Effectiveness of preoperative plasmapheresis in a pregnancy ...

http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2013; 29(5): 508–510 ! 2013 Informa UK Ltd. DOI: 10.3109/09513590.2012.754871

THYROID

Effectiveness of preoperative plasmapheresis in a pregnancy complicated by hyperthyroidism and anti-thyroid drug-associated angioedema B. Ekiz Bilir1, N. Soysal Atile1, O. Kirkizlar2, Y. Ko¨mu¨rcu¨3, S. Akpinar2, A. Sezer4, M. Demir2, and S. Hekimog˘lu5 1

Department of Internal Medicine, Division of Endocrinology and Metabolism, 2Department of Internal Medicine, Division of Hematology, Department of Internal Medicine, 4Department of General Surgery, and 5Department of Anesthesiology and Intensive Care Medicine, Medical Faculty, Trakya University, Edirne, Turkey Abstract

Keywords

Hyperthyroidism is not a rare entity in pregnancy and 85% of these cases attributed to Graves’ disease (GD). There is no therapeutic modality for GD considered as totally safe in pregnancy. Fetal and neonatal risks of maternal hyperthyroid disease are related to the hyperthyroidism itself and/or to the medical treatment of the disease. There are no data supporting an association between congenital anomalies in the fetus and propylthiouracil (PTU). Hepatotoxicity, cytopenias – especially agranulocytosis and quite rarely, angioedema, may be seen as side effects of PTU. In this case report, we examine an instance of Graves’ hyperthyroidism diagnosed during pregnancy. In this case, a serious side effect during antithyroid drug usage was encountered, eventually resulting in surgery in the second trimester. This intervention was assisted by the use of plasmapheresis to obtain rapid normalization of serum thyroid hormone levels.

Angioedema, hyperthyroidism, plasmapheresis, pregnancy

Introduction Graves’ disease (GD), the most common cause of hyperthyroidism, is 5–10 times more prevalent in women and has a peak incidence during the reproductive years. The incidence of hyperthyroidism in pregnancy is reported to be between 0.1% and 0.4%, with the etiology in 85% of these cases attributed to GD [1,2]. With respect to the risk of fetal and maternal side effects of anti-thyroid therapy, the treatment of maternal hyperthyroidism must be evaluated and managed very carefully. There is no therapeutic modality for GD considered to be totally safe in pregnancy. In this case report, we examine an instance of Graves’ hyperthyroidism diagnosed during pregnancy. In this case, a serious side effect during anti-thyroid drug usage was encountered, eventually resulting in surgery in the second trimester. This intervention was assisted by the use of plasmapheresis to obtain rapid normalization of serum thyroid hormone levels.

Case A 22 year-old woman without any systemic illness was admitted with complaints of nausea, vomiting, nervousness and weight loss. She was in her 14th week of a healthy pregnancy, which was her second. Her first pregnancy resulted in spontaneous abortion in the 5th week for an unknown reason. At her physical examination, arterial blood pressure was 120/60 mmHg, heart Address for correspondence: Neslihan Soysal Atile, Department of Endocrinology and Metabolism, Medical Faculty, Trakya University, Edirne 22030 Turkey. Tel: 00 90 284 2357641-2636. Fax: 00 90 284 2352730. E-mail: [email protected]

History Received 22 November 2011 Revised 18 November 2012 Accepted 21 November 2012 Published online 5 February 2013

rate 80 beats per minute (bpm) and rhythmic, thyroid was grade II palpable and her skin was moist. There was no thyroidal disease in her family history. Her thyroid function tests revealed a primary thyrotoxic pattern with elevated free T3 (8.37 pg/ml; normal reference range (NRR): 2–3.9 pg/ml) and fT4 (3.03 ng/dl, NRR: 0.61–1.12 ng/dl) and suppressed TSH levels (0.04 mIU/ml; NRR: 0.4–4 mIU/ml). Her thyroid auto-antibodies were positive with anti-thyroid peroxidase Ab (Anti-TPO): 62.7 IU/ml (NRR: 0–9) and TRAb (TSH receptor antibody): 42.54 U/l (NRR: 9–14). Thyroid ophthalmopathy was not present at the ophthalmologic examination. Thyroid ultrasonography revealed a heterogeneous gland echogenicity without any nodule. On the basis of this data, GD was diagnosed and propylthiouracil (PTU) 50 mg tablet tid was prescribed. On the 17th day of PTU usage, swelling, especially perioral and periorbital edema, and an itchy, red-colored rash, which had spread to her entire body, were noticed. When she was admitted to our hospital, drug-induced angioneurotic edema due to PTU was diagnosed and Methylprednisolone ampule 20 mg/day and Pheniraminehydrogen maleate ampule 45 mg/day were prescribed. At her physical examination, blood pressure was 120/ 70 mm Hg, heart rate 120 bpm and rhythmic, and temperature 37.8 C. She also had anasarca-type edema and an erythematous, warm, macular rash. She had the following lab results: total blood count was normal, CRP 10.3 mg/dl (NRR: 0–0.8 mg/dl), fT3 4.49 pg/ml, fT4 1.12 ng/dl and TSH 0.04 mIU/ml. Because she had a severe side effect, called angioneurotic edema, due to PTU usage, it was decided that the other thionamide ATD-methimazole (MMI) – was not appropriate for her because of the cross-reaction and teratogenic risks associated with this drug. The other treatment

