Transient Hyperthyroxinemia in Newborns From Women With Autoimmune Thyroid Disease and Raised Levels of Thyroid Peroxidase Antibodies

By Kvetny, Jan; Poulsen, Hedvig

Abstract

Objective. Although it is well established that maternal thyroid disease and increased levels of thyrotropin receptor antibodies (TRab) during pregnancy are associated with a number of complications, is the significance of increased levels of thyroid peroxidase antibodies (TPOab) alone a matter for discussion? The aim of the present study was to examine whether transplacental passage of TPOab from women with autoimmune thyroid disease (AITD) interferes with thyroid function in the neonate.

Methods. Pregnant women with AITD (raised levels of TPOab) and their neonates were monitored with regard to variations of thyroid hormones, thyrotropin (TSH), and TPOab. Pregnant women with non- AITD served as controls.

Results. The neonates from mothers with AITD, independently of the presence also of TRab in the mothers, had a transient hyperthyroxinemia one week following birth. Neonatal TPOab correlated with that of the mothers at gestation and was cleared concomitantly with normalization of thyroxine. A high frequency (21%) of severe hyperbilirubinemia was observed in neonates from mothers with AITD.

Conclusion. Children of mothers with raised levels of TPOab, have a transient hyperthyroxinemia one week after birth accompanied by a high frequency of hyperbilirubinemia suggesting that clinical examination and blood testing should be performed consecutively during die first postnatal week.

Keywords: Thyroid peroxidase antibody, hyperthyroxinemia, pregnancy, neonate

Introduction

It is well established that maternal hypothyroxinemia and hyperthyroxinemia during pregnancy are associated with a number of complications during pregnancy and in the offspring [1-3]. It is also well known that fetal/neonatal thyroid disease may be caused by transplacental thyrotropin receptor antibody (TRab) passage [4-6], and that neonatal thyrotoxicosis is associated with a number of serious complications including cardiac failure, pulmonary hypertension, and respiratory distress [4,7,8]. However, the significance of increased levels of thyroid peroxidase antibodies (TPOab) alone is a matter of discussion, although it is generally anticipated that transplacental antibody passage from a mother with autoimmune thyroid disease (AITD) to her fetus is not destructive to the thyroid [9,1O].

A previous report of an association between elevated maternal TPOab levels and an IQ loss in the offspring without signs of maternal hypothyroxinemia [11], has raised the question of whether raised levels of TPOab without concomitant presence of TRab or, as the definitive stimulating agent in autoimmune hyperthyroid disease is not known, the presence of thyroid disease in the mother without known autoimmune agent, or the treatment per se, may be harmful. Therefore, a study of die neonatal thyroid hormone variations and outcomes in offspring from women with well-controlled AITD (raised levels of TPOab) was performed with special reference to thyroid hormone variations and outcomes in mothers with TRab present and in offspring from mothers without autoimmune thyroid disease.

Subjects and methods

Subjects

As part of a quality assessment program (which does not require approval from the local ethical committee) we retrospectively examined the pregnancies and outcomes of twenty consecutive women with AITD (raised levels of TPOab > 60 U/mL) from 2002 to 2004. Of these, 11 had been attending the diyroid clinic before pregnancy and nine had been admitted around the 12th gestational week by the general practitioner. As it is generally accepted that the etiological agent causing AITD is not yet known, and to exclude an effect of thyroid disease per se, neonates (n = 12) in the same period from consecutive women with well-controlled non-autoimmune (without the presence of TRab or TPOab) thyroid disease (eight with nodular toxic goiter and four with myxedema following thyroidectomy) served as controls. All patients had the diyroid disease diagnosed before pregnancy and medical treatment was initiated in all women at least one year before pregnancy.

The patients were examined monthly both clinically and biochemically (thyrotropin (TSH), T^sub 4^, T^sub 3^, thyroxin binding capacity (TBC), TPOab, TRab). In the neonates TPOab and TRab were assessed at birth (cord blood) and 15 days postpartum. Thyroid function was determined at birth (cord blood) and on postnatal days 5 and 15. The medication was titrated during pregnancy so that the values of TSH were kept within the reference interval. This procedure implicated an increase in the daily dose of 1-T^sub 4^ in patients with myxedema and a steady decrease of methimazole dose in patients with hyperthyroidism to maintain TSH within the reference range.

