Hyperthyroïdie et Grossesse

Transcription

1 Club Thyroïde, Paris 9 juin 2018 Hyperthyroïdie et Grossesse De la Mère à l Enfant Professeur Juliane Léger Endocrinologie diabétologie Pédiatrique Centre de Référence des Maladies Endocriniennes de la Croissance et du Développement Hôpital Universitaire Robert Debré, Paris

2 Hyperthyroïdie et grossesse Pourquoi faire un diagnostic? La mère Le foetus, le nouveau-né, l enfant Evolution de la grossesse Evolution du foetus et de l enfant Foetus et nouveau-né: à risque de morbidité et mortalité Bisschop PH, Van Trotsenburg P NEJM 2014

3 Foetus and neonates at risk for hyperthyroidism with known Graves disease on antithyroid treatment during pregnancy with hyperthyroidism diagnosed for the first time during pregnancy On remission of GD Mother who has been treated for GD and previous history of radical treatment (131 I, thyroïdectomy) Mechanism: transfert of TSH-R Ab from mother to fetus If TSH-R Ab negative, no specific risk and no specific neonatal follow-up Other causes?

4 Foetal and neonatal hyperthyroidism Exceptional causes Activating mutation of the TSH-R gene Toxic nodule Mc Cune Albright syndrome (Gnas gene)

5 Foetal and Neonatal Graves Disease Epidemiology Prevalence of Graves disease in pregnant women: approximately 0.2 % Prevalence of hyperthyroidism in offspring of women with Graves disease : 1-2 %

6 Key role of management of Graves disease during pregnancy Antenatal Diagnosis and Treatment of Foetal Thyroid Disorders Untreated mother - Foetal hyperthyroidism Treated mother (antithyroid drug) - Foetal hyperthyroïdism - Foetal hypothyroidism ATD cross the placenta, exposing the foetus to a risk of hypothyroidism

7 Thyroid function maturation during foetal and neonatal period

8 Key role of management of Graves disease during pregnancy Antenatal Diagnosis and Treatment of Foetal Thyroid Disorders Mother

9 Management of foetal and neonatal Graves disease Case 1 29 yrs old mother. GD was diagnosed 3 years ago. ATD treatment (Carbimazole) First pregnancy 2 yrs ago: foetal death in utero (30 WG, cardiac insufficiency) Second gestation: PTU since 4 WG

10 Mother : Evolution during pregnancy Week GA T4L pmol/l TSH mu/l TRAb UI/l PTU Mg/d ,5 <0,01 <0,01 <0,

11 Management of foetal and neonatal Graves disease Question 1 What are the prenatal tests to be considered to predict foetal thyroid function?

12 Is there a threshold of maternal TRAb levels indicating a risk for fetal hyperthyroidism? Current guidelines recommend TRAb determination at T2 (20-24 wg) and a close follow-up if TRAb is over 2 to 3 times the upper limit. De Groot L et al. JCEM 2012 TBII level > 3.3 times the upper reference range: fetus and newborn should be considered as being «at risk» for hyperthyroidism All hyperthyroid neonates were born to mothers with TRAK levels > 5 IU/l (T2): sensitivity 100%, specificity 43% Abeillon-du-Payrat J et al. EJE 2014

13 Mother : Evolution during pregnancy Week GA T4L pmol/l TSH mu/l TRAb UI/l PTU Mg/d ,5 15,3 <0,01 <0,01 <0,01 <0,01 39 > , Foetal goiter

14 Size of thyroid (diameter mm) Foetal goiter Foetal thyroid by ultrasound 80 - Normative data according to GA % 20-5 % 0 - I 17 I 22 I 27 I 32 Gestational age (weeks)) Normal values I 37 Ranzini AC et al. J Ultrasound Med 2001 Gietka-Czernel M et al. 2012)

15 Management of foetal and neonatal Graves disease Question 2 What other investigations are needed?

16 Graves disease in pregnant women Evaluation of Foetal Thyroid Function Foetal Growth Foetal heart rate Bone maturation: distal femoral centre at 32 weeks

17 Evaluation of Foetal Bone Maturation Distal femoral ossification center (OC) < 28 wk undetectable 32 wk dot like (< 3 mm) 35 wk consistently visible Accelerated Bone maturation OC visible < 31 wk Delayed Bone maturation OC absent 33 wk

