Management of Thyroid dysfunction in Pregnancy- An Audit done in a District General Hospital in the UK, 2018

Dr Indrajit Talapatra (MRCP, UK), Dr Jonathan Ward (MBChB) and Dr Ian O’Connell (FRCP)
Department of Endocrinology, Royal Albert Edward Infirmary, Wigan, UK

AIMS:
To find out if the patients with thyroid problems during the gestational period are managed adequately and in line with the existing Guidelines
METHODS:
Patients who were pregnant with thyroid problems seen at the clinic in Leigh Infirmary between January and April 2018 were included in the audit.

 

Guidelines:
The Guidelines of the American Thyroid Association (2017), British Thyroid Foundation, European Thyroid Association, Norfolk and Lothian Guidelines were all considered

Introduction:

Hypothyroidism in Pregnancy (ref: Oxford):
(1) 1-2% Overt hypothyroidism, 2.5% Subclinical
(2) Risks of inadequate treatment: 2-fold increased risk of spontaneous miscarriage, preeclampsia, pregnancy induced hypertension, anaemia and Postpartum haemorrhage
(3) Foetal thyroxine production starts at 12 weeks
(4) Risks of impaired foetal intellectual and cognitive development, perinatal death, IUGR, pre-term delivery

Euthyroid but positive thyroid autoantibodies:
(1) Two fold increased risk of miscarriage
(2) The mother can occasionally develop hypothyroidism towards the end of pregnancy after 28 weeks
(3) Increased risk of postpartum thyroiditis

 

Hyperthyroidism in Pregnancy (Ref:Oxford):
(1) 0.2% of pregnant women
(2) Aggravation of disease in first trimester with chances of remission in second half of pregnancy and recurrence in post-partum period
(3) Maternal complications of uncontrolled thyrotoxicosis include Pregnancy, Pre-term delivery, CCF, miscarriage and abruptio placentae
(4) Foetal complications include Foetal hypothyroidism, Foetal and neonatal hyperthyroidism, IUGR, Prematurity and Stillbirth
(5) Foetal hyperthyroidism: The Foetal HR is to be kept<140/min; Neonatal hyperthyroidism occurs in 1% of infants and usually subside by 6 months. Untreated cases though have 30% mortality. Treatment is needed with Anti thyroid drugs and B-blockers.

 

Transient hyperthyroidism of Gestational period (Ref: Oxford):
This is responsible for 2/3 of hyperemesis due to raised B-HCG, resolves usually by 20 weeks, distinguished by no goitre, no opthalmopathy, no thyroid antibodies and minimally raised FT3

Post-Partum thyroid dysfunction (ref: Oxford)
(1) 5-10% following delivery
(2) more common in patients with type 1 diabetes mellitus
(3) Hyperthyroidism can develop within 4 months. Usually resolves spontaneously in 2-3 months
(4) Hypothyroidism can develop 4-6 months after delivery; there is an increased risk of post-partum depression
(5) Hyperthyroidism followed by hypothyroidism
(6) Spontaneous recovery in 80% within 6-12 months of delivery
(7) Graves’s disease may relapse post-partum and lymphocytic thyroidis may cause hypothyroidism

