|Year : 2014 | Volume
| Issue : 1 | Page : 35-38
Management of Graves' disease during pregnancy in developing countries: A report of two cases and a review of the literature
Kennedy I. Akhuemokhan1, Reuben A. Eifediyi2
1 Department of Medicine, Irrua Specialist Teaching Hospital, P.M.B 08, Irrua, Edo State, Nigeria
2 Department of Obstetrics and Gynaecology, Irrua Specialist Teaching Hospital, P.M.B 08, Irrua, Edo State, Nigeria
|Date of Web Publication||15-May-2014|
Dr. Kennedy I. Akhuemokhan
Department of Internal Medicine, Irrua Specialist Teaching Hospital, P.M.B 08, Irrua, Edo State
Source of Support: None, Conflict of Interest: None
Grave's disease account for about 85% of hyperthyroidism during pregnancy. If not properly managed, it can result in severe maternal, fetal and neonatal morbidity and mortality. Anti-thyroid drugs are the main treatment for Grave's disease during pregnancy. The lowest possible dose should be used to maintain maternal free thyroxine levels at or just above the upper limit of the normal non-pregnant normal range. Fetal thyroid function depends on the balance between the trans-placental passage of thyroid-stimulating maternal antibodies and thyroid-inhibiting anti-thyroid drugs. In developing countries where propylthiouracil is either expensive or not available the use of carbimazole at lower doses is safe. Two cases are here presented to buttress this view.
Keywords: Grave′s disease, hyperthyroidism, pregnancy
|How to cite this article:|
Akhuemokhan KI, Eifediyi RA. Management of Graves' disease during pregnancy in developing countries: A report of two cases and a review of the literature. J Med Trop 2014;16:35-8
|How to cite this URL:|
Akhuemokhan KI, Eifediyi RA. Management of Graves' disease during pregnancy in developing countries: A report of two cases and a review of the literature. J Med Trop [serial online] 2014 [cited 2019 Oct 22];16:35-8. Available from: http://www.jmedtropics.org/text.asp?2014/16/1/35/132577
| Introduction|| |
Hyperthyroidism complicates approximately 0.1 - 0.2% of pregnancies, with 85% of cases due to Graves' disease. , Hyperthyroidism in pregnancy is associated with maternal and fetal/neonatal morbidity, and mortality. Maternal complications include abortion, pre-eclampsia, preterm labor, placental abruption, congestive heart failure, and thyroid storm. Fetal and neonatal complications include stillbirth, low birth weight, goiter, hyperthyroidism, and hypothyroidism. ,, Adequately treated Grave's disease usually has no adverse impact on the outcome of pregnancy.  Anti-thyroid drugs (ATD) are used to treat Grave's disease during pregnancy. , The lowest possible dose should be used to maintain maternal free thyroxin levels at the upper limit of the normal non-pregnant normal range.  Foetal thyroid function depends on the balance between the trans-placental passage of thyroid-stimulating maternal antibodies and thyroid-inhibiting anti-thyroid drugs. Serum thyroid stimulating hormone (TSH) and either total or free thyroxin levels should be measured in foetal cord blood at delivery in women with active Graves' disease, and those with a history of radioactive iodine ( 131 I) mediated thyroid ablation or thyroidectomy who have anti-TSH-receptor antibodies.  Neonatal thyrotoxicosis can occur in the first few days of life after clearance of maternal anti- thyroid drug, and can last for several months, until maternal antibodies are also cleared.
The objective of this report is to stress the fact that management of Graves' disease in pregnancy is challenging in developing countries but can been achieved with commonly available drugs and adequate patient monitoring.
| Case Reports|| |
A 33-year-old Gravida 4, Para 2 + 1, at 10 weeks gestation, referred to us on account of undetectable TSH, elevated thyroid hormones and symptoms of hyperthyroidism (Test for anti-TSH receptor antibodies are not readily available). She had no history of thyroid disease. A diagnosis of Grave's disease in pregnancy was made. She was commenced on Carbimazole tablets 10 mg twice daily (Propylthiouracil is not readily available; it has to be imported and is expensive), and Propranolol tablet, 20 mg daily. She was re-evaluated every 4 weeks with a thyroid function test, and the drugs reviewed until she was maintained on just 5 mg of Carbimazole daily at 26 weeks gestation. Fetal heart rate monitored by cardiotocography (CTG) was between 180 and 210 beats per minutes initially but progressively came down to between 124 to 172 beat per minutes from the 27 th week till delivery. She had an uneventful labor, with spontaneous vaginal delivery at 38 weeks gestation. The baby was healthy at birth and was followed for 6 months without any clinical or laboratory evidence of thyroid disease. She was continued on Carbimazole at the maintenance dose of 5 mg daily for another 8 weeks after delivery before it was discontinued.
