19 Janet Brennand The Ian Donald Fetal Medicine Unit, Queen Elizabeth University Hospital, Glasgow, UK The advent of fetal blood sampling has allowed direct and accurate quantification of fetal thyroid function. Fetal thyroid hormone synthesis commences at 10–12 weeks’ gestation. Prior to this the fetus relies on placental transfer of maternal thyroid hormones. Fetal serum thyroid‐stimulating hormone (TSH), thyroxine‐binding globulin (TBG), free and total thyroxine (T4) and triiodothyronine (T3) increase with advancing gestation, from 14–16 weeks onwards [1,2]. The concentrations of total and free T4 (FT4) reach adult levels by 36 weeks’ gestation. In contrast, T3 concentrations are lower than adult levels throughout pregnancy. There is no relationship between maternal and fetal thyroid hormone levels, confirming that development of the fetal pituitary–thyroid axis is independent of the mother. Fetal TSH concentrations are low until 15–18 weeks’ gestation, and the lack of correlation between it and thyroid hormone concentrations indicates that thyroid maturation is independent of TSH. Fetal TSH receptors become responsive to TSH at 20 weeks’ gestation. Thyroid hormones promote normal growth, development and neurological function. Disruption of normal thyroid function, if unrecognized and untreated, can therefore have significant long‐term sequelae. Thyroid dysfunction in the fetus can result from a primary problem affecting the fetus. More commonly it occurs secondary to maternal thyroid disease and/or its treatment. The presence of fetal goitre indicates thyroid dysfunction, provided other differential diagnoses of a fetal neck mass, such as cystic hygroma, cervical teratoma and haemangioma, have been excluded. The goitre may represent fetal hyperthyroidism or hypothyroidism. The serious adverse consequences of fetal hyperthyroidism are miscarriage and intrauterine death, and of hypothyroidism neonatal cretinism. Fetal hyperthyroidism is most likely to occur secondary to maternal Graves’ disease as a result of placental transfer of autoantibodies. TSH receptor‐stimulating antibodies (TRAbs) are of the IgG class and therefore readily able to cross the placenta and stimulate the fetal thyroid gland. TRAbs can stimulate the fetal thyroid from 20 weeks’ gestation. TRAbs are increased in at least 80% of women with Graves’ disease. It has been estimated that neonatal thyrotoxicosis occurs in 2–10% of babies born to women with Graves’ disease [3]. The risk of fetal hyperthyroidism is related to TRAb concentrations. The placenta is more permeable to IgG in the second half of pregnancy and fetal concentrations of TRAbs reach maternal levels at around 30 weeks’ gestation. As a result, fetal hyperthyroidism usually develops in the second half of pregnancy A pregnant woman with Graves’ disease can be categorized as follows [3]. Fetal tachycardia (>160 bpm) is the most common feature of fetal hyperthyroidism, although it is not always present. Other findings include intrauterine growth restriction (IUGR), accelerated bone maturation, cardiomegaly, cardiac failure and hydrops. A large fetal goitre can cause hyperextension of the fetal neck resulting in malpresentation. Oesophageal compression may result in polyhydramnios with its associated risk of preterm labour. Ultrasound can detect fetal goitre, which is the earliest ultrasound feature of fetal thyroid dysfunction and appears before fetal tachycardia. Fetal goitre is defined as a thyroid circumference equal to or greater than the 95th centile for gestational age and normative fetal thyroid measurements have been defined [4]. Colour flow Doppler may help differentiate between a hyperthyroid and a hypothyroid goitre. Hyperthyroidism is associated with a signal throughout the gland, whereas a signal confined to the periphery of the gland is suggestive of hypothyroidism [5,6]. In at‐risk pregnancies monthly ultrasound should be carried out from around 20 weeks’ gestation to assess thyroid size. Cordocentesis is the only direct method of assessing fetal thyroid function. This is an invasive procedure, with a risk of miscarriage, and should be reserved for cases in which it is impossible to distinguish fetal hyperthyroidism from fetal hypothyroidism on clinical grounds, or for cases where the response to fetal therapy is not as anticipated (i.e. deterioration despite treatment). Treatment by maternal administration of antithyroid drugs is both safe and effective in the management of fetal hyperthyroidism. Propylthiouracil is the drug of choice because of the reduced risk of side effects. If the mother is euthyroid she may require thyroxine supplementation. This may also be necessary for women already on antithyroid medication who need to increase the dose. Worldwide, iodine deficiency is the leading cause of fetal hypothyroidism. Other causes include thyroid dysgenesis, thyroid dyshormonogenesis, TSH receptor mutations and TSH receptor blocking IgG, antithyroid drugs and radioactive iodine after 10–12 weeks’ gestation [7]. Maternal thyroid disease associated with thyroid autoantibodies can cause fetal hypothyroidism. Anti‐thyroperoxidase antibodies cross the placenta in the third trimester but have little effect on fetal thyroid function. However, although