Guidelines on the Management of Hypothyroidism in pregnancy
(1) Trimester-specific reference ranges for TSH and T4 (total or free) should be established in each antenatal hospital setting. Local variations may occur; The following reference range upper limits are recommended: first trimester, 2.5 mU/l; second trimester, 3.0 mU/l; third trimester, 3.5 mU/l. A major and substantial change in the new American guidelines 2017 includes raising the upper limit in the normal thyroid function tests. For thyroid stimulating hormone (TSH), the upper limit was 2.5 in the 2011 guidelines; now, it is 4.0
(2) TSH should be measured at the beginning of pregnancy. If TSH is elevated, FT4 and TPOAb (Thyroid Peroxidase Antibodies) should be determined. This will enable subclinical hypothyroidism or overt hypothyroidism to be diagnosed.
(3) Treatment with Levothyroxine is strongly recommended for antibody positive (TPOAb) women with TSH >2.5, and for antibody negative women with TSH levels higher than 10 (American Guidelines 2017)
(4) The daily iodine intake during pregnancy and lactation should be at least 250 μg and should not exceed 500 µg. A sufficient iodine intake is usually provided by supplementing euthyroid pregnant and lactating women with formulas containing 150 μg of iodine/day, ideally before conception.
(5) Levothyroxine therapy may be considered in isolated hypothyroxinaemia detected in the first trimester because of its association with neuropsychological impairment in children (European Thyroid association Guidelines, 2014). Levothyroxine therapy is not recommended in isolated hypothyroxinaemia detected in the second to third trimester.
(6) The recommended treatment of maternal hypothyroidism is administration of oral levothyroxine. The use of levothyroxine-T3 combinations or desiccated thyroid is not recommended.
(7) Women with known thyroid dysfunction who are taking levothyroxine may need the dose increased by 30% or 25-50 mcg daily once they become pregnant. The starting dose however is 100 mcg daily
(8) Patients should have regular blood tests (every 4-6 weeks) throughout pregnancy so that the dose can be adjusted if necessary
(9) If the patients are prescribed supplements containing iron or calcium they should take these several hours (at least 4 hours) before or after the levothyroxine since these can alter the absorption of levothyroxine.
(10)After the birth of the child the patient will need to return to the dose of levothyroxine she was taking prior to becoming pregnant.
(11)Women diagnosed with Subclinical hypothyroidism during pregnancy with TSH less than 5 mU/l and negative TPOAb could stop levothyroxine after delivery and have thyroid function checked 6 weeks after delivery
(12)The patient should have a blood test to check the thyroid hormone levels a few weeks after the birth. It is safe to breast-feed while taking Levothyroxine.
(13)Women diagnosed with Subclinical hypothyroidism during pregnancy and continued on Levothyroxine should be re-evaluated 6 months and 1 year after delivery to ascertain the continuing requirement for levothyroxine
(14)In the UK all babies get a heel-prick blood test to screen for hypothyroidism shortly after birth and treatment can be started soon if the baby needs levothyroxine. Hypothyroidism is extremely rare in new-born babies in the UK, only about one baby in every 4000 is born with hypothyroidism.
.

Guidelines on the Management of Hyperthyroidism in Pregnancy
(1) Propylthiouracil should always be used in the first trimester of pregnancy. Thereafter Carbimazole is to be used from the second trimester (because of increased risk of maternal hepatotoxicity with Propylthiouracil). Opinions vary; however some agree that Propylthiouracil is the drug of choice (risks of aplasia cutis, choanal and oesophageal atresia remain with Carbimazole)
(2) A short course of 40 mg of propranolol can be used thrice daily for 2-3 weeks while the anti-thyroid drug starts to produce its action
(3) Thyroid function is to be monitored every 4-6 weeks
(4) Once the thyroid function becomes normal, the aim will be to use a minimal dose of anti-thyroid medication
(5) Free Thyroxine level (FT4) will need to be kept at the upper limit of normal and Thyroid Stimulating Hormone (TSH) at the lower limit of normal (<2.5 mu/l- 1st trimester, <3 mu/l- 2nd trimester, <3.5 mu/l- 3rd trimester)
(6) In 30% cases Anti thyroid medications can be discontinued at 32-36 weeks, provided the thyroid function remains normal for a minimum period of 4 weeks on the lowest dose of ATD
(7) In the presence of a large goitre (thyroid swelling) or eye disease, the anti thyroid medication is not to be discontinued
(8) If the daily dose intake of Propylthiouracil is <200 mg or Carbimazole <20 mg, chance of hypothyroidism of the baby following delivery is much less
(9) Breast feeding is safe in daily doses of <150 mg of Propylthiouracil or <15 mg of Carbimazole. If a higher dose is recommended, breast feeding is to be done prior to the administration of the drug and the dose can be divided throughout the day
(10)Surgery is rarely needed in pregnancy. It is only recommended if there are serious side effects from the drug. If at all it is required, it is to be done in the second trimester
(11)Radioiodine treatment is contraindicated in pregnancy, during breastfeeding and for 4 months prior to conception
(12)There is a possibility of flare up of the disease after the birth of the baby and hence the thyroid function of the mother is to be monitored closely
(13)TRAb (TSH receptor antibodies) should be checked at booking and 3rd trimester (according to American Guidelines) because of increased risk of foetal and neonal hyperthyroidism

