MATERNAL GRAVES DISEASE AND ABNORMAL CYP2D6 GENOTYPE WITH FETAL HYPERTHYROIDISM

Abstract

Objective:

Fetal hyperthyroidism is a rare yet potentially fatal complication of past or present maternal Graves disease (GD). Our objective was to present a unique case of fetal hyperthyroidism in a mother with a prior history of GD and a cytochrome P450 2D6 (CYP2D6) polymorphism.

Methods:

The clinical course in addition to serial laboratory and imaging results are presented. These include thyroid-stimulating hormone, free thyroxine, and thyrotropin receptor antibody levels, as well as fetal ultrasound, doppler fetal heart rate, and cordocentesis testing.

Results:

A 27-year-old with a history of GD previously treated with radioiodine and a known cytochrome P450 polymorphism was referred to an endocrinology clinic at 17 weeks gestation for evaluation and management of fetal thyrotoxicosis. Despite close follow-up with a multidisciplinary care team and an aggressive “block and replace” treatment approach, progressive disease resulted in intrauterine fetal demise at 28 weeks gestation.

Conclusion:

To our knowledge, this is the first published case report of fetal hyperthyroidism accompanied by a maternal CYP2D6 polymorphism. We hypothesize that the maternal CYP2D6 poor metabolizer phenotype prevents formation of antithyroid drug (ATD) metabolites and thus decreases the efficacy of ATD treatment. We suggest this as an area of future research.

INTRODUCTION

Fetal hyperthyroidism is a rare yet potentially fatal complication of past or present maternal Graves disease (GD). The overall incidence of fetal hyperthyroidism is 1 in 50,000 births and the prevalence is 1 to 5% of women with GD. The diagnosis of fetal hyperthyroidism is based upon maternal history, serum thyrotropin receptor antibody (TRAb) levels, and fetal ultrasonography. Fetal ultrasound findings consistent with fetal hyperthyroidism include fetal tachycardia, intrauterine growth restriction, the presence of a fetal goiter, accelerated bone maturation, cardiac anomalies, and fetal hydrops. The etiology is transplacental crossing of TRAbs resulting in fetal hyperthyroidism. This can occur within the setting of active GD, but also has been seen in the setting of previously treated Graves disease, as autoantibodies can still circulate and be produced. We present a case of severe fetal hyperthyroidism in a woman with a cytochrome P450 2D6 (CYP2D6) polymorphism culminating in fetal demise despite multidisciplinary care including aggressive antithyroid drug (ATD) therapy.

CASE REPORT

A 27-year-old female with a history of Graves disease and CYP2D6 deficiency presented to the endocrinology clinic at 17 weeks gestation after screening ultrasound demonstrated a fetal goiter and fetal tachycardia up to 190 beats per minute (bpm). Her history of Graves disease included treatment with 26.93 mCi iodine-131 at age 23 requiring thyroid hormone replacement shortly thereafter. She was maintained on an unusual regimen of both desiccated thyroid extract and levothyroxine prior to pregnancy. The patient was diagnosed with a CYP2D6 polymorphism at the age of 18 after evaluation for a poor response to multiple antidepressant medications. She was found to be homozygous for a CYP2D6 polymorphism with 2 copies of the gene that produces inactive enzyme and is associated with poor metabolizer phenotype. Her antenatal period was uneventful through the first trimester. At 17 weeks of gestation, a fetal ultrasound demonstrated fetal tachycardia, a fetal goiter, and pericardial effusion (Fig. 1). Her labs were significant for thyroid-stimulating hormone (TSH) 6.0 μIU/mL (normal, 0.35 to 4.94 μIU/mL), free thyroxine (FT4) of 1.15 ng/dL (normal, 0.80 to 1.90 ng/dL), and TRAb measured >40.0 IU/L (normal, 0.00 to 1.75 IU/L) (Table 1 and Fig. 1). She was referred to endocrinology for further evaluation and transitioned to levothyroxine monotherapy, in addition to being started on methimazole (MMI) 5 mg daily and metoprolol for treatment of fetal hyperthyroidism.

Fig. 1.

Fetal goiter at 16 weeks, 1 day.

Table 1.

