Fetal treatment for early dyshormonogenetic goiter
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PRENATAL DIAGNOSIS Prenat Diagn 2009; 29: 543–545. Published online 27 February 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2237 RESEARCH LETTER Fetal treatment for early dyshormonogenetic goiter Anne Francois 1 , An Hindryckx 1 , Hilde Vandecruys 2 , Dominique Van Schoubroeck 1 , Christine Vanhole 3 , Karel Allegaert 3 and Roland Devlieger 1 * 1 Department of Obstetrics and Gynaecology, Division of Mother and Child, University Hospitals Leuven, Belgium 2 Department of Neonatology, Division of Mother and Child, University Hospitals Leuven, Belgium 3 Department of Obstetrics and Gynaecology, General Hospital Virga Jesse, Hasselt, Belgium KEY WORDS: fetal goiter; hypothyroidism; prenatal treatment; L-thyroxin CASE REPORT A 39-year-old Caucasian primigravida was referred to our center at 21 weeks of gestation because of fetal goiter. There were no relevant obstetrical or medical antecedents. The patient did not take any medication. No abnormal iodine intake to recall. At ultrasound the fetal thyroid was found to be symmetrically enlarged with a volume of 26.5 × 13.8 × 16 mm (>P95 for 21 weeks) and had a homogeneous aspect (Figure 1). There was some compression but no deviation of the trachea. The stomach was normally filled and there was a borderline increased amount of amniotic fluid (AF). The mother had a normal thyroid gland with normal thyroid func- tion, no antithyroglobuline, no antithyroidperoxidase and no antithyroid stimulating hormone (TSH) receptor anti- bodies were found. Urinary iodine was within nor- mal limits (159 µg/L). Amniocentesis was performed at 23 weeks of gestation: TSH 3.26 mIU/L, T4 1.1 µg/dl and free T4 0.31 ng/dl. Weekly in utero treatment with L-thyroxin was commenced at 10 µg/kg/day of esti- mated fetal weight. Cordocentesis was conducted at 25 weeks because of mild increase in volume of the goiter (37 × 22 × 24 mm). Cord blood TSH was 94.92 mIU/L (normal range 1.5 – 10 mIU/L), T4 was 3.0 µg/dL (normal range 1.16–9.7 µg/dL). Because of persisting hypothyroidism the L-thyroxin dose was augmented to 150 µg and then to 200 µg weekly for 7 weeks. (Table 1) A stabilization in volume of the goiter was noticed. Cor- docentesis at 32.6 weeks showed improved TSH (36.85 mIU/L) and a still rather low concentration of FT4 (0.84 ng/dL). At 33.5 weeks the mother went in sponta- neous labor. Cesarean section was performed for breech presentation. A baby girl weighing 1890 g was delivered with Apgar scores of 8 and 9 at 1 and 5 min. Umbilical artery pH was 7.36. There was a visible fetal goiter with moderate extension of the neck (Figure 1). No stridor or respiratory repercussions of the goiter were documented. *Correspondence to: Roland Devlieger, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Herestraat 49, B-3000 Belgium. E-mail: [email protected] Cord blood TSH was 17.20 mIU/L and FT4 was 0.96 ng/dL. An ultrasound of the thyroid on day 2 showed a hypo-echogene slightly heterogeneous thy- roid gland: right lobe: 1.9 × 0.9 × 2.9 cm, left lobe 1.6 × 0.9 × 3 cm. Iodine scintigraphy revealed a nor- mal but enlarged thyroid gland with an iodine capitation index of 18% (normal range 1–5%). Bone maturation was assessed by ossification of the distal epiphysis of the femur. Ossification was absent at 35 weeks, but was documented at 42 weeks of postmenstrual age, reflect- ing only moderate delayed bone maturation. Postnatal hearing evaluation was normal. L-thyroxin 40 µg/day IV was administered during 7 days followed by 40 µg/day by oral route from day 8 onwards. This treatment resulted in further progressive disappearance of the goiter. Postnatal growth was evalu- ated at the corrected age of 2 and 9 months and was nor- mal. Psychomotor development, assessed at 9 months by Bayley’s scales of infant development, was within nor- mal limits (IQ motor 91, IQ mental 98). Further etiologic evaluation by perchlorate scintigraphy is scheduled at the age of 2 years. DISCUSSION In the absence of maternal thyroid disease and iodine deficiency, fetal goitrous hypothyroidism is rare and usu- ally due to dyshormonogenesis, as a result of defects in the pathway leading to the normal synthesis of thy- roid hormones. Dyshormonogenesis is caused by gene