The neonates were examined for signs of neonatal complications: severe hyperbilirubinemia (serum bilirubin >300/xmol/L on postnatal day 5 [12J), hypoglycemia at birth (blood sugar values <2.5 mmol/L 2 hours after birth), and respiratory distress (denned as follows: at gestational age <30 weeks a ratio PaO^sub 2^/(FiO^sub 2^ 95)- PaCO^sub 2^ of <0.36; at gestational age >30 weeks a ratio PaO^sub 2^/ (FiO^sub 2^ 95)-PaCO^sub 2^ of <0.22). Examination of the thyroid state included examination of the following: goiter, proptosis, temperature, heart rate, and diarrhea.

Methods

Determination of TPOab was performed by Statens Serum Institut, Copenhagen using radioimmunoassay (RIA; DYNOtest antiTPO, BRAHMS Diagnostica, Berlin, Germany); values < 60 U/mL were considered negative and expressed as 0 U/mL and values > 1500 U/mL were given as 1500 U/mL. Determination of TRab was performed by MediLab, Copenhagen (TRAK-assay, BRAHMS Diagnostica, Berlin, Germany); values of 0.0-1.0 U/L were considered normal.

Serum TSH was determined using immunochemiluminometric technology and a third-generation assay (Advia Centauer Ready-Pack, Bayer Corporation, Leverkusen, Germany) with an intra-assay coefficient of variation (CV) of 4.1%. Serum total T^sub 3^ (CV 2.3%) and serum total T^sub 4^ (CV 1.9%) were determined by competitive immunoassays and immunochemiluminometric technology (Advia Centauer Ready-Pack, Bayer Corporation). T^sub 4^ uptake (TBC) for calculation of free T^sub 4^ index (FT^sub 4^I) (CV 2.6%) was measured using a double antibody competitive immunoassay using immunochemiluminometric technology (Advia Centauer Ready-Pack, Bayer Corporation). FT^sub 4^I was calculated as T^sub 4^ T^sub 4^ uptake. Age-dependent reference values established in our laboratory were as follows: TSH: postnatal days 1-3 = 0.13-9.22 mU/L, postnatal days 4-30 = 0.16- 8.48 mU/L, adults = 0.56-4.53 mU/L; FT^sub 4^I: postnatal days 1-3 = 62.9-203.5 nmol/L, postnatal days 4-30 = 65.0-196.6 nmol/L, adults = 65.5-129.6 au; T^sub 3^: postnatal days 1-3 = 0.64-4.18 nmol/L, postnatal days 4-30 = 0.74-4.18 nmol/L, adults= 1.31-2.90 au.

Statistics

Values for TPOab and TSH were not normally distributed and were compared with the non-parametric Mann-Whitney test. Student's t tests were used for comparison of normally distributed parameters. The Spearman correlation coefficient was used to evaluate the correlation of the variables. The discontinuous variables were compared with a χ^sup 2^-test. A p value of < 0.05 was considered statistically significant. Bonferroni's adjustment was applied to compensate for multiple comparisons. As the study was performed as an observational study, a sample size calculation was not performed.

Results

The study population initially comprised 20 women with AITD. One pregnancy was terminated in gestational week 15 (see below). Nine women had previously had spontaneous abortions (n=10) at a time when their thyroid status was unknown.

Thirteen women had myxedema and were treated with 1-T^sub 4^ and seven had thyrotoxicosis (difiuse toxic goiter as determined by ultrasonography) and were treated with methimazole. Ten women were first time pregnant. Three women had had one or two children previously, but reported no history of neonatal thyroid disease.

No pregnancies were associated with preeclampsia, gestational hypertension, or perinatal mortality, but one pregnancy was terminated in gestational week 15 because of a chromosomal abnormity (trisomy 18). There were no premature births (gestational duration 38-41 weeks). One woman had an acute cesarean section and seven women had elective cesarean sections. All children had Apgar scores of 10 (10 min) and no children had signs of respiratory distress syndrome. The children were examined by a pediatrician and found clinically euthyroid at birth. Ultrasonic examination during pregnancy and clinical examination at birth revealed that no neonates had goiter.