 

Criteria:
For patients with hypothyroidism in pregnancy
(1) Measurement of level of TSH during pregnancy
(2) FT4 level kept >15
(3) TPO and TSH Receptor antibodies measured (particularly in Subclinical hypothyroidism or SCH)
(4) Treatment with Thyroxine in SCH and TPO antibody cases if TSH is > 2.5
(5) Dosage of Thyroxine increased at the onset of pregnancy by 30%
(6) Patient seen every 4-6 weeks and dose of thyroxine adjusted
(7) Levothyroxine reduced to preconception dose after delivery
(8) Gap of 4 hours between iron and thyroxine
(9) Patient gets blood tests after delivery
For patients with hyperthyroidism in pregnancy
(10) PTU in first trimester and Carbimazole from 2nd trimester
(11) Monitoring LFTs on PTU
(12) ATD discontinued after being on minimum dose of Carbimazole around 32-36 weeks
(13) TRAb measured at birth and in 3rd trimester (particularly in patients who had RAI and in 3rd trimester otherwise)

Results: No of Patients: 21
No of Patients with Hypothyroidism: 16
No of patients with Hyperthyroidism: 5 (1 had subclinical hyperthyroidism prior to becoming pregnant; developed frank hyperthyroidism during pregnancy but not sure if it was Transient Thyrotoxicosis of Gestational Period; hence not put on PTU)
In Hypothyroid patients (including subclinical hypothyroidism):
(1) FT4 level >15: 13 out of 16 (81.25%)
(2) TSH <2.5 when seen at the OPD: 12 out of 16 (75%); 3 out of the 4 patients with TSH > 2.5 were new at the OPD
(3) TPO and TSH Receptor antibodies measured (particularly in SCH): 4 out of 16
2 patients had SCH with TSH > 2.5 and had TPOs checked (100%) and were positive
(4) Treatment with Thyroxine in SCH (TSH >2.5) and TPO antibody positive cases: 2 out 2 (100%)
(5) Dosage of Thyroxine increased at the onset of pregnancy by 30% :12 out of 16 (75%); of the remaining 4 patients 3 were new and the dosage was not increased by GP.
(6) Patient seen every 4-6 weeks and dose of thyroxine adjusted: 16 out of 16 (100%)
(7) Levothyroxine reduced to preconception dose after delivery: 4 patients had delivery during this period; 3 out of 4 (75%) had their dose of Thyroxine reduced to pre-conception dose; 1 patient did not deduce the dose despite advice to do it
(8) Gap of 4 hours between iron and thyroxine: 6 patients were taking iron supplements and all were advised (100%)
(9) Patients got blood tests after delivery: 4 out of 4 patients (100%)
In Patients with Hyperthyroidism:
(1) PTU in first trimester:3 out of 5; of the remaining 2 patients, 1 patient in early pregnancy was on no treatment at the time of the audit and 1 patient conceived while on Carbimazole, did not inform us and had miscarriage in early pregnancy
(2) Carbimazole from 2nd trimester: 1out of 3 patients (33%); remaining 2 patients had PTU in all three trimesters
(3) Monitoring LFTs on PTU: 3 out of 3 (100%);
(4) ATD discontinued after being on minimum dose of Carbimazole around 32-36 weeks (2 out of 3)
(5) TRAb measured in 1st and in 3rd trimester (particularly in patients who had RAI and in 3rd trimester otherwise): None had RAI treatment; 3 out of 4 patients (75%), including the patient who was on no treatment at the time of the audit, had TRAB estimated.

