Overtreatment of Transient Maternal Hyperthyroidism Resulting in Fetal Goiter.

Abstract

A 25-year-old gravida 1 para 0 pregnant woman was referred to our fetal center at 33 weeks and 1 day of gestation after an incidental fetal neck mass was identified on ultrasonography. Her pregnancy was complicated by weight loss, hair loss, and palpitations in early gestation as well as persistent nausea and vomiting. This prompted an evaluation that was notable for a low thyroid-stimulating hormone (TSH) level (0.06 mIU/L; normal range: 0.27–4.20 mIU/L) and an elevated free thyroxine (T4) level (2.11 ng/dL [27.16 pmol/L]; normal range: 0.86–1.76 ng/dL [11.0–22.6 pmol/L]). The thyroid antibody panel, including thyroid peroxidase antibody and thyroglobulin antibody, was normal. She was diagnosed with hyperthyroidism and treated with propylthiouracil (PTU) at a dose of 150 mg twice a day. Both the TSH and free T4 concentrations normalized on this regimen. A third-trimester fetal growth scan showed a new finding of a fetal neck mass consistent with a fetal goiter, prompting referral to our center for further evaluation.Early detection and expedited management of fetal goiter is important for optimal infant outcomes. Referral to a tertiary center is recommended if there is a concern for a large fetal goiter. When a pregnant woman is referred to the Texas Children’s Hospital Fetal Center because of a fetal goiter, we perform fetal imaging to determine the risk of postnatal airway obstruction and, if this risk is present, establish a plan for management in the delivery room. We also assess for other abnormalities because many fetuses with a goiter also have other findings, such as a pericardial effusion or a hyperextended neck. If there is an esophageal obstruction because of the mechanical effect of the goiter, this may limit fetal swallowing of the amniotic fluid. In turn, this may lead to polyhydramnios and a small stomach size seen on ultrasonography. Based on prenatal findings, specialty consultations are arranged to develop an appropriate plan and educate the family.Fetal goiter can be associated with a hyperthyroid, euthyroid, or hypothyroid state and thus, our team attempts to assess the thyroid status of the fetus. Fetal thyroid testing can be performed with cordocentesis. (1) However, as with all invasive procedures, we recommend weighing the risks and benefits before pursuing cordocentesis, because sometimes an amniocentesis or conservative management is more appropriate. Unfortunately, normograms of amniotic levels of thyroid function tests are not available. (1)(2)If a woman is diagnosed with hyperthyroidism in the first trimester, our team confirms this diagnosis by reviewing the timing of the clinical presentation, her specific symptoms, and her thyroid test results. Because human chorionic gonadotropin (hCG) has a structure similar to that of TSH, when hCG levels peak around the end of the first trimester, temporary symptoms of maternal hyperthyroidism (known as gestational transient thyrotoxicosis) can occur, particularly in patients with persistent nausea and vomiting. (3)(4)(5) To differentiate this temporary effect of elevated hCG levels from true hyperthyroidism, women with gestational transient thyrotoxicosis rarely have a goiter, ophthalmologic manifestations, tachycardia, or tremors. (5)(6)(7) Women with this transient form typically have lower levels of total T4 and normal triiodothyronine (T3) levels compared with those patients with true hyperthyroidism who have elevated total T4 and T3 levels. (3)(5)(7) As expected, women with gestational transient thyrotoxicosis will have normal results on thyroid tests after hCG levels decline, whereas women with true hyperthyroidism have persistently abnormal thyroid results. Treatment is not required for women with gestational transient thyrotoxicosis because laboratory abnormalities and any presenting symptoms will subside once the hCG levels return to normal. (3)(5)(6)(7)If a woman is confirmed to have true hyperthyroidism, we evaluate the patient for Graves disease by obtaining thyroid function measurements as well as TSH receptor antibody levels that consist of stimulating and/or blocking antibodies. Women with a higher amount of thyroid-stimulating immunoglobulin antibodies (TSIs) will have symptoms of hyperthyroidism. If a greater amount of stimulating antibodies cross the placenta compared to blocking antibodies, thyroid production in the fetus will be increased. (8)(9)(10) Testing of the fetus in this scenario will show elevated T3/T4 levels and low TSH levels because of the negative feedback on the fetal thyroid gland. (8)During this woman’s initial visit to our center, laboratory testing showed normal levels of TSH (1.8 IU/mL), free T4 (0.6 ng/dL [7.7 pmol/L]), free T3 (262 pg/dL [4.03 pmol/L]), and TSI levels (103%, normal <130%). As a result, the