generally stimulatory TRAbs can be inhibitory, resulting in fetal hypothyroidism. Ultrasound features include IUGR, goitre and decreased fetal movements. There may be tachycardia or bradycardia and in severe cases complete heart block. Cardiomegaly and delayed skeletal maturation may occur. Fetal hypothyroidism is often unrecognized and should be considered in all women with a history of thyroid disease and/or antithyroid medication. If fetal hypothyroidism is secondary to maternal antithyroid therapy, the dose of the drug should be reduced with the aim of keeping maternal FT4 levels at the upper end of the normal range for gestational age. Ultrasound of the fetal thyroid should be carried out at no greater than fortnightly intervals to ensure reduction in size, which is usually noted within 2 weeks of reducing therapy [8]. Transplacental transfer of T4 is inadequate to treat fetal hypothyroid goitre. The intra‐amniotic route is used and 250–500 µg of T4 at 7–10 day intervals is a proposed regimen [9]. The success of treatment can be monitored by ultrasound assessment. If the fetal condition deteriorates despite treatment, cordocentesis is needed to measure fetal TSH and FT4 levels. Congenital adrenal hyperplasia (CAH) occurs when abnormal adrenal steroidogenesis results in androgen excess. Five enzymes are responsible for the conversion of cholesterol to cortisol, and a defect in any one of these will cause precursors to be diverted to the production of androgens. CAH is an autosomal recessive condition and in 90–95% of cases is due to a deficiency of 21‐hydroxylase. Androgen excess in utero leads to virilization of a female fetus and in the severe form is associated with salt loss secondary to aldosterone deficiency. Androgen excess does not affect development of fetal male genitalia. Virilized females may be assigned the wrong gender at birth and are likely to require corrective genital surgery. The aim of therapy is to prevent virilization of a female fetus. The fetal adrenal gland can be suppressed by maternal administration of dexamethasone. A minimum dose of 20 µg per kilogram pre‐pregnancy weight in two divided doses is the recommended regimen and therapy must be commenced at 6–7 weeks’ gestation when the external genitalia begin to differentiate [10]. This regimen means that seven of eight pregnancies are exposed to unnecessary steroid therapy early in the first trimester. Non‐invasive analysis of cell‐free fetal DNA from maternal blood can identify the Y chromosome from 7 weeks’ gestation and therapy could be discontinued in the pregnancies with a male fetus without waiting for CVS results. If the fetus is female, treatment will have to continue until genetic results from CVS are available, still exposing three of eight fetuses to potentially unnecessary treatment. Future detection of the genetic defect by non‐invasive means will be the only way to eliminate this blind approach to early therapy. There are no reported teratogenic effects of antenatal dexamethasone treatment. Information regarding longer‐term effects is limited and parents must be made aware of this when discussing the pros and cons of therapy. These comprise irregular fetal heart rhythm, fetal tachycardias and fetal bradycardias. Rhythm disturbances are encountered in approximately 2% of pregnancies during routine ultrasound. M‐mode and pulsed‐wave Doppler echocardiography are the main diagnostic techniques. The common dysrhythmias are discussed here. The reader is referred to other literature for a more comprehensive discussion of all dysrhythmias and their diagnosis [11–13]. This is typically described as a ‘missed beat’ and is usually due to atrial extrasystoles. These extrasystoles are more common in the third trimester and are detected in 1.7% of fetuses after 36 weeks’ gestation. Ventricular extrasytoles are much rarer. The extrasystoles are benign and usually resolve prior to delivery. Occasionally (2–3% of cases) a sustained tachycardia develops and it is wise to auscultate the heart regularly to ensure this does not occur. A fetal tachycardia is defined as a sustained heart rate above 180 bpm. Fetal tachycardia occurs in 0.5% of pregnancies and is therefore relatively common. Supraventricular tachycardia (SVT) is the most common type (66–90% of cases), followed by atrial flutter (10–30%). Atrial fibrillation and chaotic atrial tachycardia are much less common and ventricular tachycardia is extremely rare during fetal life. The most common type of SVT is a re‐entry phenomenon where an accessory conducting pathway allows rapid retrograde passage of the electrical impulse from ventricle to atrium, establishing a re‐entry circuit. This is defined as atrioventricular (AV) re‐entrant tachycardia. In this type of SVT the time interval between ventricular and atrial contraction (VA interval) is short. In SVT caused by atrial ectopic tachycardia or permanent junctional reciprocating tachycardia, the VA interval is long. Establishing the length of the VA interval is important when deciding on therapy. In SVT the fetal heart rate is often in the region of 240 bpm with reduced variability. The ratio of atrial to ventricular contractions (AV ratio) is 1 : 1. The atrial rate is very fast at 350–500 bpm. At