 

Summary:
(1) We were good in maintaining the TSH <2.5 and FT4 > 15 in most patients with Hypothyroidism; in those where the TSH was >2.5 in 1st trimester, the dosages of Levothyroxine were not increased by GPs
(2) We do not routinely measure antibodies in pregnant patients with Hypothyroidism
(3) In both patients with subclinical Hypothyroidism while pregnant, the GPs measured their antibodies and put the patient on Levothyroxine
(4) All patients with Hypothyroidism who were seen at the OPD and required adjustment of the dosages of Levothyroxine had their dosages amended
(5) All patients were routinely seen at regular intervals
(6) All patients were advised to reduce the dosages of their Levothyroxine to the pre-conception dosages soon after delivery
(7) All patients taking iron and Levothyroxine simultaneously were advised to keep a gap of 4 hours minimum between Levothyroxine and iron supplements
(8) All patients who delivered during the period of the audit were seen following their audit, dosages of Levothyroxine adjusted if necessary and discharged
(9) In patients with hyperthyroidism from 2nd trimester onwards Carbimazole was not administered in all patients; PTU was continued in 2 out of 3 patients with continuous monitoring of LFTS and culminated in successful deliveries
(100Antithyroid medication could be stopped in 2 out of 3 patients at 36 weeks

Conclusion:
(1) All GPs and Midwives should be informed about increasing the dosage of Levothyroxine in pregnant patients with Hypothyroidism
(2) All GPs should be made aware of checking TPO in pregnant patients with subclinical Hyperthyroidism and if it is positive and TSH >2.5 should start Levothyroxine
(3) The patients need to be seen continuously throughout pregnancy and the dosages of Levothyroxine and anti-Thyroid medications adjusted accordingly and the dosage of Levothyroxine needs to be reduced to pre-conception dose following delivery
(4) It needs to be established whether we should continue with Propylthiouracil in all trimesters in Hyperthyroidism with monitoring of LFTs or we should consider Carbimazole from 2nd trimester onwards
(5) Trust Guidelines need to be developed in patients with pregnancy and thyroid dysfunction

 

Ref:

(1) Endocrinology in Pregnancy. Oxford Handbook of Endocrinology and Diabetes. Edited by Wass J, Owen K, Advisory Editor, Turner H, 3rd Edition, 2014: 425-432
(2) Marcos Abalovich, Nobuyuki Amino, Linda A. Barbour, Rhoda H. Cobin, Leslie J. De Groot, Daniel Glinoer, Susan J. Mandel, and Alex Stagnaro-Green. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline; JCEM, 2007 92(8): S1-S47
(3) Lothian Guidance for Diagnosis and Management of Thyroid Dysfunction in Pregnancy.
(4) Norfolk and Norwich University Hospitals NHS Foundation Trust: Trust Guideline for: The management of Thyroid Dysfunction in Pregnancy
(5) Alexander Erik K., Pearce Elizabeth N., Brent Gregory A., Brown Rosalind S., Chen Herbert, Dosiou Chrysoula, Grobman William A., Laurberg Peter, Lazarus John H., Mandel Susan J., Peeters Robin P., and Sullivan Scott. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid; 27 (3) : March 1, 2017
(6) John Lazarus, Rosalind S. Brown, Chantal Daumerie, Alicja Hubalewska-Dydejczyk, Roberto Negro, Bijay Vaidya. 2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children. Eur Thyroid J 2014;3:76–94
(7) http://www.btf-thyroid.org/professionals/197-guidelines

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