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 Antithyroid Drug-induced Fetal Goitrous Hypothyroidism

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john

john

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PostSubject: Antithyroid Drug-induced Fetal Goitrous Hypothyroidism   Antithyroid Drug-induced Fetal Goitrous Hypothyroidism Icon_minitimeMon Jun 20, 2011 7:08 am

Antithyroid Drug-induced Fetal Goitrous Hypothyroidism

Key Points

  • Treating pregnant women with antithyroid
    drugs (ATDs) puts the fetus at risk of overtreatment and thus
    subsequent development of fetal hypothyroidism and goiter formation
  • Fetal goitrous hypothyroidism can cause
    severe pregnancy-related complications and potentially harm fetal growth
    and neurological development
  • Treatment of fetal goitrous
    hypothyroidism with intra-amniotic levothyroxine achieves better results
    than simply discontinuing maternal ATD treatment
  • Awareness of the pregnancy-related changes to maternal thyroid status is essential when treating maternal hyperthyroidism
  • Close monitoring of the maternal thyroid status, especially estimates of free T4 levels, is the best way to avoid overtreatment
  • Centralized care of pregnant women with
    Graves disease in specialized multidisciplinary units is urgently needed
    to maintain optimal fetal development

Abstract and Introduction



Abstract


Maternal overtreatment with antithyroid drugs
can induce fetal goitrous hypothyroidism. This condition can have a
critical effect on pregnancy outcome, as well as on fetal growth and
neurological development. The purpose of this Review is to clarify if
and how fetal goitrous hypothyroidism can be prevented, and how to react
when prevention has failed. Understanding the importance of
pregnancy-related changes in maternal thyroid status when treating a
pregnant woman is crucial to preventing fetal goitrous hypothyroidism.
Maternal levels of free T4 are the most consistent indication
of maternal and fetal thyroid status. In patients with fetal goitrous
hypothyroidism, intra-amniotic levothyroxine injections improve fetal
outcome. The best way to avoid maternal overtreatment with antithyroid
drugs is to monitor closely the maternal thyroid status, especially
estimates of free T4 levels.


Introduction


In pregnant women, overtreatment with
antithyroid drugs (ATDs) puts the fetus at great risk. Iatrogenic fetal
hypothyroidism can impair the neurological development and growth of the
child.[1-4]
Furthermore, a fetal goiter can cause tracheal compression, which
increases the risk of developing polyhydramnios (owing to reduced
swallowing ability), premature labor (attributable to rupture of the
fetal membranes caused by the polyhydramnios), dystocia (because
ofhyperextension of the fetal neck) and airway obstruction at birth.[5]
Premature labor is the main cause of newborn morbidity and mortality in
all pregnancies. The risk connected with premature labor, which must be
prevented, increases if the fetus has other fetal diseases in addition
to hypothyroidism, such as iatrogenic hypothyroidism. Whether
discontinuation of maternal ATD treatment is sufficient when a fetal
goiter develops or if the fetus needs direct treatment with
intra-amniotic levothyroxine injections is a subject of debate. However,
the development of iatrogenic fetal goiters can be prevented if the
endocrinologist is aware of the changes in maternal thyroid status and
metabolism that occur during pregnancy.
This article reviews the reported cases of
fetal goiter formation attributable to overtreatment of maternal
hyperthyroidism with ATDs. The aim of this Review is to clarify if and
how such cases could have been prevented, and how to react when
prevention has failed.Thyroid Status in Pregnancy