Progression of Fetal Hyperthyroidism with Therapy

Gestation	17 weeks	19 weeks	21 weeks	23 weeks	25 weeks	27 weeks
Fetal heart rate (bpm)	190–200	160	150–160	140	140’s	140’s
Relative fetal goiter size		Increased	Increased in size	Unchanged	Increased in size	Unchanged
Maternal TSH (μIU/mL)	28.0	3.8	0.24	0.13	1.81	-
ATD dose	5 mg daily MMI	7.5 mg daily MMI	10 mg daily MMI	20 mg BID MMI	Transitioned to PTU 250 mg TID	No change

Abbreviations: ATD = antithyroid drug; BID = twice a day; BPM = beats per minute; MMI = methimazole; PTU = propylthiouracil; TID = three times a day; TSH = thyroid-stimulating hormone.

At 19 weeks of gestation, the patient had a repeat fetal ultrasound which showed an improvement in fetal heart rate in the range between 140 and 160 bpm, along with a reduction in pericardial effusion, but an unchanged fetal goiter. Methimazole was increased to 7.5 mg daily for a goal fetal HR in the 140's bpm (Table 1). Follow-up ultra-sound at 21weeks + 3 days showed that the goal fetal heart rate was attained, but revealed a worsening fetal goiter and pericardial effusion, and MMI was increased to 10 mg daily (Fig. 2). Given the lack of response to treatment, and after discussion with perinatology, cordocentesis was obtained to further guide thionamide therapy and to ascertain fetal thyroid status. Cordocentesis was performed at 23 weeks without complication and laboratory results showed a fetal hematocrit of 25.5% (normal, 42.0 to 65.0 %), fetal FT4 of >5 ng/dL (normal, <0.4 to 0.7 ng/dL), and total T3 (TT3) of 173 ng/dL (normal, <5.0 to 49.5 ng/dL), consistent with marked fetal hyperthyroidism (Table 2). Fetal deoxyribonucleic acid was also tested and found to be negative, ruling out a potentially genetic cause of nonimmune mediated fetal hydrops. MMI was increased to 20 mg twice a day, periumbilical fetal transfusion was performed given the anemia, and intramuscular steroids were given.

Fig. 2.

Fetal goiter at 21 weeks, 3 days.

Table 2.

Cordocentesis at 23 Weeks Gestation

Cordocentesis labs	Ref. range	Value
Hematocrit	42.0–65.0 %	25.5 (L)
T4, free (Ref. 22)	<0.4–0.7 ng/dL	>5.00 (H)
T3, total (Ref. 23)	<5–49.5 ng/dL	173 (H)

Abbreviations: H = high; L = low; Ref. = reference; T3 = triiodothyronine; T4 = thyroxine.

At 25 weeks of gestation, fetal heart rate remained at goal, however, the fetal ultrasound continued to show an enlarged goiter and worsening signs of hydrops fetalis. Given treatment failure and the patient's known history of CYP2D6 poor metabolizer phenotype, the possibility of her deficiency affecting methimazole metabolism was considered. MMI was transitioned to propylthiouracil (PTU) 250 mg 3 times a day. Repeat cordocentesis was not performed after careful discussion amongst a multidisciplinary care team. It was felt that the risks of procedural complications outweighed the benefits of additional laboratory data in the setting of clinically apparent progressive fetal thyrotoxicosis. At 28 weeks of gestation, the patient presented to a birthing assessment center with complaints of leaking fluid and decreased fetal movement. Fetal heart rate was not detected and intrauterine fetal demise was confirmed.

DISCUSSION

We hypothesize that the profound elevation of TRAb antibodies and early presentation portended our patient's aggressive clinical course. In normal embryogenesis, the fetal thyroid gland begins to produce thyroid hormone at around 10 weeks gestation and TSH receptors start to respond to stimulation by TSH and TRAb during the second trimester (1). Therefore, fetal hyperthyroidism secondary to maternal Graves disease typically presents after 20 weeks gestation. Fetal concentration of immunoglobin G TRAb antibodies reach maternal levels around 30 weeks gestation (1,2). Our patient began to exhibit signs of fetal hyperthyroidism prior to 17 weeks gestation with the first goiter documented at 16 weeks + 1 day. There are few case studies of maternal Graves disease-associated fetal hyperthyroidism presenting prior to 20 weeks, and 1 previous case study documented presentation at 18 weeks (3,4). Along with timing, there have been many case studies that have documented an increased risk of fetal hyperthyroidism when TRAb levels are elevated >3 times the upper limit of normal (5–9).