18 Graves disease in pregnant women Evaluation of Foetal Thyroid Functionn Foetal Growth Foetal heart rate Bone maturation: distal femoral centre at 32 weeks Colour flow doppler of the foetal thyroid

19 Doppler Colour of Foetal Thyroid Hyperthyroid Hypothyroid Diffuse In the periphery Luton D et al. JCEM 2005

20 Graves disease in pregnant women Evaluation of Foetal Thyroid Functionn Foetal Growth Foetal heart rate Bone maturation: distal femoral centre at 32 weeks Colour flow doppler of the foetal thyroid Cordocentesis for direct evaluation of foetal thyroid status?

21 Cordocentesis Allows direct assessment of foetal thyroid function Morbidity: 1%, expert centre++ foetal bradycardia, infection, abortion Should be considered with caution only when foetal thyroid function cannot be interpreted

22 Serum TSH, FT4 and FT3 levels during the foetal period Thorpe-Beeston et al NEJM 1991

23 Serum TSH and FT4 levels during the foetal period Guibourdenche et al. Ann Clin Biochem 2001

24 Management of foetal and neonatal Graves disease Case 1 Foetus at risk for hyperthyroidism. TRAb : 24 UI/L; Goiter at wks GA Mother: thyroid function normal with PTU 200 mg/d Normal foetal growth, fetal heart 140/mn, OC absent, color flow doppler: not informative Hyperthyroid risk? Hypothyroid risk?

25 Management of foetal and neonatal Graves disease Risks of foetal hyperthyroidism Heart failure Death in utero Prematurity/ IUGR Microcephaly Craniosynostosis Cognitive impairment Poorly controlled maternal hyperthyroidism (?) Risks of foetal hypothyroidism Cognitive impairment or subtle developmental defect? Cordocentesis TSH: 60 µiu/l FT4: 5 pmo/l = decreased ATD dosage

26 Management of foetal and neonatal Graves disease Correlation between PTU/MMI-CMZ doses and foetal thyroid status? Some authors didn t find any correlation but limited studies: (Gardner DF et al. JCEM 1986; Cheron RG et al. NEJM 1981; Momotani N et al. JCEM 1997) PTU > 150 mg/d: potential to induce foetal hypothyroidism During the third trimester, no more than mg/d PTU is required to treat foetal hyperthyroidism Case 1: ATD dosage (PTU) was reduced from 200 to 100 mg/d (32 wk GA)

27 Mother : Evolution Week GA T4L pmol/l TSH mu/l TRAb UI/l PTU Mg/d ,5 15,3 20 <0.01 <0.01 < > ,

28 Size of thyroid (diameter mm) Foetal thyroid by ultrasound Foetal goiter slightly decreased 80 - Normative data according to GA % 20-5 % Normal values 0 - I 17 I 22 I 27 I 32 I 37 Gestational age (weeks))

29 Management of neonatal Graves disease Baby Born at 38 wks GA DeterminationBirth of thyroid weight: 2870 function G (25 th on perc.) cord blood at birth may validate the Birth prenatal length: 47 cm treatment strategy but is not predictive of subsequent Head circumference: neonatal 32.5 thyroid cm dysfunction Cord blood TSH: 33 miu/l FT4: 12 pmol/l TRAb: 19 IU/L Determination of TRAb levels in cord blood is useful as this will allow to discharge from follow-up neonates with negative TRAb levels

30 Management of neonatal Graves disease FT4 increase between days 2 and 7 (TSH decrease/undetectable) but not at birth was predictive of the development of hyperthyroidism Hypothyroidism may be related to ATD or to the coexistence of TSH-receptor blocking antibodies (rare) TRAb status should be checked in the third trimester in mothers with GD and on cord blood in their neonates; if positive, it indicates a high risk of neonatal hyperthyroidism. FT4 and TSH measurement at birth should be repeated between days 2 and 7 days

31 Management of foetal and neonatal Graves disease Evolution of thyroid function of neonates (n = 33) born to mothers with TRAb+ during gestation (T3) Besançon A et al. EJE 2014

32 Management of foetal and neonatal Graves disease Serum TH levels during the first postnatal month in the group without positive TRAb levels median (interquartile range) min-max Besançon A et al. EJE 2014