During the first trimester, maternal serum concentrations of total T4
rise because of a combination of the thyrotropic effect of human
chorionic gonadotropin (hCG) and the stimulatory effect of estrogen on
the concentration of thyroid binding globulin (TBG). Furthermore, the
hCG-induced stimulation of the TSH receptor leads to an increase in the
production of thyroid hormones, which then leads to a decrease in TSH
levels by negative feedback to the pituitary gland.[6]
Reference values based upon thyroid function variables of pregnant
women indicate that during the first trimester normal levels of maternal
total T4 are increased by ~50% compared to the usual
nonpregnant values (which vary between laboratories because of the
different assays used).[7-9]
In the second and third trimesters, the hCG-induced stimulation of the
thyroid gland decreases, while the maternal level of total T4
continues to be above, or at least in the high end, of the nonpregnant
reference values, and levels of TSH continue to be in the low end of the
range.[10,11]
Other changes also influence maternal thyroid status, such as increased
renal iodine clearance, increased blood volume, and placental-fetal
exchange and metabolism of thyroid hormones.[12,13] The placental-fetal exchange and metabolism of thyroid hormones is particularly important to the fetus.
The fetus begins to metabolize thyroid
hormones early in the first trimester, but the production and secretion
of fetal thyroid hormones does not reach notable levels until
midgestation.[14]
Until then the fetus is dependent on the maternal supply of thyroid
hormones; even at term up to 30% of the fetal thyroid hormones are of
maternal origin.[15-17] Although the supply of maternal T4
is extremely important for the fetus, quantitatively, the levels of
fetal thyroid hormones are much lower than the maternal thyroid hormone
levels. This balance is secured by a preferential placental deiodination
(by type 3 deiodinases) of T4 to the presumably inactive reverse T3, which prevents fetal hyperthyroidism.[13,18]
However, once the fetal thyroid gland becomes functional, TSH-receptor
autoantibodies (TRAbs) that are able to cross the placenta freely will
affect the fetal thyroid gland (Figure 1). Fetuses of mothers with
TSH-receptor stimulating immunoglobulins (TSIs), as found in Graves
disease, are therefore at risk of developing hyperthyroidism—even when
the mother is euthyroid.[19-21]
ATDs (such as thionamides) given to the mother also cross the placenta
and block the activity of fetal thyroid peroxidase (and peripheral
deiodination when the mother is treated with propylthiouracil), which
increases the risk of developing fetal hypothyroidism and thus a fetal
goiter. Before the onset of fetal thyroid function there is no need to
assume that ATDs will have a direct effect on the fetus;[22] however, iodide uptake and colloid formation begin as early as the eleventh week after conception.[12]
Treating maternal Graves disease with ATDs, therefore, requires a
careful balance between securing sufficient fetal production of thyroid
hormones (and supply of maternal T4), while preventing fetal hyperthyroidism attributable to thyroid-stimulating antibodies.


Antithyroid Drug-induced Fetal Goitrous Hypothyroidism 738812-thumb1
(Enlarge Image)



Figure 1.







Pathways of Fetal Goiter Development in Connection to Maternal
Antithyroid Drug Treatment for Graves disease. Both maternal
autoantibodies and ATDs can cross the placenta and exert their effect on
the fetal thyroid gland, at worst, leading to fetal goiter formation
and hypothyroidism, which puts the fetal outcome at risk. Abbreviations:
ATD, antithyroid drug; TPO, thyroid peroxidase.



The changes in thyroid status during
pregnancy, especially in women with autoimmune diseases, complicate the
interpretation of maternal thyroid status and thus the need for
treatment with ATDs. The first case of a goiter in a newborn baby
attributable to maternal propylthiouracil treatment was published by
Eaton in 1945.[23] Yet, the task of treating pregnant women with Graves disease still remains a puzzle to many physicians.

Fetal Goitrous Hypothyroidism



In total, we found 48 cases of fetal goitrous hypothyroidism attributable to maternal ATD treatment reported in 20 case reports[24-43] and seven larger investigations[44-50]
between 1980 and 2009. The cases were divided into two groups according
to intervention: group A with regulation of maternal ATD treatment
supplemented by invasive treatment with intra-amniotic levothyroxine
injections (23 cases), and group B with noninvasive regulation of the
maternal ATD dose only (25 cases). Details of the review criteria and
the individual patients are provided in Supplementary information
online.

Maternal Thyroid Status


Across the two groups, 12 women had been
diagnosed with Graves disease before their current pregnancy and 11
women were diagnosed with this condition during their current pregnancy.
At the time of fetal goiter diagnosis, the average dose of
propylthiouracil was 289.0 mg/day (information from 19 of 23 patients)
in group A and 222.8 mg/day (information from 17 of 25 patients) in
group B. No correlation was found between the duration of maternal
thyroid disease and the dose of propylthiouracil. Seven women received
imidazole derivatives (such as methimazole and carbimazole) during the
first trimester, three of whom[27,44] were switched to propylthiouracil during the second trimester.
In group A, when a goiter was discovered, ATD
treatment was discontinued in three patients, reduced in 12 patients,
reduced then discontinued in three cases, discontinued then restarted in
one case, and not changed in two patients (information from 21 of 23
patients). In group B, ATD treatment was discontinued in three patients,
reduced in 12, reduced then discontinued in two, and in three cases the
mother received supplemental levothyroxine treatment (information from
20 of 25 patients).
TRAb levels were only reported in 14 patients
(61%) from group A and in 12 patients (48%) from group B. Nine women in
group A were positive for TRAb, while five had negative or normal
levels. Five women in group B had positive TRAb levels, while seven had
negative or normal levels. Across the groups, only in eight patients did
the authors differentiate between TSIs and TSH-receptor binding
inhibitory immunoglobulins (TBIIs). Information on levels of TBIIs was
given in five patients,[25,26,33,44]
three of whom had both positive TBII and TSI levels. Three women in
group A (information from 11 of 23 cases) had a TSH level >4.5 mU/l
at the time of goiter discovery (four had a TSH level >2.5 mU/l),
while TSH levels were only reported in seven patients in group B, one[49] of whom had a TSH concentration >2.5 mU/l (TSH <2.5 mU/l during the first trimester is currently recommended[51]). Thus in most cases, the observed TSH levels did not indicate maternal hypothyroidism.
In the publications where both reference
ranges and analyses were provided (15 patients across both groups), data
showed that all women but two[26] had levels of free T4 below or in the lower part of the reference range at the time of goiter discovery. In some patients, free T4 levels were low even when TSH levels were below or in the very low part of the reference range.[28,29,38,42] Thus, maternal hypothyroxinemia seems to be the most reliable maternal indicator of fetal hypothyroidism.