A 29-year-old Gravida 2, Para1+0, a known patient with Grave's disease diagnosed 2 years before presentation. She was referred to us at 9 weeks gestation because of worsening symptoms of hyperthyroidism and deranged thyroid hormone profile, TSH = 0.1 ng/dl (0.4-7.0 ng/ml), Total T3 =4.1 ng/ml (0.8 - 2.0 ng/dl), Total T4 =22.0 ng/ml (5.0 - 13.0 ng/ml). She was euthyroid on 10 mg Carbimazole daily before she became pregnant.
She was put on 10 mg of Carbimazole tablet twice daily and Propranolol tablet 20 mg twice daily, monitored and reassessed every 4 weeks with a thyroid hormone profile. The Propranolol was discontinued after 8 weeks and the Carbimazole was reduced to 10 mg daily at 30 weeks gestation. Fetal heart rate monitored by means of a CTG was between 170 and 190 beats per minutes and from the 24 th week till delivery it was between 116 to 158 beat per minutes. She was stable thereafter and at 37 weeks gestation she went into labor and had a spontaneous vaginal delivery. The baby was assessed to be healthy at birth and at 6 months of age without any clinical or laboratory evidence of thyroid disease. Thyroid hormone profile of both mother and child at delivery were TSH =3.4 mU/L, Total T3 = 2.2 ng/dl, Total T4 =15.9 ng/dl, and TSH =3.95 mU/L, Total T3 =1.8 ng/dl, Total T4 =11.0 ng/dl, respectively. She was continued on carbimazole at 10 mg daily for another 3 months. Currently, she is on 5 mg of Carbimazole daily.
Graves' disease was diagnosed clinically in both patients. They both had diffusely enlarged thyroid gland confirmed by ultrasound scan, proptosis, and other signs of Graves' ophthalmopathy. We could not check their TSH-receptor antibodies.
| Discussion|| |
Graves' disease, an autoimmune disease in which thyroid stimulating antibodies bind to and activate the thyrotropin receptor on thyroid cells resulting in hyperthyroidism.  The occurrence of Graves' disease is similar in Caucasians and Asians, with a lower incidence in African Americans.  Major risk factors for Graves' disease include female gender and genetic predisposition. Graves' disease is approximately eight times more common in women than men and often occurs in clusters in families.  It is estimated that hyperthyroidism is present in approximately 0.1-0.2% of pregnancies.  It is the second most common endocrine disorder in pregnancy, following only diabetes mellitus.  Graves' disease is the most common cause of hyperthyroidism during pregnancy, accounting for 85-95% of cases. 
Patients suspected of having hyperthyroidism require measurement of serum TSH, Thyroxine (T4) and Tri-iodothyronine (T3) levels, and anti-TSH receptor antibodies (TRAb). Virtually, all patients with significant symptoms have a serum TSH <0.1 mU/L, as well as concurrent elevations in serum free T4 and T3 levels. However, interpretation of thyroid function tests must take into account the human chorionic gonadotropin (hCG)-mediated decrease in serum TSH that occurs during pregnancy; which at the end of 1 st trimester, when the hCG values peaks, serum TSH levels may be transiently lowered to values below 0.4 mU/L in ∼20% of euthyroid women. ,, Patients with Graves' disease usually have positive thyroid antibodies (TG-Ab and TPO-Ab). Since TRAb production tends to undergo immunologic remission during the second half of pregnancy, detection of TRAb may depend upon gestational age at determination. ,
All hyperthyroid women of childbearing age should seek contraceptive counseling, to avoid pregnancy.  An explanation of the different hyperthyroid therapeutic choices is important for those women planning pregnancy: Ablative therapy, by 131 I or surgery, or medical therapy. Anti- thyroid drug treatment is preferred during pregnancy. Radioactive iodine is contraindicated during pregnancy because it can result in neonatal hypothyroidism and cretinism.  Surgery is reserved for patients who require large doses of anti-thyroid drugs, or those who demonstrate poor medication tolerance or adherence and continue to remain hyperthyroid. , If surgery is necessary, it is preferred during the second trimester to decrease the risk of spontaneous abortion. 