33 Management of foetal and neonatal Graves disease Case 1 Clinical manifestations - hyperexcitability - increased appetite - Flushing/sweating - diarrhea - poor weight gain Baby at day 4 Criteria for admission -Need for β-blockers -Hemodynamic instability -Arythmia, heart failure -Tracheal compression due to goiter On examination - tachycardia (170/mn) - goiter - small fontanelle - stare and eyelid retraction - warm, moist skin - hypertension

34 Management of foetal and neonatal Graves disease Case 1 Baby at day 4 FT4 = 93 pmol/l FT3 = 27.6 pmol/l TSH = 0.07 mui/l ATD treatment initiated How long should ATD treatment be continued?

35 Management of neonatal Graves disease Characteristics of seven neonates treated by CMZ and with transient hyperthyroidism Besançon A et al. EJE 2014

36 Management of neonatal Graves disease CMZ/MMI treatment: 1 mg/kg/d Dose should be decreased when FT4 levels are within the reference range Propanolol 2 mg/kg/d twice a day (tachycardia) for 1-2 weeks «block and replace» in some cases Recommendation TH should be measured weekly until TH levels stable and every 2 weeks thereafter Treatment should be stopped when TRAb level disappear from the serum (1-2 months depending of initial levels) Safety of breast feeding (Azizi F et al. JCEM 2000) Besançon A et al. EJE 2014 Van der Kaay DCM et al. Pediatrics 2016

37 Case 1 Evolution Age Day4 Day 11 Day 15 Day2 1 Day2 8 Day3 5 Day4 2 2m 3m 4m T3L T4L TSH TRAb 19, <1.4 CMZ 1x3 1x3 1x3 1x2 1x2 1x2 1x2 0.5x2 LT

38 Alternative management Titration without «block and replace» Mother at the end of gestation was treated with PTU 50 mg/d. TRAb = 10 ui/l Age Cord blood Day 3 Day 6 Day 10 Day 15 Day 22 Day 35 Day 50 T3L T4L TSH TRAb 11, ,2 CMZ mg/d

39 Management of neonatal Graves disease Question What follow-up is indicated, if any? Review management post partum. Check for exacerbation

40 Management of neonatal Graves disease Neurodevelopmental impact Risk of prematurity, IUGR Craniosynostosis, microcephalie Hypo/hyperthyroidism during pregnancy

41 Lancet Diabetes Endocrinol 2016

42 Management of neonatal Graves disease Neurodevelopmental impact Risk of prematurity, IUGR Craniosynostosis, microcephalie Hypo/hyperthyroidism during pregnancy Assessment of long term cognitive function

43 Management of foetal and neonatal Graves disease Case 2 25 yrs old mother. GD was diagnosed 10 years ago. ATD treatment (Carbimazole) First pregnancy. ATD treatment was stopped 4 months before. Third Trimester (29 wks): FT4 : 49 pmo/l, FT3 : 17 pmo/l PTU 50 mg/d at 33 wks (GA) TRAb: 6.5 iu/l

44 Central Hypothyroidism due to inadequately treated mother with GD during gestation Baby born at 34 weeks GA (caesarian section) with IUGR. BW: 2090 g; BL: 42 cm; HC: 29 cm Age Cord blood Day 3 Day 5 Day 8 Day 15 Day 40 year 2 T3L T4L TSH TRAb 6 5 L T4 µg/d 10 µg/d for 1 year

45 Fœtal Hyperthyroidism followed by neonatal central hypothyroidism due to inadequately treated mother with GD JCEM 2003 Mandel SH. J Pediatr 1986 Mandel SH. J Pediatr 1990 Hashimoto H. J Pediatr 1995 Inadequately treated mothers with GD Hyperthyroid fœtal environment may impair maturation of the fœtal hypothalamic-pituitary-thyroid system

46 Management of neonatal Graves disease JCEM 2007 Inadequately treated mothers with GD

47 Loss of integrity of thyroid morphology in children born to mothers with inadequately treated GD Kempers MJE et al. JCEM 2007

48 JCEM 2013 Prevalence of birth defect : 3-6 % MMI/CMZ and PTU are associated with urinary system malformation, and PTU with malformations in the face and neck region MMI/CMZ-exposed children : Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis are common (combined adjusted OR = 21.8 ( )