Fetal Thyroid Status


On average, the fetal goiters were detected
by ultrasound examination at gestational week 29 in both groups. The
earliest detection of a fetal goiter was in gestational week 19.[38]

Upon discovery of the fetal goiters, fetal
blood or amniotic fluid sampling was performed in all patients in group A
to confirm the diagnosis of fetal goitrous hypothyroidism. Fetal blood
sampling showed levels of TSH between 9.7 mU/l and 1,640.0 mU/l (median
38.0 mU/l; information from 19 of 23 patients). TSH levels from the
amniotic fluid sampling were only available in six patients, with an
average level of 4.6 mU/l. In group B, information was generally lacking
about fetal goiter size and particularly fetal thyroid status. Though
not surprising given the noninvasive approaches used in patients from
group B, this hindered a comparison of the severity of fetal
hypothyroidism between the two groups. However, in three studies[28,43,46]
in group B, fetal blood levels of TSH (range 40.2-56.0 mU/l) were given
at the time of goiter discovery, and did not differ from those of group
A. In addition, fetal goiter size did not seem to differ between the
two groups.
Intra-amniotic levothyroxine injections
(group A) were given between one and six times with an average dose of
279 |ig per injection (dose provided for 49 of 58 injections). A
decrease in goiter size was seen within 0.5-2.5 weeks after the first
injection where information was given on the gestational week of the
subsequent examinations (10 patients).
Fetal blood or amniotic fluid sampling was
only performed in eight patients in group A after the primary diagnosis
of fetal hypothyroidism. Although these tests were not always performed
at the first ultrasound examination following the first injection of
levothyroxine, those performed 1-7 weeks after the first injection all
showed normalization or improvement of the fetal thyroid status. In
group B, a decrease in goiter size was reported within 1- 9 weeks of the
maternal ATD treatment regimen being altered (information from 13
patients). However, in four patients in group B, the goiter size was
unchanged after 2- 5 weeks.[28,39,49]

Obstetric Outcome


Some studies indicate that male fetuses are
more prone to develop goitrous hypothyroidism attributable to maternal
ATD treatment than female fetuses.[52]
Our review of the literature does not support this hypothesis, as we
found a total of15 female and 12 male fetuses with iatrogenic goiter (in
21 cases there was no information on the fetal sex).
In group A, the fetal goiters resolved in 10
patients, while in seven patients a goiter could still be seen or
palpated at birth (
Table 1
). However, the goiters had decreased in size after treatment in 16 of
the 19 patients for whom this information was provided. This finding
should be viewed in light of the fact that as pregnancy progresses, the
fetal thyroid gland will physiologically increase in size. The three
cases that did not show a decrease of the absolute goiter size could,
therefore, reflect a relative decrease compared to gestational age. Six
neonates in group B had a goiter at birth, and seven did not, while no
information was provided for the remaining 12 neonates.
In group A, 16 neonates were euthyroid (73%),
while six were hypothyroid (information from 22 neonates). In group B,
11 neonates were euthyroid (50%), eight were hypothyroid, one was
subclinically hypothyroid and two were hyperthyroid (information from 22
neonates). Across the two groups, postnatal thyrotoxicosis developed in
six cases (
Table 1
). This finding could be attributed to the slower clearance of the
maternal TRAbs than that of propylthiouracil. Thus one must be aware
that a neonate, though hypothyroid during intrauterine life because of
overtreatment with propylthiouracil, can develop autoimmune
thyrotoxicosis after birth.
The median fetal birth weight was 2,891 g in
group A and 3,115 g in group B (information from 17 and eight neonates,
respectively) (
Table 1
). In three cases, the weight of the newborn compared to gestational age was below the Scandinavian growth curve minimum;[53] however, only one case[28] fell below an American gender-specific growth curve.[54]
Gestational age at birth was an average of 36.5 weeks in group A and
35.5 weeks in group B (information from 18 and six births, respectively)
(
Table 1
). These results were in accordance with previous conclusions that there
is a connection between maternal hypothyroidism or thyroid
autoimmunity, and preterm delivery and small birth weights.[55]