PTU was stopped. We discussed with the family that the fetal goiter was most likely caused by hypothyroidism as a result of the maternal PTU therapy.Fetal ultrasonography showed a moderate-sized goiter without obstruction of the upper airway or esophagus and there was no evidence of hyperextension of the neck (Fig 1). The fetal heart rate was in the normal range and amniotic fluid levels were normal. Echocardiography showed mildly accelerated flow through a tortuous ductus arteriosus, mildly dilated and hypertrophic left and right ventricles, and a small pericardial effusion (Fig 2). In case of premature delivery, we treated the pregnant woman with 2 doses of betamethasone 24 hours apart.The woman was offered cordocentesis to further evaluate the thyroid hormone status of the fetus versus expectant management; the couple decided to opt out of any invasive testing. Our team explained to the family that the goiter did not appear to be obstructing the fetal airway (because there was no hyperextension of the neck and visualization of the airway with ultrasonography showed it to be appropriate) and there were no signs of esophageal obstruction (because the stomach was normal sized and no polyhydramnios was noted). However, we emphasized that we would still plan for the possibility of airway obstruction because our prenatal accuracy of airway obstruction is not 100% precise and if the goiter increased in size during gestation, airway obstruction could occur at a later time point. We discussed the plan for admission to the NICU after delivery and reviewed the different respiratory support options that may be needed, depending on the infant’s gestational age and whether there was airway obstruction.The woman was monitored with biophysical profiles and fetal Doppler evaluations twice a week with a plan for a scheduled cesarean section at 39 weeks’ gestation if testing did not show any concerns. The ultrasonographic evaluations showed a decrease in size of the fetal goiter (Figs 3 and 4) and there continued to be lack of evidence for fetal airway compromise. Fetal monitoring remained normal in the following weeks.The female neonate was delivered at 39 weeks and 1 day by cesarean section. In addition to neonatology, otolaryngology and surgery were present at the delivery in case the infant had an airway obstruction. The newborn was placed on oxygen immediately after birth, but the oxygen was quickly weaned off because of normal oxygen saturations. The infant did not have any respiratory distress or signs of goiter. Her Apgar scores were 8 and 8 at 1 and 5 minutes, respectively. She was admitted to the NICU for monitoring and further evaluation. Her initial vital signs included a heart rate of 110 beats/min, respiratory rate 50 breaths/min, temperature 99°F (37.2°C), blood pressure 75/50 mm Hg, and oxygen saturation 97%.The endocrinology team recommended neck ultrasonography to assess the infant’s thyroid gland and laboratory tests to measure her thyroid function. Thyroid ultrasonography showed a borderline enlarged thyroid, with the right lobe measuring 2.4 × 1×1.4 cm and the left lobe measuring 2.3 × 1×1.3 cm. The normal lobe size is approximately 2 × 0.9 × 1 cm. The infant’s TSH (2.6 IU/mL) and free T4 (4 ng/dL [51.48 pmol/L]) were noted to be normal. Cardiology recommended echocardiography, which showed no structural defects, normal biventricular function, absence of ventricular hypertrophy or dilation, and no pericardial effusion.The infant remained stable and was discharged at 4 days of age with a plan for repeat thyroid testing 2 days later. These repeat laboratory tests were unremarkable with a normal TSH, normal total T3, and slightly elevated free T4. The infant was most recently evaluated at 12 months of age when she was noted to be doing well and developing appropriately.Fetal goiter is a rare congenital malformation (occurring in 1 of 40,000 births) that can be found in a fetus who is hyperthyroid, euthyroid, or hypothyroid. (11)(12) In most cases, the goiter is identified after the first trimester and fetuses often have a triad of associated findings: anterior cervical mass, neck hyperextension, and polyhydramnios. (13)(14) Additional concerns associated with fetal goiter include endocrine abnormalities, mechanical compression of the airway, esophageal obstruction, and the possibility of neurologic deficits (if associated with congenital hypothyroidism). (11)(12)The most common cause of fetal goiter is maternal Graves disease. (12)(15) In this scenario, a large amount of maternal TSIs cross the placenta, and these antibodies directly activate fetal thyroid follicular cells to produce and release T3/T4, leading to fetal hyperthyroidism. (11)(12) During pregnancy, the treatment of hyperthyroidism associated with Graves disease includes low-dose thionamide to decrease maternal thyroid production and, if