mutations that are all, except for rare cases, inherited in an autosomal recessive way. The enzymes involved are thyroid peroxidase, thyroglobuline, pendrin (Pendred syndrome: characterized by sensorineural deafness and goiter), NIS (sodium iodide symporter) or THOX 2 (thy- roid oxidase 2) (Park et al., 2005). The fetal thyroid gland can be assessed with sufficient accuracy by ultrasound and nomograms for fetal thyroid transverse width and circumference from 14 weeks of gestation to term have been published. A goiter can be seen as a homogeneous echogenic, symmetric mass in the anterior portion of the fetal neck (Achiron et al., 1998). Three-dimensional sonography in combination Copyright 2009 John Wiley & Sons, Ltd. Received: 26 October 2008 Revised: 22 January 2009 Accepted: 23 January 2009 Published online: 27 February 2009
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Transcript of Fetal treatment for early dyshormonogenetic goiter
PRENATAL DIAGNOSISPrenat Diagn 2009; 29: 543–545.Published online 27 February 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2237
RESEARCH LETTER
Fetal treatment for early dyshormonogenetic goiter
Anne Francois1, An Hindryckx1, Hilde Vandecruys2, Dominique Van Schoubroeck1, Christine Vanhole3,Karel Allegaert3 and Roland Devlieger1*1Department of Obstetrics and Gynaecology, Division of Mother and Child, University Hospitals Leuven, Belgium2Department of Neonatology, Division of Mother and Child, University Hospitals Leuven, Belgium3Department of Obstetrics and Gynaecology, General Hospital Virga Jesse, Hasselt, Belgium
KEY WORDS: fetal goiter; hypothyroidism; prenatal treatment; L-thyroxin
CASE REPORT
A 39-year-old Caucasian primigravida was referred toour center at 21 weeks of gestation because of fetalgoiter. There were no relevant obstetrical or medicalantecedents. The patient did not take any medication. Noabnormal iodine intake to recall. At ultrasound the fetalthyroid was found to be symmetrically enlarged with avolume of 26.5 × 13.8 × 16 mm (>P95 for 21 weeks)and had a homogeneous aspect (Figure 1). There wassome compression but no deviation of the trachea. Thestomach was normally filled and there was a borderlineincreased amount of amniotic fluid (AF). The motherhad a normal thyroid gland with normal thyroid func-tion, no antithyroglobuline, no antithyroidperoxidase andno antithyroid stimulating hormone (TSH) receptor anti-bodies were found. Urinary iodine was within nor-mal limits (159 µg/L). Amniocentesis was performed at23 weeks of gestation: TSH 3.26 mIU/L, T4 1.1 µg/dland free T4 0.31 ng/dl. Weekly in utero treatment withL-thyroxin was commenced at 10 µg/kg/day of esti-mated fetal weight. Cordocentesis was conducted at25 weeks because of mild increase in volume of thegoiter (37 × 22 × 24 mm). Cord blood TSH was 94.92mIU/L (normal range 1.5–10 mIU/L), T4 was 3.0 µg/dL(normal range 1.16–9.7 µg/dL). Because of persistinghypothyroidism the L-thyroxin dose was augmented to150 µg and then to 200 µg weekly for 7 weeks. (Table 1)A stabilization in volume of the goiter was noticed. Cor-docentesis at 32.6 weeks showed improved TSH (36.85mIU/L) and a still rather low concentration of FT4(0.84 ng/dL). At 33.5 weeks the mother went in sponta-neous labor. Cesarean section was performed for breechpresentation.
A baby girl weighing 1890 g was delivered withApgar scores of 8 and 9 at 1 and 5 min. Umbilicalartery pH was 7.36. There was a visible fetal goiter withmoderate extension of the neck (Figure 1). No stridor orrespiratory repercussions of the goiter were documented.
*Correspondence to: Roland Devlieger, Department of Obstetricsand Gynaecology, University Hospitals Leuven, Herestraat 49,B-3000 Belgium. E-mail: [email protected]
Cord blood TSH was 17.20 mIU/L and FT4 was0.96 ng/dL. An ultrasound of the thyroid on day 2showed a hypo-echogene slightly heterogeneous thy-roid gland: right lobe: 1.9 × 0.9 × 2.9 cm, left lobe1.6 × 0.9 × 3 cm. Iodine scintigraphy revealed a nor-mal but enlarged thyroid gland with an iodine capitationindex of 18% (normal range 1–5%). Bone maturationwas assessed by ossification of the distal epiphysis ofthe femur. Ossification was absent at 35 weeks, but wasdocumented at 42 weeks of postmenstrual age, reflect-ing only moderate delayed bone maturation. Postnatalhearing evaluation was normal.