Three neonates[35,37,41] suffered from respiratory distress at birth (
Table 2
); in two[35,41] no goiter was seen as the possible cause of this distress. In one neonate,[37]
who was born at gestational week 30, the respiratory distress must be
attributed not only to a prominent goiter but also to prematurity of the
lungs at delivery.
More than half of the fetuses were delivered by cesarean section (information from 21 patients). In five patients[29,33,38,40,44]
a cesarean section was required because of breech presentation, which
has previously been correlated with maternal hypothyroxinemia and
hypothyroidism.[56,57] In two women, cesarean sections were performed because of fetal distress,[31,37]
in one of whom this distress was probably attributable to the
intra-amniotic levothyroxine injection that was given within 24 h of the
mother going into preterm labor.


Severe Complications


Reports were given on several of the
complications associated with fetal goitrous hypothyroidism including
polyhydramnios, hyperextension of the fetal neck, intrauterine growth
restriction (IUGR)[28,29,43] and fetal hydrops[32] (
Table 2
). Although no statistical comparison was applied between group A and
group B because of the small sample size, the gravest outcomes were
undoubtedly seen in group B, with two stillbirths recorded (
Table 2
).[39,44]
In neither of these two cases did the goiters occur earlier in the
pregnancy nor were they larger at the time of discovery than in other
cases from group A or group B. Furthermore, cases of retarded bone
development,[36,44,46] advanced bone ossification[30] and congenital malformations[32] were reported across both groups (
Table 2
).
A general lack of follow-up information
characterized the publications included in both groups. In group A,
follow-up examinations were performed between 2 weeks and 3 years after
birth in 12 children and found no neurological and/or motorical sequelae
in any of the children. The weight of one child was within the tenth
percentile at 3 years of age.[28]
Seven children in group B had neurological and/or motorical evaluations
performed between 12 days and 20 months after birth. All the children
were developing normally. No reports were given on neurological
retardation.
How to Avoid Maternal Overtreatment


The cases presented in this Review included a
range of severe complications that have been associated with thyroid
dysfunction and autoimmunity during pregnancy:[55,58-60]
stillbirth, premature labor, increased risk of breech presentation,
IUGR, delayed bone development, polyhydramnios and fetal hydrops. This
observation stresses the importance of avoiding iatrogenic fetal
goitrous hypothyroidism.


Treatment with ATDs During Pregnancy


Up to 0.4% of all pregnant women have been
reported as hyperthyroid (not including the more common transient
gestational thyrotoxicosis), with autoimmunity being the primary
etiology in 90% of cases.[61,62]
Untreated hyperthyroidism during pregnancy is associated with an
increased risk of preeclampsia, congestive heart failure, fetal
mortality, infants born small for gestational age and thyroid storm—the
risk of these complications increases with increasing maternal
autoantibody levels.[60,63,64] Therefore, treatment of maternal hyperthyroidism is necessary.
Guidelines have so far recommended treatment
with ATDs rather than with radioiodine or surgery unless severe adverse
effects associated with the drugs occur.[51]
Supplementing ATD treatment with levothyroxine (the 'block-replace'
regimen administered to three patients in group B) is not recommended.
This treatment strategy can result in the use of higher doses of ATD to
keep the woman euthyroid compared to the use of ATDs alone, thus
increasing fetal ATD exposure.[65]

The ATDs that are most frequently used (in
pregnant women and the general population) are propylthiouracil and
methimazole. In contrast to findings from the 1970s,[66] more recent research has indicated that placental transfer of methimazole is not greater than that of propylthiouracil.[67-69]
However, propylthiouracil is still recommended as the first-line ATD
during pregnancy, because of the possible association of methimazole
with congenital abnormalities. Several studies have reported congenital
abnormalities (especially aplasia cutis congenita and choanal atresia)
in fetuses exposed to methimazole during the first trimester of
pregnancy.[70-73] Barbero et al.[74] found an odds ratio of 18 for choanal atresia among infants who were exposed to methimazole in utero compared
to infants who were not exposed to this drug. These cases have led to a
general acknowledgment of a so-called 'methimazole embryopathy'. By
contrast, cases of congenital malformations connected to
propylthiouracil treatment are few. In one case reported by Yanai et al.,[12]
a child was born with severe malformations after propylthiouracil
exposure. To our knowledge, one case of choanal atresia after
propylthiouracil treatment during pregnancy has been reported.[75]
In a study published in 2010, several instances of birth defects after
maternal propylthiouracil treatment were found, as well as a significant
association (P <0.01) between methimazole treatment and choanal atresia.[76]
Thus, although methimazole-induced embryopathy is well established, a
teratogenic effect of propylthiouracil still cannot be eliminated.
Maternal adverse effects associated with
propylthiouracil treatment have lately been given much attention. In
spring 2010, the FDA issued a warning about the risk of liver failure in
connection to treatment with propylthiouracil.[77]
Leading up to this warning was an increasing awareness of the
hepatotoxicity of the drug, with several reported instances of liver
transplantation (with poor survival rates) following
propylthiouracil-induced acute liver failure in both children and
adults.[78-81] Neonatal hepatitis after maternal propylthiouracil treatment during pregnancy has also been reported.[82] However, isolated case reports of methimazole-associated liver failure can also be found.[83-85]