needed, β-blockers to treat maternal symptoms. (8)(16) The treatment goal of pregnant women with Graves disease is to maintain a state of mild hyperthyroidism because maternal medications can potentially cause side effects in the fetus that may be more severe than fetal hyperthyroidism (eg, severe fetal hypothyroidism). (8)(16) During the first trimester, if affected women need to be treated with a thionamide, PTU is preferred because methimazole, although more effective, is possibly teratogenic during early gestation. (16) After the first trimester, physicians should have a discussion with the pregnant woman to determine whether transitioning to methimazole is appropriate.Thyroidectomies can be offered to women with Graves disease who are unable to take thionamides (usually because of side effects) and this surgery is typically performed during the second trimester. (8)(16) Of note, women with Graves disease who have had a thyroidectomy can still produce TSIs; if a large amount of these antibodies cross the placenta, the fetus can still be at risk of developing hyperthyroidism even if the pregnant woman is euthyroid.Although maternal Graves disease can lead to fetal hyperthyroidism, in a small number of cases, if the amount of maternal blocking antibodies that cross the placenta is greater than the maternal stimulating antibodies, the fetus can develop hypothyroidism. (9)(10) Fetal hypothyroidism can also occur if maternal thionamide treatment leads to an excessive amount of placental transfer of thionamide to the fetus, as occurred in this case. (4)(7)The management of fetal goiter depends on whether the fetus is hyperthyroid, hypothyroid, or euthyroid. Treatment options for goiter associated with fetal hypothyroidism are limited because thyroxine administered to a pregnant woman does not cross the placenta and direct administration of thyroxine to the fetus by intravascular and intramuscular routes is associated with high rates of complications. (13)(14)(17) If the fetus is suspected to have hypothyroidism, intra-amniotic thyroxine administration during the third trimester can be used to treat the fetus, as reported in some case series. (18)(19)(20)(21) However, there are no clear guidelines about the appropriate dosage and frequency of intra-amniotic thyroxine administration. In the current case, we consulted with a few experts around the world and there was no consensus about the most appropriate management approach.In approximately 5% of pregnant women with Graves disease, the fetus will display some degree of hyperthyroidism, particularly in women with TSI levels greater than 500%. (22)(23)(24) In this scenario, women should be monitored more closely with serial fetal testing and ultrasonography. Clinical manifestations of fetal hyperthyroidism include fetal tachycardia, heart failure, goiter, fetal growth restriction, and hydrops. (22) Treatment of affected fetuses includes maternal propranolol and antithyroid medication. Some centers have found that serial umbilical blood samplings can be useful for fine-tuning medication dosing. (25) A study published in 2003 found that postnatal outcomes were optimal with repeat umbilical blood sampling in women who had elevated TSIs, fetal goiter, intrauterine growth restriction, and/or cardiomeg-aly. (25) In this study, umbilical blood testing was first done during the second trimester and repeated 2 to 3 weeks later, with adjustment in maternal medications as needed. (25)In fetuses with a goiter that is associated with evidence of tracheal compression or mediastinal displacement or when there is a strong concern for airway compromise based on ultrasound or fetal magnetic resonance imaging findings, prenatal planning for ex utero intrapartum treatment (EXIT) procedure is encouraged. This involves multidisciplinary coordination with the neonatologist, surgeon, fetal interventionist, anesthesiologist, and maternal-fetal medicine specialist. (26) In most cases, the goiter usually expands anteriorly, pushing the overlying flexible cervical aponeurosis and avoiding posterior pressure on the trachea; thus, the EXIT procedure is rarely necessary in fetuses with a goiter.The woman described in this case had a fetal goiter secondary to unnecessary maternal administration of PTU in the setting of likely hCG-mediated transient maternal hyperthyroidism. In this case, a positive outcome with minimal intervention was achieved despite the multitude of possible complications that could have occurred. Our discussion reflects the different possibilities that can result from maternal thyroid disorders, which can guide prenatal planning and family education. A multidisciplinary approach is crucial in the management of fetal goiter.Nephrotoxicity in Neonates: 1. C; 2. C; 3. B; 4. D; 5. E.Marijuana Use during Pregnancy and Lactation and Long-term Outcomes: 1. C; 2. A; 3. D; 4. C; 5. B.