L-thyroxin 40 µg/day IV was administered during7 days followed by 40 µg/day by oral route from day 8onwards. This treatment resulted in further progressivedisappearance of the goiter. Postnatal growth was evalu-ated at the corrected age of 2 and 9 months and was nor-mal. Psychomotor development, assessed at 9 months byBayley’s scales of infant development, was within nor-mal limits (IQ motor 91, IQ mental 98). Further etiologicevaluation by perchlorate scintigraphy is scheduled atthe age of 2 years.
DISCUSSION
In the absence of maternal thyroid disease and iodinedeficiency, fetal goitrous hypothyroidism is rare and usu-ally due to dyshormonogenesis, as a result of defectsin the pathway leading to the normal synthesis of thy-roid hormones. Dyshormonogenesis is caused by genemutations that are all, except for rare cases, inheritedin an autosomal recessive way. The enzymes involvedare thyroid peroxidase, thyroglobuline, pendrin (Pendredsyndrome: characterized by sensorineural deafness andgoiter), NIS (sodium iodide symporter) or THOX 2 (thy-roid oxidase 2) (Park et al., 2005).
The fetal thyroid gland can be assessed with sufficientaccuracy by ultrasound and nomograms for fetal thyroidtransverse width and circumference from 14 weeks ofgestation to term have been published. A goiter can beseen as a homogeneous echogenic, symmetric mass inthe anterior portion of the fetal neck (Achiron et al.,1998). Three-dimensional sonography in combination
Copyright 2009 John Wiley & Sons, Ltd. Received: 26 October 2008Revised: 22 January 2009
Accepted: 23 January 2009Published online: 27 February 2009
544 A. FRANCOIS ET AL.
Figure 1—A. 3D image of the fetal goiter at 21 weeks of gestation. B. Sagittal section through the fetal goiter at 21 weeks: one lobe of thethyroid is marked. C. Picture of the baby after birth. A moderate goiter is visible
Table 1—Diminution of amniotic fluid levels of TSH with intra-amniotic treatment of thyroxin during gestation
Gestational age (weeks) 23 24 25 26 27 28 29 30 31 32TSH (mIU/L) 2,27 2,11 1,95 1,44 1,03 0,69 0,45 0,32 0,24 0,18IA thyroxin administered (µg) 35 43 150 200 200 200 200 200 200 200
IA, intra-amniotic; TSH, thyroid stimulating hormone.
with color Doppler can be used for assessment of itsvolume and vascularization especially in follow up forin utero treatment.
To the best of our knowledge only 14 previous casesof fetal goitrous hypothyroidism in a euthyroid motherwith prenatal treatment have been reported in Englishliterature. The average gestational age at diagnosis was28 (range 20–34) weeks. Most 11/14 (78%) diagnosiswere made after 23 weeks of gestation (Abuhamadet al., 1995; Volumenie et al., 2000; Agrawal et al.,2002; Caron et al., 2003; Matsumoto et al., 2003; Ghaziet al., 2005; Hashimoto et al., 2006; Wu et al., 2007).
Regarding the best management of fetal goiter, severalissues remain debated in the literature.
First, the optimal way to monitor the fetal thyroidstate remains debated. As fetal goiter can be a sign ofboth hyper- and hypothyroid fetal state, imaging stud-ies are not sufficient for the diagnosis. The correlationbetween AF and fetal serum levels of TSH, T3 and T4remains unclear. Several authors have reported on thevalue of AF TSH in diagnosis as well as in follow up offetal hypothyroidism, avoiding the risk associated withcordocentesis. Unfortunately, reference intervals for AFTSH and FT4 have only been established for the thirdtrimester of pregnancy. Additionally, a poor correlationbetween AF thyroxin and fetal serum thyroxin was found(Abuhamad et al., 1995; Volumenie et al., 2000). In ourcase, AF TSH values clearly underestimated the degreeof hypothyroidism and therapy was adjusted based onthe results of the cordocentesis. In the literature, cor-docentesis was still performed to evaluate fetal thyroidstatus in 12/14 (86%) of cases. Cordocentesis enables amore accurate diagnosis, but is associated with fetal lossrates between 0.5% and 1.4%. Experience, used tech-nique, gestational age at cordocentesis and complicationsas chorioamnionitis, placental site and cord bleeding,bradycardia and prolonged procedure time may be of
importance. Our case illustrates that multiple invasiveprocedures (a total of 12 amniotic punctures and twocordocentesis) increases the risk for iatrogenic pretermbirth. Noninvasive monitoring of fetal thyroid state couldavoid this risk and has been attempted using CompoundW, a 3,3′diiodothyronine sulphate (T2S) cross-reactivematerial. Hypothyroid fetuses showed low compound Wlevels in cord blood and low to normal range W valuesin maternal serum without the increase during progres-sion of gestation, implicating that serial measurementsof serum W in maternal serum could be useful as anoninvasive technique for the diagnosis of fetal hypothy-roidism (Abuhamad et al., 1995; Wu et al., 2007). Sofar, this method has not been validated in large series.