Although still controversial, a pragmatic
suggestion has been to treat pregnant women with propylthiouracil during
the first trimester of pregnancy (to avoid the teratogenicity of
methimazole) and then switch to methimazole treatment during the second
and third trimesters (to minimize the risk of hepatotoxicity associated
with propylthiouracil).[81]
However, more research is needed to establish whether or not such a
transition would do more harm than good to both mother and fetus.


Importance of Careful Monitoring—The Mother


Development of a fetal goiter is a clear
indication of fetal thyroid gland dysfunction. However, slight maternal
overtreatment with ATDs without fetal goiter formation might still put
the fetus at risk of growth restriction and compromised neurological
development. Maternal ATD treatment spans a continuum from a
well-balanced treatment through slight overtreatment to the extreme
cases of gross overtreatment in which fetal goiter formation occurs.
Where on this continuum the risks of severe pregnancy-related
complications and long-term consequences begin is not evident. Pregnant
women should be kept on optimal ATD regimes by careful monitoring;
however, the risk of overtreatment with ATDs during pregnancy exists
even in skilled hands.
The cases presented in this Review
demonstrated no connection between the fetal thyroid status and the
maternal dose of ATD. Doses of propylthiouracil as small as 50 mg daily
caused fetal overtreatment in some patients. Maternal levels of TRAb
also do not seem to be connected to the development of the fetal
goiters. Cases of both negative and positive antibody levels were found;
in the latter, TSIs, TBIIs, or both were detected (this finding has no
implications for maternal TRAb-monitoring with regards to predicting
intrauterine or neonatal thyrotoxicosis according to the current
guidelines[51]).
One must consider that the natural suppression of the immune system
during pregnancy will invariably lead to decreased antibody levels and
improvement, if not remission, of autoimmune disease—thus decreasing the
requirement for ATDs.[45,86-88]
Interestingly, even in the reviewed cases with highly suppressed
maternal TSH concentrations, the fetuses had severe hypothyroidism, and
in fact only a minority of the women had a TSH level >2.5 mU/l. Even
the women with very low TSH concentrations had free T4 concentrations in the low part of the reference range. Maternal free T4 levels were thus the only consistent indicator of maternal and fetal thyroid status (similar results were found by Momotani et al.[89]).
The apparent discrepancy between the levels of free T4 and TSH can be ascribed to the unstable or latent reaction of pituitary TSH to the changes in T4 levels that occur with the changes in thyroid hormone status during pregnancy, and to adjustments of ATD dose.[90,91]
Thus, in pregnant women with hyperthyroidism, overtreatment might be
caused by difficulties in interpreting the levels of free thyroid
hormones. Pregnancy-related hyperestrogenism induces a rise in TBG and
thus in total T levels. As the active component of the circulating
thyroid hormones is the free part, an estimate of the free T4 concentration is essential. Free T4 estimates can generally be derived in three ways: by one of the commercially available free T4 methods used in many clinical biochemical laboratories, or by measurement of total T4 and applying some correction for the binding proteins, such as a T3 or T4 uptake (resulting in a free T4 index), or by direct measurement of TBG (giving a T4:TBG ratio). However, the measurement of free T4
is an estimate and not a quantitatively correct value, and none of the
methods correct sufficiently for the extreme increase in levels of TBG
that occur during pregnancy. However, a correct interpretation is more
likely if a free T4 index (or T4:TBG ratio) is used, rather than the so-called direct methods. Interpreting the latter form of free T4 estimate is extremely difficult during pregnancy and further complicated by methodological differences between laboratories.[90-93]