The goal of therapy is to control maternal disease while minimizing the risk of fetal hyperthyroidism or hypothyroidism by using the smallest possible dose of anti-thyroid drug (ATD). In most patients, clinical improvement is seen in 2 to 6 weeks, and improvement in thyroid function tests occur within the first 2 weeks of therapy, with normalization to biochemical euthyroidism in 3 to 8 weeks in over 50% of patients.  With clinical and thyroid function test improvement, the daily dose is adjusted according to the results of thyroid hormone profile done every 2-4 weeks.  Serum TSH remains suppressed despite the normalization of thyroid hormone levels for many weeks, frequently through pregnancy. The ATD dosage should be maintained at a minimum and drugs discontinued, when feasible. Combined administration of ATD and Thyroxine to the mother should be avoided, since trans-placental passage of ATD is high while negligible for thyroid hormones, hence Thyroxine will not protect the fetus from ATD-induced hypothyroidism. It is important not to over treat because it may result in maternal or foetal hypothyroidism.  Monitoring is crucial with assessment every 2 to 4 weeks. 
Propylthiouracil (PTU), Methimazole (MMI), and Carbimazole (CBZ) converted to MMI by the liver are equipotent in the management of hyperthyroidism in pregnancy, with similar placental transfer kinetics. , The American Thyroid Association recommends the use of PTU only in the first trimester of pregnancy, to be switched to MMI by the second trimester.  Neonatal outcomes are not different with either drug. However, MMI should be considered a second choice and used in the first trimester when PTU is not available, if the patient is intolerant to PTU, or fails to become euthyroid on PTU.
Both PTU and MMI are secreted in human milk, although PTU is less because of more extensive binding to albumin. At moderate doses of MNI or PTU, the risk for the infant is practically negligible.  It is prudent to monitor the infant's thyroid function periodically during the time of ATD administration, although thyroid function is not affected in breastfed infants, even when ATD induced maternal hypothyroidism occurs. 
Propranolol may be used transiently to control symptoms of acute hyperthyroid disease and for pre-operative preparation, with no significant teratogenic effects. However, for long-term Propranolol administration, monitor fetal growth because of the possibility of intrauterine growth restriction. 
The selection of PTU over MMI as the drug of choice to treat Graves' disease during Pregnancy should not be based on statements like PTU has less placental transfer than MMI, and that PTU leads to less fetal hypothyroidism or that exposure to MMI during pregnancy leads to a decreased intellectual function in children. Our pregnant patients with Graves' hyperthyroidism are treated with CBZ because PTU is not available, with good results as shown above. The American Thyroid Association and the American Association of Clinical Endocrinologists currently recommend MMI as the preferred anti-thyroid drug in any patient with Graves' disease except during the first trimester of pregnancy.  Throughout the rest of the world, MMI and CBZ are widely used to treat hyperthyroidism in pregnant women.  This may be due to severe hepatic injury and liver failure linked to PTU use compared to MMI as the incidence of PTU hepatic failure does not correlate to PTU dosage or duration or patient age. 
It has been shown that PTU and MMI have similar placental transfer kinetics.  Although a possible association between MMI exposure during pregnancy and fetal congenital defects may exist, it has not been proven and may be secondary to hyperthyroidism.  The two agents were similar regarding the effects on fetal thyroid status, and the selection of PTU over MMI to treat hyperthyroidism during pregnancy is not justified. 
Ultimately, the risks for hyperthyroidism in pregnancy outweigh the risks for rare hepatic injury and embryopathy associated with these anti-thyroid drugs. Management with anti-thyroid drugs should be approached with the goal of attaining the upper limits of normal. This is because subclinical hyperthyroidism does not have any adverse effect of pregnancy or delivery or the baby, but it reduces the amount of drugs that we give to patients. 
The effects of pregnancy on the regulation of thyroid function need to be recognized, assessed, and managed. The metabolic rate, blood flow, heart rate, and cardiac output, and other various subjective sensations such as fatigue and heat intolerance that may suggest the possibility of coexistent thyrotoxicosis are increased in pregnancy.
Graves' disease is altered during pregnancy, with a tendency for exacerbation in first trimester, amelioration during second and third trimesters, and a rebound during the postpartum period. These phases are important since all ATD cross the placenta and may affect fetal thyroid function and ATD remains the treatment of choice in Graves' disease during pregnancy. Fetal and neonatal hyperthyroidism is due to the trans-placental transfer of maternal stimulating TSH-receptor antibodies (TRAb) and the risk can be assessed by fetal ultrasonographic data, tachycardia, growth retardation, and accelerated bone maturation. The proper management of pregnant patients with Graves' disease remains a challenge and in communities where Propylthiouracil is not available, Carbimazole can be used with similar outcomes. The role of monitoring cannot be overemphasized as the management is dynamic even after delivery. Maternal and fetal morbidity and mortality can be reduced if the lowest possible dose of Carbimazole is used to maintain maternal serum FT 4 levels at or just above the upper limit of the normal non-pregnant reference range, or serum total T 4 levels at 1.5 times the normal non pregnant reference range, as in the cases mentioned above.