49 Adjusted Odds ratio with 95% CI ranked for each ATD therapy Andersen SLA et al. JCEM 2013

50 Including pregnant Both agranulocytosis and liver failure are rare in pregnant women The major burden of side effects to the use of ATD in pregnancy is birth defect Laurberg P, Andersen SL,JCEM, EJE, 2016

51 The use of ATD during gestational weeks should be restricted as much as possible, critical period of organogenesis P Lauberg, S L Andersen, EJE 2014

52 Proposed measures to reduce the number and severity of antithyroid drug-associated birth defect P Lauberg, S L Andersen, EJE 2014

53 Fetal and neonatal hyperthyroidism Case 3 Boy born at 34 wk gestation with IUGR BW 1710 g, BL 43 cm, HC 30 cm Tachycardia (180/min) Referred on day 6 Goiter Small size fontanels Poor weight gain Thyroid ultrasonography: diffuse goiter FT3 : 36 pmol/l (N ) FT4 > 100 pmol/l ( 14-35) TSH<0.001 mu/l

54 Case 3 Arguments for the fetal hyperthyroidism onset Doppler echography at 31 wks - fetal tachycardia - high speed blood flow - normal heart morphology Thyroid ultrasonography: diffuse goiter Distal femoral and proximal tibial ossification points present at birth (32 wks) What investigations are required? At birth: FT3 : 8 pmol/l (N 1-2.9) FT4 : 77 pmol/l (N 10-19) TSH<0.001 mu/l

55 Case 3 Mother Hyperthyroidism diagnosed at 9 months of age Thyroidectomy at the age of 9 yr for GD Levothyroxine: 75 µg/day No thyroid autoimmune disease for the baby TRAb -

56 Case 3 TSH receptor gene activating mutation (heterozygous mutation) Mother and child Ser505ASN C.1514G>A

57 Management strategy of pregnancies at risk of non autoimmune congenital hyperthyroidism Management of the pregnant mother Prenatal diagnosis and treatment for the infant Increase Levothyroxine dose at the beginning of each pregnancy and monitor maternal thyroid function each month Early diagnosis during foetal life for the next baby (TSH-R gene) (chorionic villi sampling at 12 wks GA) In case of affected foetus: - introduce PTU and increase Levothyroxine dose for the mother in order to treat foetal hyperthyroidism. - monitor thyroid ultrasonography, foetal growth, foetal heart rate, bone maturation

58 Management Algorithm for at risk pregnancies in mother with GD (current or past) Mother treated years earlier for GD and taking levothyroxine after radioiodine or thyroidectomy Increase levothyroxine dose at the start of pregnancy Mother taking ATD before pregnancy Mother diagnosed for the first time during pregnancy Titration of ATD dose (PTU) recommended Restrict the use of ATD in weeks 6-10 of pregnancy Monitor thyroid function every 4-6 weeks and adjust the treatment dose if necessary to keep the mother euthyroid. Check compliance with treatment throughout pregnancy TRAb determination early in pregnancy and during the second half of gestation Goitre of the fœtus at any time during monitoring by thyroid ultrasonography (starting at 20 weeks and every 4-6 weeks) TRAb negative TRAb positive TRAb positive TRAb negative No risk of fœtal/neonatal hyperthyroidism In most cases Suspected fœtal hyperthyroidism Consider TSH-R gene mutation if no history of maternal autoimmune disease (TRAb - ) Suspected fœtal hyperthyroidism Start maternal ATD in combination with Levothyroxine Suspected fœtal hyperthyroidism Increase maternal ATD dose Suspected fœtal hypothyroidism Decrease maternal ATD dose Suspected fœtal hypothyroidism MMI/CMZ usually mg or less daily PTU usually mg or less daily After birth, check infants at risk of hyperthyroidism. Review management postpartum

59 Management of Foetal and neonatal hyperthyroidism conclusion Take home messages Maternal thyroid disorders: impact on pregnancy, foetus and child outcome Therapeutic approach to normalize thyroid function of the mother, the foetus should be carefully evaluated and weighed again potential risks: multidisciplinary team Careful management during the neonatal period Long term follow-up Multidisciplinary expert team +

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