The use of reference ranges that include
women who are not pregnant is probably a further explanation of maternal
overtreatment. Many authors have stressed this point and advocated the
introduction of local trimester-specific reference ranges according to
the methods used in the local laboratory.[8,9] Vaidya et al.[94]
even showed that using reference ranges that are not specific to the
gestational age would misdiagnose as euthyroid up to 30% of pregnant
women who were in fact hypothyroid. Complicating the use of reference
ranges further, Boas et al.[10]
showed that the intraindividual variation in thyroid hormone levels
throughout pregnancy was considerably smaller than the interindividual
variation.[10]
The authors suggest that a woman's levels of thyroid hormones should be
evaluated in comparison to her own earlier levels instead of a
population-based reference range. Boas et al.[10]
thus proposed a predictive model to calculate the woman's individual
euthyroid status throughout pregnancy. This model would be possible in
women treated for hyperthyroidism or hypothyroidism because of the
regular monitoring of their thyroid status and would ease the
interpretation of the individual thyroid hormone measurements.
In their interpretation of maternal thyroid
function, specialists who monitor pregnant women during ATD treatment
should pay the utmost attention to four factors. First, the latency of
reaction of TSH levels to alterations in free T4 levels. Second, the correct interpretation of free T4 and free T3
estimates during pregnancy according to the applied method for
measurement. Third, trimester-specific reference intervals for all the
measured variables. Finally, the concept of intraindividual versus
interindividual variations of thyroid-related hormones.
The maternal free T4 estimate was
the only reasonably consistent indication of maternal and fetal thyroid
status. To avoid maternal overtreatment with ATDs, close monitoring of
free T4 levels, to keep them within the laboratory's trimester-specific reference range, is crucial (
Box 1
).

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john

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PostSubject: Re: Antithyroid Drug-induced Fetal Goitrous Hypothyroidism   Antithyroid Drug-induced Fetal Goitrous Hypothyroidism Icon_minitimeMon Jun 20, 2011 7:11 am

Importance of Careful Monitoring—The Fetus


To assess the benefit of different treatment
methods, this Review only focuses on cases of fetal goitrous
hypothyroidism discovered by fetal ultrasound examination. However, many
more instances of fetal goitrous hypothyroidism will probably have
occurred where no fetal ultrasound examinations of the thyroid gland
were performed, as illustrated by case reports and reviews of fetal loss
in connection with maternal ATD treatment.[95-97]

Regular ultrasound examinations are of value
in monitoring fetal development during maternal ATD treatment. In a
prospective study, 115 propylthiouracil-treated pregnant women were
monitored throughout pregnancy.[98]
Information on ultrasound examinations of the fetal thyroid gland
existed for 51 fetuses. Five of these children (9.8%) developed a goiter
during gestation—three of them because of fetal hypothyroidism. The
propylthiouracil-exposed fetuses were born significantly earlier (P = 0.018) and with a lower birth weight (P = 0.018) than those in the nonexposed control group (1,141 fetuses). Similar results were found by Cohen et al.,[49]
who monitored 20 pregnant women who received propylthiouracil treatment
with serial ultrasonographic examinations of the fetal thyroid gland.
In five cases (25%) a fetal goiter developed and maternal
propylthiouracil dose was accordingly decreased on the basis of an
assumption of fetal hypothyroidism. The authors stressed that such
findings would not have been expected (and propylthiouracil dose
presumably not have been decreased) on the basis of the maternal thyroid
status alone. Besides fetal goiter, ultrasonographic signs of fetal
thyroid dysfunction include IUGR, hydrops and cardiac failure.[51]

Other methods of monitoring fetal thyroid status have been suggested. Nachum et al.[45]
performed a prospective study of invasive evaluation of fetal thyroid
status by cordocentesis (fetal blood sampling) in fetuses of mothers who
received ATDs. Cordocentesis was recommended in patients with raised
levels of maternal TSIs, fetal tachycardia, goiter, IUGR or fetal
hydrops. However, in the nine women who accepted this offer, only five
fetuses had abnormal thyroid hormone levels; hence, use of such an
invasive method seems unnecessarily risky.
Apart from prenatal ultrasonography,
noninvasive methods of monitoring fetal thyroid status are still to be
developed. Although intriguing, maternal venous blood sampling followed
by measurement of the so-called 'compound W' as an expression of fetal
thyroid status must still be considered as experimental.[99,100]How to React to Overtreatment



Diagnosing Fetal Goitrous Hypothyroidism


Should a fetal goiter be identified at
prenatal ultrasound examination, the distinction between fetal goitrous
hypothyroidism and fetal goitrous hyperthyroidism is extremely important
in determining the subsequent course of action (Figure 1). Failure to
treat either hypothyroidism or hyperthyroidism during pregnancy
endangers the fetus and pregnancy outcome.[59]