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DOI: 10.3109/09513590.2012.754871

modality available was radioactive iodine (RAI) therapy, but it is contraindicated in pregnancy so it could not be used. It was decided to observe the patient without any medication to see if the autoimmune GD might go into remission over the course of the pregnancy. At the end of one week-observation period, sinus tachycardia attacks, reaching a rate of 150 bpm and causing angina pectoris in the absence of ECG signs, were experienced. Because of these new complaints, low-dose propranolol (40 mg/ day) was prescribed. Progressive thyroid hormone increment in the beta blocker therapy obliged us to give the patient a total thyroidectomy during the second trimester. To prepare the patient for surgery at the 20th week of gestation, thyroid hormone levels had to be reduced. Because she had a thyrotoxic laboratory panel of fT3 4.18 pg/ml, fT4 1.73 ng/dl and TSH 0.02 mIU/ml, to attain rapid normalization of free thyroid hormone levels plasmapheresis was planned. The patient required plasmapheresis during the 2nd trimester of pregnancy because ATD could not be used. Plasmapheresis was performed through Fresenius Blood cell Separation system AS.TEC 204TM and PL1 disposable sets with one volume per day. She had prepared by femoral venous catheter and 3 cycles of plasmapheresis were performed: one cycle with 5% albumin and two cycles with fresh frozen plasma (FFP) as replacement fluid (using a sandwich method). Acid citrate dextrose was used as an anticoagulant for plasmapheresis. The patient experienced no electrolyte imbalance and no complications related to catheter or anticoagulation. Fetal heart beat was checked before and after every cycle and no fetal complication was observed. Surgery was performed on the patient just after the 3rd plasmapheresis cycle on the same day while the thyroid function tests were as follows: fT3: 4.37 pg/ml, fT4: 1.41 ng/dl TSH: 0.03 mIU/ml. No medication was administered prior to the surgery. Her heart rate was 145 bpm, blood pressure 135/60 mm Hg and body temperature 36.5 C. Anesthesia was induced intravenously using 1 mg/kg remifentanyl, 2 mg/kg propofol and 0.1 mg/kg vecuronium bromide. Anesthesia was maintained with one minimum alveolar anesthetic concentration of sevoflurane in 50% oxygen/air mixture and vecuronium bromide under controlled ventilation. Standard fluid therapy was administered. Because her heart rate was 135 bpm, remifentanyl infusion 0.25 mg/kg/min was immediately started and the tachycardia was controlled after 15 minutes. 2 U FFP were given to the patient intraoperatively. Hemodynamic and other vital parameters were stable. She was observed for any possible postoperative complication. On the first postoperative day, levothyroxine replacement therapy was started, with the dose incrementally raised to 100 mcg/day over one week. 18 weeks after the thyroidectomy, she delivered her baby. Neonatologists were informed about the TRAb positivity of the mother, but no hyperthyroidism in the infant was observed either the prenatal or post partum periods. She is still receiving followed up care and is euthyroid; her baby is healthy.

Discussion Hyperthyroidism in pregnancy is not an uncommon problem. Because nonspecific symptoms of hyperthyroidism such as tachycardia, warm moist skin, tremor and systolic murmur may be mimicked by normal pregnancy, the delineation between normal pregnancy and true hyperthyroidism and gestational thyrotoxicosis is very important [3]. The presence of a significant goiter, classic thyroid ophthalmopathy, pretibial myxedema, clinical evidence of autoimmunity, TRAb positivity, and a

