Subclinical Hypothyroidism pendant la grossesse: traiter ou ne pas traiter. Professor Catherine Nelson-Piercy, Londres

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1 Subclinical Hypothyroidism pendant la grossesse: traiter ou ne pas traiter Professor Catherine Nelson-Piercy, Londres

2 Controversies: Thyroid disease in pregnancy 2 Should women with subclinical hypothyroidism (SCH) be treated in pregnancy? Should all pregnant women with autoimmune hypothyroidism have increased T4 dose? Should women be changed from carbimazole to propylthiouracil in early pregnancy?

3 35 year old woman 3 Previous miscarriage at 7 weeks gestation Positive pregnancy test 2 weeks ago LMP 6 weeks ago Family history of autoimmune hypothyroidism TSH 3.6 mu/l, ft4 14 pmol/l Would you prescribe thyroxine?

4 Definitions 4 Overt hypothyroidism TSH thyroxine or an isolated TSH concentration > 10 mu/l. Subclinical hypothyroidism (SCH) TSH normal thyroxine

5 Overt Hypothyroidism is not the same as SCH 5 Treating overt hypothyroidism leads to improved obstetric and neonatal outcomes. Evidence for the management of subclinical hypothyroidism and appropriate treatment targets in pregnancy are lacking. Despite this, international guidelines have set a low TSH threshold for the diagnosis and treatment of both new and pre-existing hypothyroidism in pregnancy. This threshold potentially increases the prevalence of SCH in pregnancy and may medicalise women despite a lack of clear evidence that treatment improves outcome. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21: Lazarus J, Brown RS, Daumerie C, et al European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3:76-94.

6 Hypothyroidism in pregnancy Good control normal maternal course thyroid function test in each trimester if euthyroid, T4 requirements usually stable Overt maternal hypothyroidism intellectual impairment in childhood pre-eclampsia IUGR, abruption, prematurity fetal death

7 odified from Casey et al. Obstet Gynecol 2006; 108: Alterations in thyroid function tests in pregnancy TBG Total T4 HCG TSH Free T Weeks of gestation

8 What is a normal TSH in pregnancy 8 Upper limit for TSH outside of pregnancy is 4.12 mu/l. Guidelines recommend a TSH concentration < 2.5 mu/l in first trimester 1st trimester TSH from cohorts of women without pre-existing thyroid disease 4.87 mu/l in China Li et al. J Clin Endocrinol Metab 2014;99: mu/l in the United States Casey et al. Obstet Gynecol 2007;109: mu/l in the UK Cotzias et al. Eur J Obstet Gynecol Reprod Biol 2008;137:61-6. Cohort study of > 17,000 pregnant women (Casey et al) 3.4% had SCH diagnosis based on TSH > 97.5th centile, corrected for gestational age (TSH> mu/l). Threshold of 2.5 mu/l associated with higher prevalence of gestational hypothyroidism: > 15% US and Netherlands; 28% of Chinese Similarly, 43% of women with known hypothyroidism are under-replaced when the normal TSH is set at <2.5mU/L. Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ 2014;349:g4929.

9 Raised maternal TSH and offspring IQ 25,216 women screened in 2nd trimester 62 with highest TSH compared with 124 controls 2/15 psychometric tests in the offspring aged 7-9 yrs showed impaired outcome effect more marked if not taking thyroxine ie. impaired function in 8 tests and 7 point in IQ Mean TSH of 13.2 mu/l ie. Overt hypothyroidism Haddow et al. NEJM 1999; 341:

10 Studies of maternal hypothyroxinaemia and subsequent IQ of their offspring Pop et al. Clin Endo 2003; 59: prospective 3 year follow-up study compared 57 cases with FT4 <10 th percentile and normal TSH at 12/40 with 58 controls thyroid function test in each trimester Bayley scales of infant development aged 1 and 2 children had delayed mental and motor function BUT if maternal FT4 increased at 24 and 32/40 the scores did not differ from controls

11 Studies of maternal hypothyroxinaemia and subsequent IQ of their offspring Kooistra et al. Pediatrics 2006; 117: studied 1361 pregnant women with normal TSH compared 108 neonates of mothers with FT4 <10 th percentile, and 96 from controls Neonatal Behavioural Assessment Scale used at 3 wks Regression analysis showed that T1 maternal FT4 was a significant predictor of NBAS score Did not find any effect for TSH or FT4 later in gestation

12 Raised maternal TSH and offspring IQ 12 Case-control data from a Chinese population No difference in mental and psychomotor development when the maternal TSH is within the pregnancy specific reference range, even if it is above 2.5 mu/l Li et al. J Clin Endocrinol Metab 2014;99:73-9. Large prospective cohort study No association between TSH concentrations above 2.15 mu/l in the first trimester and adverse pregnancy outcome after 20 weeks. Ong GS, Hadlow NC, Brown SJ, et al. Does the TSH measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation? J Clin Endocrinol Metab 2014;99:E