Thyroid hormones and TSH varied within the reference range after the 1st trimester and during pregnancy in both women with AITD and in the group with non-autoimmune thyroid disease: TSH: 1st trimester= 3.20 mU/L (0.01-9.12); 2nd trimester= 1.62 mU/L (0.61- 3.97); 3rd trimester = 1.72 mU/L (0.65-4.21), median and range; FT^sub 4^I: 1st trimester= 150 + 86 au; 2nd trimester= 128 78 au; 3rd trimester= 122 + 58 au, mean + SD; T^sub 3^: 1st trimester = 2.8 1.2 nmol/L; 2nd trimester = 3.1 0.8 nmol/L; 3rd trimester = 3.4 0.9 nmol/L, mean SD. From gestational week 12 all women were euthyroid.

Figures 1-3 show the variat\ions of thyroid hormones and TSH in the neonate at birth, postnatal day 5, and postnatal day 15. Figure 2 demonstrates that neonates had peak FT^sub 4^I values significantly higher than those from neonates of mothers with non- autoimmune thyroid disease (day 5, p = 0.004) and their values exceeded the maximal reference range established in our laboratory. The significant decline of TSH was steeper (p -0.017, Student's t test) in neonates from mothers with AITD compared to the decline of TSH in neonates from mothers without AITD, signaling that the feedback system recognizes an increased rise of T^sub 4^ compared to controls. The values of Kr^sub 4^I were normalized after 15 days. In contrast, TSH and T^sub 3^ varied within the accepted reference range for the neonatal period (Figures 1 and 3). There was a statistically significant correlation between neonate TPOab and TPOab in the mother in the 36th gestational week (only pairs in which values of TPOab < 1500 mU/L were examined) (Figure 4). The values of TPOab decreased during pregnancy but resumed almost pre- pregnant values one month after birth. Of the 19 women terminating pregnancy, five had increased levels of TRab as well. Comparison of values in neonates from mothers with TRab and without TRab revealed that whereas FT^sub 4^I and T^sub 3^ were significantly higher at birth in neonates from mothers with TRab, there was no difference between the groups on postnatal day 5 (Table I). TRab was not detected in any of the neonates from TRabnegative mothers.

Figure 1. Variation of thyrotropin (TSH) in neonates from euthyroid mothers with autoimmune thyroid disease ([white square]- – -[white square]) and from euthyroid mothers with non-autoimmune thyroid disease (O-O). Mean+ SD shown. Dashed lines represent the reference range.

The frequency of severe hyperbilirubinemia tended to be higher in neonates in women with AITD (4/19) compared to women without AITD (0/ 12) (p = 0.09, χ^sup 2^-test), although there were no differences concerning birth weight or duration of pregnancy.

Figure 2. Variation of free thyroxine index (FT^sub 4^I) in neonates from euthyroid mothers with autoimmune thyroid disease ([white square]- – -[white square]) and from euthyroid mothers with non-autoimmune thyroid disease (O-O). Mean + SD shown. *p = 0.003, Student’s t test. Dashed lines represent the reference range.

Figure 3. Variation of triiodothyronine (T3) in neonates from euthyroid mothers with autoimmune thyroid disease ([white square]- – -[white square]) and from euthyroid mothers with non-autoimmune thyroid disease (O-O). Mean+ SD shown. Dashed lines represent the reference range.