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family history of hyperthyroidism may point to a diagnosis of true GD. In first trimester thyrotoxicosis, TRAb positivity supports the diagnosis of GD rather than gestational thyrotoxicosis. While most patients with GD have detectable TRAb, it is negative in gestational thyrotoxicosis. TRAb positivity is also important for the fetus because the babies of TRAb positive mothers are exposed to the risk of transient thyrotoxicosis due to transplacental passage of stimulatory TRAb. Fetal and neonatal risks of maternal hyperthyroid disease are related to the hyperthyroidism itself and/or to the medical treatment of the disease. If maternal thyrotoxicosis is not managed adequately, preterm delivery, preeclampsia, congestive heart failure, intrauterine death, intrauterine growth restriction and low birth weight may be encountered [4,5]. In contrast, overtreatment of the mother with thionamides can result in iatrogenic fetal hypothyroidism and goiter. So, the treatment of maternal hyperthyroidism must be evaluated and managed judiciously. Three anti-thyroid therapy modalities are used in non-pregnant adults: anti-thyroid medications, RAI therapy and surgery. The main class of ATD is thionamides, which consists of PTU and MMI. During treatment, the maternal thyroxine level should be kept in the upper third of the reference range or just above the upper normal limit to meet the fetal thyroid hormone requirements, using the lowest possible ATD dosage. There are no data to support an association between congenital anomalies and PTU. However, MMI-related embryopathy, which includes aplasia cutis, choanal atresia, tracheal-esophageal fistulae, hypoplastic nipples, facial anomalies and psychomotor delay, has been reported recently [6,7]. Therefore, especially during the first trimester, which is the organogenesis period, PTU is preferred to MMI. The most common adverse effects of thionamides are skin rash and pruritus, but they are generally not life threatening. Angioedema, hepatotoxicity and cytopenias, especially agranulocytosis, may also occur. Angioneurotic (or Quincke’s) edema is defined as the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. If angioedema progresses rapidly, it should be treated as an emergency because of the risks of airway obstruction and suffocation. If it is diagnosed in conjunction with a special drug used, the drug should be discontinued and another therapeutic alternative must be determined. The adjunctive therapies used in hyperthyroidism, which include beta-blockers, potassium-iodide, corticosteroids and bileacid sequestrants, cannot be used for a long time during pregnancy due to their teratogenic potential. Propranolol in the late pregnancy may cause mild and transitory neonatal hypoglycemia, apnea, and bradycardia. Neonatal hypothyroidism and goiter, which may be so severe as to lead to asphyxiation because of tracheal obstruction, have been associated with repeated use of iodides during pregnancy [8]. Because of the absolute contraindication of RAI diagnostic tests and therapy during pregnancy, this modality also cannot be used in pregnant women who are thyrotoxic. Pregnancy categories of PTU, MMI and potassium iodide are all category-D. Beta-blockers are category C in the 1st trimester, category D in the 2nd and 3rd trimesters. Subtotal thyroidectomy is only considered during pregnancy as a therapeutic alternative for maternal GD if a serious adverse reaction to ATD therapy occurs, if persistently high doses of ATD are required to control maternal hyperthyroidism, or if a patient is nonadherent to ATD therapy and has uncontrolled hyperthyroidism. Surgery is performed in the second trimester, when


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organogenesis is complete and, thus, the fetus is at minimal risk for teratogenic effects of medications. During the trimester, the uterus is relatively resistant to contraction-stimulating events, so preterm delivery risk is also minimal. In addition, after 12 weeks, the likelihood of spontaneous abortion is reduced. In terms of the teratogenicity of the medications, no anesthetic drug has been proven to be teratogenic in people. In the literature, there are some rare case reports of therapeutic plasmapheresis during molar pregnancies [9–11] and during pregnancies in which ATD is contraindicated [12]. During plasmapheresis, FFP plasma has some advantages over albumin as replacement fluid. It contains thyroxine binding protein (TBG) and TBG helps to decrease plasma free T3 and T4 levels. However, its use entails a higher risk of infection and electrolyte imbalance. In American Society for Apheresis guideline, plasmapheresis in hyperthyroidism and thyroid storm is defined as category III (Optimum role of apheresis therapy is not established. Decision making should be individualized) and recommendation grade 2 c (weak recommendation, low-quality or very low-quality evidence) [13]. These evidences depend on mostly case reports and there is no prospective trial in these diseases. And, in these diseases therapeutic plasma exchange (TPE) is not chosen as a first line treatment. But, in rare cases such as in our patient, who is enable to be euthyroid prior to thyroidectomy with other treatments are candidates for plasmapheresis. Patients applies plasmapheresis can have complications due to catheterization, anticoagulation or reactions to replacement fluids (allegical reactions, hypocalsemia, etc). The pregnant patients are also under risk of premature birth with these complications. But, generally plasmapheresis is a well tolerated procedure. And, TPE can safely performed during pregnancy. In conclusion, plasmapheresis can be safely used in pregnant women who need rapid removal of plasma thyroid hormones. Because there is enormous experience in plasma exchange in pregnancy, especially in Rh alloimmunisation management, when conditions warrant, plasmapheresis can be used as a therapeutic alternative for hyperthyroidism in pregnancy.

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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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