 1999; 84:1813-1821
Gonzalez-Jimenez A, Fernandez-Soto ML, Escobar-Jimenez F, Glinoer D, Navarrete L. Thyroid function parameters and TSH-receptor antibodies in healthy subjects and Graves' disease patients: a sequential study before, during and after pregnancy. Thyroidology 1993;5:13-20
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-555
Hidaka Y, Tamaki H, Iwatani Y, Tada H, Mitsuda N, Amino N. Prediction of post-partum Graves' thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy. Clin Endoc 1994;41:15-20
Klein RZ, Haddow JE, Faixt JD, Brown RS, Hermos RJ, Pulkkinen A, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endoc 1991;35: 41-46
Lazarus JH, Kokandi A: Thyroid disease in relation to pregnancy: A decade of change. Clin Endocrinol 2000; 53:265-278
Lazarus JH, Parkes AB, Premawardhana LD. Postpartum thyroiditis. Autoimmunity 2002;35:169 173
Muller AF, Drexhage HA, Bergout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endoc Rev 2001;22:605-630
Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, Donkers MM, Komproe IH, van Son MM, Vader HL. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 1995;80:3561-3566.
Pop VJ, Brouwers EP, Vader HL, Vulsma T, can Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003;59:280-281.
The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society