Discussion

The major finding in the present study was a transient hyperthyroxinemia one week after birth in neonates from mothers with AITD compared to neonates from euthyroid persons (represented by the reference interval) and compared to neonates from mothers with well- controlled non-autoimmune thyroid disease. In the absence of thyroid disease in the mother, the peak TSH will rise at term and cause a marked stimulation of the thyroid and an increase in the concentrations of both serum T^sub 4^ and T^sub 3^ within 24 hours [13]. The TSH rise at term was preserved and although T^sub 3^ values also peaked on the 5th postnatal day, the values, in contrast to the values of FT^sub 4^I, remained within the age-relevant reference range. It may be discussed whether TPOab is responsible as a number of women also had raised levels of TRab, which is known to cause transient hyper/hypothyroidism in neonates due to the transplacental passage of maternal TSH stimulating or blocking auto antibodies [6]. However, as the thyroid hormone variations did not differ between neonates from mothers with and without raised levels of TRab at postnatal day 5, is it feasible that TPOab causes the transient hyperthyroxinemia due to the fact that TPO antibodies can mediate complement-dependent thyroid cell cytotoxicity, an observation that may be in accordance with recent observations [14]. In favor of a cytotoxic effect rather than a stimulatory effect is our observation of a significant rise only in T^sub 4^. This suggestion is supported by the observation that TPOab in neonates corresponds to that of mothers in gestational week 36 in agreement with previous studies [9], and that FT^sub 4^I levels in the neonate normalized concomitantly with the clearance of maternal antibodies from the infant’s circulation. In contrast to a recent study [10] in which it was concluded that children of mothers with autoimmune thyroid disease often have thyroid antibodies without signs of thyroid disease, the present study demonstrates hyperthyroxinemia on the 5th postnatal day. The present study differs from most others as the values of TSH and T^sub 4^ were kept within the reference range by medical treatment in the women. This observation and the fact that these variations were not observed in the outcome from mothers with non-AITD indicate that neither thyroid disease per se nor the medical treatment was a causative factor. It may be discussed why TPOab did not excite an effect before term or at birth, but the cytotoxic effect leading to leak of T^sub 4^ probably awaits maturation of the thyroid gland. Our observation of a decrease in TPOab during pregnancy is well in accordance with previous reports [15].

Figure 4. Correlation between thyroid peroxidase antibody (TPOab) levels in women with raised levels of TPOab in gestational week 36 and in neonates. R = 0.78, p < 0.001 (only pairs in which values of TPOab are < 1500 mU/L are shown).

Table I. Postnatal values of TSH and thyroid hormones in neonates from TRab positive mothers compared to values in neonates from TRab negative mothers.

We can only speculate why no postnatal signs of hyperthyroidism (irritability, tachycardia, hypertension, poor weight gain) were observed. One explanation might be the short duration of the hyperthyroxinemia, but a more plausible reason may be that the neonates were not observed with regard to these signs one week after birth. We observed a high frequency of severe hyperbilirubinemia in newborns from mothers with AITD and raised levels of TPOab. The frequency was not statistically significantly higher than in the neonates from mothers without AITD, probably due to the small number, but much higher than that reported in other studies [12,16]. This observation may correspond with a recent report of hyperbilirubinemia in a case of neonatal thyrotoxicosis [17].

The long-term effect awaits longitudinal studies, but it has previously been suggested that raised levels of TPOab during pregnancy may cause cerebral damage to the fetus [U]. We present herein a report of a transient hyperthyroxinemia/thyroiditis and an accompanying high frequency of hyperbilirubinemia. It is well known that the central nervous system of the guinea pig, sheep, and monkey is relatively mature at birth, whereas that of man is less mature and a ‘brain growth spun’ during the neonatal period has been described [18] that may be impaired by the transient hyperthyroidism.

In conclusion, in the present study we describe a condition of ‘autoimmune congenital transient hyperthyroidism’ in neonates from mothers with raised levels of TPOab due to a cytotoxic effect of TPOab on the neonate thyroid, and suggest that clinical examination and blood testing should be performed consecutively during the first postnatal week.

Acknowledgements

The authors want to thank Maria Kvetny, MA scientific linguistic consultant, Institute of Odontology, Faculty of Health Sciences, University of Copenhagen, for linguistic support.

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JAN KVETNY & HEDVIG POULSEN

Endocnnological Clinic and Obstetrical Clinic, Esbjerg County Hospital, Esbjerg, Denmark

(Received 11 July 2005; revised 23 February 2006; accepted 19 July 2006)

Correspondence: Jan Kvetny, Chief Physician, MD, DMSc, section of Endocrinology, Department of Internal Medicine, Hospital of Storstroem County, DK-4700 Naestved, Denmark. Tel +45 55729000 ext. 4136. Fax +4555 734813. E-mail: jan@kvetny.dk

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