Two cases of maternal Graves disease
illustrate a core dilemma when trying to establish the cause of fetal
goitrous hypothyroidism, which could be either maternal ATD
overtreatment or passive transfer of autoantibodies.[26] As mentioned previously, maternal free T4
concentration is a stronger indicator of fetal thyroid status than the
maternal ATD dose. However, in these two cases, the maternal free T4 levels were within the high part of the reference range,[26] but total T4 levels should have been more elevated in a euthyroid pregnant woman. Thus, the free T4 levels could have been incorrectly interpreted depending on the method used for estimating free T4.
However, both TBII and TSI levels were raised. The fetal goiters could,
therefore, have been of either iatrogenic or autoimmune origin, and
given the maternal antibody status, the fetuses could have had either
hypothyroidism or hyperthyroidism.
Although the etiology of a fetal goiter might
never be established, several methods have been suggested to
distinguish between fetal hypothyroidism and hyper-thyroidism.
Ultrasonography remains the gold standard of fetal examination in
pregnancies where the mother receives ATDs.[51] In a study by Cohen et al.,[49]
five cases of fetal goiters were discovered by serial ultrasonographic
evaluations of the fetal thyroid gland. Upon discovery of a goiter,
maternal propylthiouracil dose was decreased in expectance of the goiter
formation being attributable to propylthiouracil overtreatment.
However, two of the five fetal goiters did not decrease in size after
the maternal propylthiouracil dose reduction. On the contrary, the
fetuses were hyperthyroid owing to placental transfer of stimulatory
autoantibodies and were born thyrotoxic. The authors suggested
establishment of fetal thyroid status by fetal blood sampling in
patients where a decrease of propylthiouracil dose was not followed by a
decrease in fetal goiter size. However, as hyperthyroidism during
pregnancy is dangerous, this approach has the danger of delaying
treatment and thus putting the fetus at an unnecessary risk.
In a study by Huel et al.,[101]
39 cases of fetal goiters related to maternal hyperthyroidism were
found between 1993 and 2006. The goiters were discovered by monthly
ultrasound screenings that began at gestational week 22 (several of the
patients included in this study were reported as part of previously
published studies by the same research group[44,46]).
The investigators recorded the fetal heart rate (tachycardia >160
bpm) and examined fetal bone maturation, growth parameters and
vascularization of the fetal thyroid gland. They hypothesized that in
patients with fetal hypothyroidism, a peripheral vascularization
(Doppler signal) would represent an inactive hypertrophic gland, whereas
in patients with fetal hyperthyroidism, a central vascularization of
the gland would represent an overactive thyroid gland.[101]
Peripheral vascularization was found in 22 of 32 hypothyroid fetuses
and in one of five hyperthyroid fetuses. Central vascularization was
seen in none of the hypothyroid fetuses and in three of five
hyperthyroid fetuses. However, these numbers are too small to be
conclusive. In two cases included in group A and group B in this Review,
reported by the same research group in 2005,[46]
the ultrasonographic descriptions stated that the fetal goiters had a
Doppler signal 'throughout the gland'. At the same time, fetal blood
sampling showed fetal TSH concentrations of 483.0 mIU/l and 10.5 mIU/l
at birth. Furthermore, the ultrasound scan of the fetal thyroid gland
showed a "markedly increased vascular flow" in one patient,[33] and a "homogenously echogenic texture and high flow" in another.[38]
Thus, in several cases ultrasound imaging illustrated a high blood flow
in the fetal goiters which, unlike the pattern of blood flow in adult
goiters, was correlated with hypothyroidism. Although an ultrasound
score suggested by Huel et al.[101]
did correctly distinguish all 36 cases of fetal hypothyroidism from
hyperthyroidism, some inconsistency still exists in the ultrasonographic
diagnostics.
Invasive assessment is a certain method of
diagnosing fetal thyroid status; however, this method does involve risks
for the fetus. A meta-analysis of 68,119 midtrimester amniocenteses
showed an excess pregnancy loss of 0.6%.[102]
This risk was decreased by the use of concurrent ultrasonographic
guidance (0.3%). The specificity of cordocentesis is higher than that of
amniocentesis because of difficulties in distinguishing maternal and
fetal thyroid hormones in the latter.[103] However, cordocentesis is a slightly more risky procedure than amniocentesis.[104,105]

Normograms for both the size of the fetal
thyroid gland, and fetal TSH and thyroid hormone concentrations at
various gestational ages, have been developed.[106,107]
The clinician should consider whether or not the risk to the fetus
associated with amniocentesis is in fact greater than the risk of a
wrong diagnosis of either goitrous hypothyroidism or hyperthyroidism (
Box 1
).