Another challenging aspect to the management of this case was the discordance between fetal heart rate normalization and cordocentesis laboratory results. This caused uncertainty in relying on fetal heart rate as a surrogate for ATD treatment response, as other case reports have shown (10,11). The current literature on treatment of fetal hyperthyroidism suggests the smallest possible dose of ATDs be used whenever possible. It is felt ATDs tend to be more potent in the fetus than in the mother, potentiating the risk of overtreatment, thus resulting in iatrogenic fetal hypothyroidism (5). It is recommended that ATD therapy is titrated every 1 to 2 weeks to obtain a goal fetal heart rate (FHR) of 140 bpm (4,12,13). The American Thyroid Association suggests close fetal surveillance and to consider cordocentesis only when fetal thyroid status and response to treatment are uncertain (5). The risks of cordocentesis include fetal bleeding from the puncture site (up 30%), cord hematoma (up to 17%), and infection. The risk of pregnancy loss due to cordocentesis is estimated to be 1 to 2% (14). In our case, despite normalization of FHR, repeat ultrasound showed worsening fetal hydrops and fetal thyroid. Cordocentesis was performed to assess the fetal thyroid response. Given the elevated fetal FT4 and TT3, there was clear discordance between normalization of heart rate and cordocentesis, thus showing that relying on FHR as a surrogate marker for fetal thyroid function is not always reliable. Indications for repeat cordocentesis are unclear, and there are few guidelines to help guide this decision (15).

One of the most unique aspects of this case was the patient's prior history of CYP2D6 polymorphism. We hypothesize that the maternal CYP2D6 poor metabolizer phenotype prevents formation of ATD metabolites and therefore decreases the efficacy of ATD treatment (16). The cytochrome p450 system is involved in the metabolism of many drugs, with CYP2D6 being one of the most thoroughly studied subgroups (17). Mutations in the CYP2D6 gene have been associated with altered metabolism in up to 25% of all marketed drugs (18). The CYPD2D6 gene is located on chromosome 22 with more than 100 allelic variants documented. It has an autosomal recessive inheritance pattern. The structural variations and polymorphisms to the gene result in a wide range of enzyme activity leading to both poor and ultra-rapid metabolism of medications. For poor metabolizers, the estimated allelic frequency is 0.4 to 5.4% across world populations. Pregnancy can also have an effect on cytochrome p450 pharmacokinetics, with studies showing that pregnancy enhances the metabolism of CYP2D6 enzymes in all but poor metabolizers (17). The cytochrome P450 enzyme family has been demonstrated to be involved in the bioactivation pathway of MMI (16). MMI has also been demonstrated to cross the placental barrier and has been detected in the fetal circulation and thyroid (18). One of the first metabolites, 3-methyl-2-thiohydantoin, is thought to contribute in extending the duration of MMI's antithyroid effect. The half-life of MMI is 2 to 6 hours, whereas 3-methyl-2-thiohydantion is approximately 3 times longer, thus prolonging MMI's antithyroidal effect. Less has been reported in the literature regarding the relationship between CYP450 and PTU metabolism (18–20). Progressive fetal hyperthyroidism despite transition of MMI to PTU would also suggest CYP2D6 polymorphism effects PTU efficacy. A limitation of the case report is that the fetal CYP2D6 genotype was unknown. However, prior studies have demonstrated fetal CYP2D6 activity is low or absent until approximately 2 weeks after birth, regardless of genotype (21). To our knowledge, an association between ATD failure and CYP2D6 deficiency has not been previously described in the literature, and this is also the first reported instance of fetal hyperthyroidism in a woman with CYP2D6 polymorphism.

CONCLUSION

In conclusion, this case report highlights the difficulties involved in the management of fetal hyperthyroidism, specifically relying on FHR as a surrogate for the response to ATD. Current guidelines recommend the lowest possible dose of antithyroid drugs in pregnancy; however, this causes a therapeutic challenge when the rare complications of fetal hyperthyroidism occur, as seen in this case report. We also believe further research into the role of cytochrome involvement in ATD metabolism is warranted.

Abbreviations

ATD

antithyroid drug

bpm

beats per minute

CYP2D6

cytochrome P450 2D6

FHR

fetal heart rate

FT4

free thyroxine

GD

Graves disease

MMI

methimazole

PTU

propylthiouracil

TRAb

thyrotropin receptor antibody

TSH

thyroid-stimulating hormone