Secondly, the modalities of prenatal therapy have notbeen established. In cases of fetal goiter most authorsagree that in utero therapy is necessary. Mechanicalobstruction of the esophagus can cause polyhydramniosand preterm labor, the mass causes the neck to extendresulting in malpresentation and the compressed tracheacan result in airway obstruction at birth, requiringintubation and ventilation (Abuhamad et al., 1995).
The number of cases treated in utero is too smallto give clear recommendations for optimal dose of T4given. Doses from 250 µg L-thyroxin in single intra-amniotic injection to over 3000 µg in repeated injectionsare reported. Goiter size decreased or stabilized in everycase even after a single intra-amniotic injection. Therewere no complications at birth in any of the cases dueto goiter size. In our case treatment was started weeklyat 10 µg/kg/day of estimated weight but had to be raiseddue to suboptimal response.
In one case report T3 was given intra-amnioticallybecause injectable T4 was unavailable at that moment(Agrawal et al., 2002). T3 effects started after 4 to8 h, fetal goiter diminished in size and AF reduced. T3has a shorter half life than T4 (1–2 days to 6–7 days
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 543–545.DOI: 10.1002/pd
FETAL TREATMENT FOR EARLY DYSHORMONOGENETIC GOITER 545
respectively), a more rapid onset of action and is morepotent than T4.
Finally, and most important, data on the long-termneurologic outcome of prenatally diagnosed fetal goitersis required to evaluate whether early in utero treatmentwill add any advantages in intellectual development.
ACKNOWLEDGEMENTS
K. Allegaert and R. Devlieger are supported by theClinical Research Fund of the University Hospitals,Leuven.
REFERENCES
Abuhamad AZ, Fisher DA, Warsof SL, et al. 1995. Antenataldiagnosis and treatment of fetal goitrois hypothyroidism: case reportand review of the literature. Ultrasound Obstet Gynecol 6: 368–371.
Achiron R, Rotstein Z, Lipitz S, Krasik A, Seidman DS. 1998. Thedevelopment of the foetal thyroid: in utero ultrasonographicmeasurements. Clin Endocrinol 48: 259–264.
Agrawal P, Stuart-Ogilvy A, Lees C. 2002. Intrauterine diagnosis andmanagement of congenital goitrois hypothyroidism. UltrasoundObstet Gynecol 19: 501–505.
Caron P, Moya CM, Malet D, et al. 2003. Compound heterozygousmutations in the thyroglobulin gene(1143delC and 6725G →A[R2223H] resulting in fetal goitrois hypothyroidism. J ClinEndocrinol Metab 88: 3546–3553.
Ghazi AM, Ordookhani A, Pourafkari M, et al. 2005. Intrauterinediagnosis and management of fetal goitrois hypothyroidism: a reportof an iranian family with three consecutive pregnancies complicatedby fetal goiter. Thyroidology 15(12): 1341–1347.
Hashimoto H, Hashimoto K, Suehara N. 2006. Successful in uterotreatment of fetal goitrois hypothyroidism: case report and reviewof the literature. Fetal Diagn Ther 21: 360–365.
Matsumoto T, Miyakoshi K, Kasai K, et al. 2003. Fetal goitroishypothyroidism followed by neonatal transient hyperthyroidism.Fetal Diagn Ther 18: 459–462.
Park SM, Chatterjee VKK. 2005. Genetics of congenital hypothy-roidism. J Med Genet 42: 379–389.
Volumenie JL, Polak M, Guibourdenche J, et al. 2000. Managementof fetal thyroid goiters: a report of 11 cases in a single perinatalunit. Prenat Diagn 20: 799–806.
Wu SY, Huang WS, Ho E, Wu ESC, Fisher DA. 2007. Compound W,a 3,3′-diiodothyronine sulphate Cross-reactive substance in serumfrom pregnant women- a potential marker for fetal thyroid function.Pediatr Res 61: 307–312.
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 543–545.DOI: 10.1002/pd