13 Thyroid autoimmunity and disease in pregnancy 13 Systematic review included 4 cohort studies of pregnancy outcome specifically in SCH 1028 women with TSH >3.0 mu/l compared with euthyroid controls (35,222) No association between isolated SCH and: miscarriage gestational diabetes placenta praevia, placental abruption, preterm labour, preterm delivery caesarean delivery Van den Boogaard E, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011;17:

14 SCH and pregnancy outcome 14 Meta-analysis increased risk of perinatal mortality and pre-eclampsia limited by inclusion of overtly hypothyroid women in the cohorts and non-matched controls. More detailed review of the data shows that SCH is not associated with either pre-eclampsia or perinatal mortality in any of the included studies. Van den Boogaard E, Vissenberg R, Land JA, et al. Hum Reprod Update 2011;17:

15 SCH and pre-eclampsia 15 Source data included in the systematic review with regards to preeclampsia were reviewed due to the unusual finding that pre-eclampsia was significant but pregnancy induced hypertension was not. Pre-eclampsia data in meta-analysis are largely weighted (91%) by Cleary- Goldman et al with OR in the meta-analysis of 1.80 ( ) Cleary-Goldman paper gives 2 adjusted OR for pre-eclampsia first trimester SCH = adj OR 0.99 ( ) second trimester SCH = adj OR 1.21 ( )

16 SCH and perinatal mortality 16 Perinatal mortality data are largely weighted by Casey et al and Allen et al. 2000: Allan et al includes both SCH and overt hypothyroidism (TSH>10). neonatal death rate in SCH = 0/172 compared to 0.4% of 9194 controls. Casey et al neonatal death rate in SCH 3/598 (0.005%) cf. controls 39/16011 (0.0024%) (p =0.21).

17 17 Thus data fail to show a consistent association between any adverse pregnancy outcome and subclinical hypothyroidism in pregnancy.

18 Does treating subclinical hypothyroidism improve pregnancy outcome? Cochrane review assessed interventions for thyroid dysfunction in pregnancy. Four randomised controlled trials were included, none of which included intervention in a cohort with isolated subclinical hypothyroidism. Insufficient data meant that no recommendations for clinical practice could be made Reid SM, Middleton P, Cossich MC, et al. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev 2013;5:CD

19 RCT of thyroid screening and T4 19 replacement: no effect on cognitive function 21,846 women screened at 12 weeks gestation either allocated to a screening group where results were seen immediately, or control group (samples stored) received T4 replacement if TSH>97.5 th or T4 < 2.5 th percentile, or both target TSH was miu/l 390 in screening group (232 SCH), 404 in control group (264 SCH) No difference in IQ test at 3 years of age (99.2 vs 100.0) calculated relative risk of an IQ below scores (75, 80, 85, 90 etc.) for verbal, performance and for full-scale IQ no difference in relative risk for any of the cut-offs median TSH where thyroxine treatment conferred no measurable difference in outcome was 3.8 mu/l. Lazarus et al. NEJM 2012; 366:

20 Thyroid autoantibodies & miscarriage 20 Thankgaratinam et al. BMJ 2011; 342: d2616

21 Thyroid autoantibodies & preterm birth Thankgaratinam et al. BMJ 2011; 342: d2616

22 Thankgaratinam et al. BMJ 2011; 342: d2616. Lazarus et al. NEJM 2012; 366: Thyroxine treatment and miscarriage Large RCT of thyroxine therapy for women with elevated TSH and/or low ft4 showed no effect of T4 on rates of: Preterm birth Birth weight n=390 vs 404

23 TABLET trial 23 RCT of 900 women 50μg thyroxine vs placebo: euthyroid women with +ve TPO Ab recruited from miscarriage and infertility clinics treatment to be taken before and during pregnancy Outcome chance of delivery beyond 34/40

24 How do these studies influence clinical practice? 24 It is sensible to screen all women with hypothyroidism at booking and before conception to ensure TSH is normal and FT3 and FT4 are not low Ideally aim for FT4 level at the upper end of the gestationspecific normal range TSH normal ranges for pregnancy need to be established there are no studies to show that T4 treatment of euthyroid women in pregnancy will influence subsequent long-term intelligence or rates of adverse pregnancy outcome

25 In summary Use TSH thresholds based on the local gestation specific reference range, rather than a universal threshold of 2.5 mu/l. Pregnant women with normal thyroxine and TSH above the local gestation specific reference range (not just >2.5 mu/l) ie. SCH Evidence that SCH causes adverse pregnancy outcome is inconsistent and conflicting. Treatment with thyroxine has not been shown to be beneficial. While results of ongoing trials are awaited, thyroxine treatment is recommended in the absence of evidence of harm. However, the possibility of overtreatment in pregnancy should be considered. Monitor for iatrogenic hyperthyroidism Be aware that most women will not need ongoing thyroid replacement after pregnancy.

26 Thank you 26 Medical complications of pregnancy conference Royal College of Physicians, London, UK November