such a fast rate 1 : 1 AV conduction is not possible. More commonly there is a degree of AV block, usually 2 : 1, but it can be greater. The fetus with a sustained tachycardia is at risk of developing cardiac failure, hydrops and ultimately death. Conservative management is an option provided the fetus is monitored closely to detect early signs of cardiac failure. Delivery, followed by postnatal therapy, is an option if close to term, but it is recognized that pharmacological control of the heart rate in the neonatal period is not always straightforward. In utero therapy is effective in restoring sinus rhythm and is the preferred option for treating preterm infants, reserving delivery for those cases that fail to respond to indirect or direct fetal therapy. The transplacental route is the route of choice for fetal therapy. A number of drugs can be used in the management of fetal tachyardia. Digoxin, flecainide and sotalol are considered first‐line treatments for SVT and atrial flutter (AF). Digoxin and flecainide are the best agents for treating SVT, and sotalol is best for AF. Better control is seen for SVT than AF. The presence of fetal hydrops or incessant SVT/AF are independently associated with slower rates of cardioversion. Digoxin can be given as a loading dose, 0.5–1 mg i.v., followed by maintenance therapy, 0.25–0.5 mg t.d.s. Maternal administration is ineffective if fetal hydrops is present. Flecainide is a proarrhythmic drug, given at a dose of 100 mg t.d.s. An effect is generally seen within 72 hours. Sotalol, also proarrhythmic, is given at a dose of 80–160 mg b.d. Owing to their good placental transfer, sotalol and flecainide are the drugs of choice if fetal hydrops is present. Maternal administration of drugs should take place in a hospital setting because of potential proarrhythmic effects (flecainide, sotalol, amiodarone). Baseline ECG and urea and electrolytes should be performed prior to starting medication; these tests should be repeated after starting therapy or increasing drug dosage, looking for prolongation of the QT interval on ECG. Serum drug levels should be monitored if facilities permit. If there is no response to maternal drug administration or there is severe hydrops, direct fetal therapy is required. This can be intravascularly via cordocentesis, intraperitoneally or intramuscularly. The risks associated with cordocentesis are greater in the presence of hydrops. Digoxin and amiodarone are the preferred drugs for direct fetal therapy. In the absence of hydrops, success rates of transplacental therapy can be up to 100%. Fetal mortality is 17% if hydrops is present. This is defined as a fetal heart rate persistently below 100 bpm. In AV block there is disturbance of electrical conduction between the atria and ventricles. Three types are described. In first‐degree block there is a prolonged AV interval and this cannot be detected on routine ultrasound. Second‐degree block is of two types. In type I there is progressive lengthening of AV conduction time until an impulse is blocked; this results in an irregular rhythm but the fetal heart rate may be normal. In type II second‐degree block there is conduction of some beats and not others, without lengthening of the AV conduction time. On M‐mode the atrial rate may be twice that of the ventricular rate (2 : 1 block) and occasionally 3 : 1 block is seen. In complete AV block (CAVB) there is complete dissociation of atrial and ventricular contractions. This rare condition (1 in 15 000–22 000 live births) has two important causes: congenital heart disease (CHD) and immune‐mediated disease. CHD accounts for 50% of cases of CAVB, the most common defects being left atrial isomerism and congenitally corrected transposition of the great vessels. Immune‐mediated disease has been the subject of fetal therapy. Transplacental transfer of maternal anti‐Ro and anti‐La antibodies results in inflammation and damage to the fetal myocardium and conduction tissue. These antibodies may be present in women with a history of Sjögren’s syndrome or systemic lupus erythematosus. The risk of CAVB in a woman with antibodies is approximately 2%, with a recurrence risk of 16%. The risk to the fetus is maximal between 16 and 26 weeks’ gestation. Poor prognostic features for CAVB include hydrops, heart rate below 55 bpm and premature delivery. The mortality ranges from 18 to 43%. There are no treatment options that are clearly effective. Steroids, either dexamethasone or betamethasone, have been administered with variable results. The same is true for beta‐sympathomimetics, which are given with the aim of increasing the fetal heart rate. The current lack of evidence confirming efficacy of therapy, and the potential maternal and fetal side effects of medication, must be borne in mind in the evaluation of whether or not to treat.
Fetal Medical Conditions
Fetal thyroid function
Fetal hyperthyroidism
Pregnancies at risk
Features
Management
Treatment
Fetal hypothyroidism
Features
Management
Congenital adrenal hyperplasia
Approach to management
Fetal dysrhythmias
Irregular fetal heart rate
Tachycardia
Supraventricular tachycardia
Atrial flutter
Management options
Bradycardia
Atrioventricular block
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