| References|| |
|1.||Galorfre JC, Davies TF. Autoimmune thyroid disease in pregnancy: A review. J Women's Health 2009;18:1847-56. |
|2.||Burrow GN. Thyroid function and hyperfunction during gestation. Endocr Rev 1993;14:194-202. |
|3.||Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN, Mestman JH. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994;84:946-9. |
|4.||Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;160:63-70. |
|5.||Kriplani A, Buckshee K, Bhargava VL, Takkar D, Ammini AC. Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy. Eur J Obstet Gynecol Reprod Biol 1994;54:159-63. |
|6.||Mitsuda N, Tamaki H, Amino N, Hosono T, Miyai K, Tanizawa O. Risk factors for developmental disorders in infants born to women with Graves' disease. Obstet Gynecol 1992;80:359-64. |
|7.||Mestman JH. Hyperthyroidism in pregnancy. In: Best Practice and Research in Clinical Endocrinology and Metabolism: The Thyroid and Pregnancy. Glinoer D, editor. Vol. 18. 2004. p. 267. |
|8.||Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ 2008;336:663-7. |
|9.||Grace WC, Susan JM. Therapy Insight: Management of Graves' disease during pregnancy. Nat Clin Pra Endocrinol Metab 2007;3:470-8. |
|10.||Polak M, Le Gac I, Vuillard E, Guibourdenche J, Leger J, Toubert ME, et al. Fetal and neonatal thyroid function in relation to maternal Graves' disease. Best Pract Res Clin Endocrinol Metab 2004;18:289-302. |
|11.||Weetman AP. Graves' Disease. N Eng J Med 2000;343:1236-48. |
|12.||Mestman JH. Hyperthyroidism in pregnancy. Endocrinol Metab Clin North Am 1998;27:127-49. |
|13.||Haddow JE, Knight GJ, Palomaki GE, McClain MR, Pulkkinen AJ. The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy. J Med Screen 2004;11:170-4. |
|14.||Dorizzi RM, Ozzola G, Sommella C, Catania F, Lelli F, Migali E, et al. An approach to establish reference intervals for thyrotropin in pregnancy using the ADVIA Centaur analyzer. Clin Lab 2010;56:417-25. |
|15.||Thung SF, Funai EF, Grobman WA. The cost-effectiveness of universal screening in pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol 2009;200:267. |
|16.||Dosiou C, Sanders GD, Araki SS, Crapo LM. Screening pregnant women for autoimmune thyroid disease: A cost-effectiveness analysis. Eur J Endocrinol 2008;158:841-51. |
|17.||Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702-55. |
|18.||Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, et al. Management of thyroid dysfunction during pregnancy and postpartum: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2007;92:S1-47. |
|19.||Wing DA, Mmiller LK, Koonings PP. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994;170:90-5. |
|20.||Clark SM, Saade GR, Snodgrass WR, Hankins GD. Pharmacokinetics and pharmacotherapy of thionamides in pregnancy. Ther Drug Monit 2006;28:477-83. |
|21.||Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynaecol 2006;108:1283-92. |
|22.||Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-9. |
|23.||Mortimer RH, Cannell GR, Addison RS. Methimazole and propylthiouracil equally cross the perfused human term placenta lobule? J Clin Endocrinol Metab 1997;82:3099-102. |
|24.||Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, et al. The role of propylthiouracil in the management of Graves' disease in adults: Report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009;19:673-4. |
|25.||Azizi F. Thyroid function in breast-fed infants is not affected by methimazole-induced maternal hypothyroidism: Results of a retrospective study. J Endocrinol Invest 2003;26:301-4. |
|26.||Redmond GP. Propranolol and fetal growth retardation. Semin Perinatol 1982;6:142-7. |
|27.||Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American thyroid association and American association of clinical endocrinologists. thyroid 2011:21:593-646. |
|28.||Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-9. |
|29.||Patil-Sisodia K, Mestman JH. Graves's hyperthyroidism and pregnancy: A clinical update. Endocr Pract 2010;16:118-29. |
|30.||Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation, 9 th ed. Philadelphia: Lippincott Williams and Wilkins; 2011. |
|31.||Momotani N, Yoshimura J, Ishikawa N, Ito K. Effects of propylthiouracil and methimazole of fetal thyroid status in mothers with graves' hyperthyroidism. J Clin Endocrinol Metab 1997;82:3633-6. |
|32.||Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006;107:337-41. |