Intra-amniotic Levothyroxine Injection


Adjustment of the maternal ATD dose
(reduction or discontinuation) is the primary means to reverse maternal
overtreatment. Supplementing this treatment with fetal intra-amniotic
levothyroxine injection should also be considered.
To our knowledge, the first report of intra-amniotic levothyroxine injection was given by Lightner et al.[108] in 1977. In 1978, Klein et al.[109]
injected levothyroxine into the amniotic cavity of five women 24 h
before they were scheduled for cesarean section at term. Cord-blood
thyroid hormone levels were examined and compared to the levels from
five control individuals. Both serum free T4 and reverse T3
levels were markedly raised (by almost three times) in the experimental
group compared to the control group, showing that the fetus was in fact
able to ingest and metabolize the injected levothyroxine.
The first case of intra-amniotic levothyroxine injection in connection with maternal ATD overtreatment was reported by Weiner et al.[24]
in 1980 and resulted in the birth of a euthyroid child. Since then a
number of intra-amniotic levothyroxine injections have been per-formed.[110,111]
A large meta-analysis has shown that the risk of abortion after
midtrimester amniocentesis is quite small, which suggests that
intra-amniotic levothyroxine injections would also have a low risk of
abortion.[102]
Most cases of intra-amniotic levothyroxine injections have been without
adverse events, however, there has been one reported case of preterm
labor within 24 h of receiving the injection.[37]
Although polyhydramnios did pose a risk of preterm labor in this case,
the coincidence between the invasive procedure and the onset of
premature labor is noteworthy.
In the cases presented in this Review, the
reduction in the size of the fetal goiter was markedly faster in group
A, where maternal ATD dose adjustment was supplemented by intra-amniotic
levothyroxine injections, than in group B. In four of 13 reported cases
of group B, goiter size was unchanged after maternal ATD dose
reduction. By comparison, all goiters of group A assessed by
ultrasonography decreased in size. Furthermore, the fetuses of mothers
who were treated by a reduction in the dose of ATDs alone generally
recovered more slowly (or not at all) from their hypothyroid state
compared to those who received the intra-amniotic levothyroxine
injections.
Although no neurological sequelae were
reported, it cannot be concluded that these events were not seen. There
were only a few reports of neurological follow-up and most of these were
focused on early infancy. An increasing amount of research has
heightened awareness among endocrinologists of the possible damage
maternal thyroid dysfunction can do to fetal neurological development.[1-3,16,112-115]
In cases of ATD overtreatment, both the mother and the fetus are
hypothyroid, thus decreasing both the beneficial placental transfer of
maternal T4 and a sustainable fetal thyroid hormone
production. How detrimental this situation might be to fetal
neurological development is not within the scope of this Review, but
would be important to assess in the future. However, it is unlikely that
evidence of the additional benefits of intra-amniotic levothyroxine
injections compared to noninvasive treatment alone will ever be achieved
given the fortunate rarity of ATD-induced fetal goiters. However, the
successful reports included in this Review and the increasing awareness
of the neurological consequences of fetal hypothyroidism and risks at
birth, speak in favor of minimizing the time of fetal hypothyroidism.
The wide variety of approaches to treatment in the reviewed cases
illustrates the lack of guidelines in this area. In patients with
verified fetal goitrous hypothyroidism, especially if complicated by
polyhydramnios, we believe that intra-amniotic levothyroxine injections
performed by experienced obstetricians will benefit the pregnancy
outcome.
Antithyroid Drug-induced Fetal Goitrous Hypothyroidism 2011_m10Conclusions




In many of the published cases of ATD-induced
fetal goiter, essential information on concomitant maternal and fetal
thyroid function was missing. The most important method to avoid fetal
goiter attributable to overtreatment of maternal Graves disease with
ATDs is close monitoring of the thyroid status of the mother. This
monitoring should be done in a specialized clinic with experts who are
able to interpret all the pitfalls in relation to the
pregnancy-associated physiological and pathophysiological changes to
maternal thyroid function. We emphasize the importance of frequent
measurements of maternal peripheral thyroid hormone levels (especially
free T4 estimates against TSH measurements), adjustment of
maternal ATD dose accordingly, as well as ultrasonographic monitoring of
fetal thyroid size and development. If a fetal goiter develops,
diagnosing fetal hypothyroidism or hyperthyroidism is essential. When
fetal hypothyroidism is diagnosed, maternal ATD treatment should be
reduced or discontinued to obtain maternal free T4 within the
trimester-specific reference range, preferably in accordance with the
intraindividual variation as well. Supplementing this strategy with
intra-amniotic levothyroxine injections can improve fetal outcome if
done by experienced obstetricians. A close collaboration between
endocrinologists, obstetricians and experts in fetal medicine is
critical to ensure a normal fetal thyroid function and an optimal
pregnancy outcome.
Antithyroid Drug-induced Fetal Goitrous Hypothyroidism 2011_m10



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