Transplacental therapy

Transplacental therapy is a non-invasive method of treating a fetal condition via maternal administration of a drug. The ideal transplacental agent is one which crosses the placenta unaltered to reach the fetus, deliver an appropriate dose of the drug to treat the underlying condition, with limited adverse effects on the mother.

Fetal arrhythmias

Fetal arrhythmias affect approximately 2% of pregnancies and ac­count for 10-20% of referrals to fetal cardiologists (3). Rhythm dis­turbances may be classified as irregular, tachy-, or bradyarrhythmia. The most prevalent fetal dysrhythmias are atrial extrasystoles. These are often found incidentally during routine fetal heart auscultation in the third trimester and tend to resolve spontaneously without intervention. Life-threatening rhythm disturbances in the fetus are rare; however, they are potentially treatable. In order to commence appropriate prenatal therapy, accurate diagnosis is essential. Clinical assessment involves fetal echocardiography to examine the fetal heart for any structural or functional defects. Conservative manage­ment is indicated in fetuses with intermittent arrhythmias who are haemo dynamically stable. The decision between fetal therapy and birth will largely be based on gestational age (as a proxy for fetal lung maturity) and fetal well-being, including the presence of hydrops fetalis, as the latter are less likely to respond to transplacental antiarrhythmic therapy.

Tachyarrhythmias

Sustained fetal tachycardia at greater than 180 beats per mi­nute (bpm) should prompt urgent referral. Structural congenital heart disease is reported in up to 5% of cases, including Ebstein's anomaly, coarctation of the aorta, and cardiac tumours (4). The most common fetal tachyarrhythmias are supraventricular tachy­cardia (SVT) and atrial flutter. Approximately 90% of fetal SVT is associated with an atrioventricular re-entry tachycardia caused by an accessory pathway between the atrium and ventricle. There is typ­ically a 1:1 ratio of atrial to ventricular contractions and a fetal heart rate of approximately 220-240 bpm. Presently there is no consensus on first-line therapy for fetal SVT. In the absence of fetal hydrops,

Table 19.1 Common antiarrhythmic agents used in the management of fetal arrhythmias

AF₁ atrial fibrillation; AV, atrioventricular; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

sotalol, flecainide, and digoxin are the most commonly used drugs. Transplacental transfer of digoxin is significantly impaired in the presence of hydrops fetalis, where flecainide may be more effective than sotalol (5).

Atrial flutter is sustained by a re-entrant pathway in the atrial wall resulting in atrial heart rates between 300 and 500 bpm. There is typically a 2:1 ratio of atrial to ventricular contractions resulting in a ventricular rate of 150-250 bpm. Atrial flutter accounts for 30% of cases of fetal tachycardia and tends to present at later gestations than fetal SVT (5). Digoxin and sotalol are typically the antiarrhythmics of choice with sotalol being the preferred agent in the presence of fetal hydrops. Once converted, maintenance therapy should be continued until after delivery. Postnatally, these neonates require careful monitoring as a significant proportion can relapse. Electro- and echocardiograms should be performed. Refractory or relapsing conditions may require interventions such as cardioversion, pacing, or alternative antiarrhythmic agents.

Bradyarrhythmias

A bradyarrhythmia is defined as a sustained fetal heart rate less than 100 bpm. This may be secondary to sinus bradycardia, blocked atrial ectopic beats, or complete heart block (CHB). CHB is caused by complete dissociation between atrial and ventricular contractions. The atrial rate is regular and normal; however, the ventricular rate is typically between 40 and 90 bpm. In 50% of cases there is asso­ciated complex congenital heart disease including left atrial isom­erism and congenitally corrected transposition. This association with congenital heart disease carries a significant risk of mortality when hydrops fetalis is present. The predominant aetiology in fe­tuses with structurally normal hearts is the transplacental passage of maternal antibodies (anti-Ro and anti-La) after 16 weeks' gesta­tion, resulting in damage to fetal cardiomyocytes and conduction tissue.

Congenital adrenal hyperplasia

CAH describes a group of inherited disorders in which enzyme de­ficiencies result in impaired cortisol biosynthesis. The incidence in Great Britain is approximately 1 in 18,000 live births (8). More than 90% of cases of CAH are caused by a deficiency of 21-hydroxylase resulting in an overproduction of adrenal androgens as well as im­paired cortisol production. Exposure to excess androgens in utero results in the virilization of the external genitalia of affected female fetuses, a hallmark of this condition. Phenotype can vary depending on the severity of enzyme deficiency. Postnatally these infants often require genitoplasty and have long-term physical and psychological complications. Since 1984, prenatal dexamethasone has been pro­posed as a therapy to prevent virilization of the external genitalia of affected female fetuses following a case series published by David and Forest (9). Dexamethasone is thought to cross the placenta unaltered and suppress the fetal hypothalamic-pituitary axis, re­sulting in decreased androgen production; however, its exact mode of action is debated.

Fetal alloimmune thrombocytopenia

FMAIT results from the production of maternal alloantibodies dir­ected against paternally inherited human platelet antigens (HPAs) located on fetal platelet membrane glycoproteins. It is the leading cause of severe thrombocytopenia in the newborn, affecting ap­proximately 1 in 1500 pregnancies (11). Approximately 85% of cases in Caucasians are caused by antibodies to HPA-1a (12). Immunoglobulin G antibodies cross the placenta and bind to fetal platelets. The antibody-coated platelets are removed from the fetal circulation via the reticuloendothelial system resulting in fetal thrombocytopenia. Despite a similar pathophysiology to haemolytic disease of the fetus and newborn, approximately 50% of cases occur in the first pregnancy. Clinical manifestations of this condition can vary in severity, the most severe complication, intracranial haemor­rhage (ICH), arises in 7-26% of untreated cases (13). ICH is associ­ated with a perinatal mortality rate of 1-7% and severe neurological sequelae such as cerebral palsy, cortical blindness, and seizures have been described in 16-26% of those who survive (13).

Presently there is no universal antenatal screening for FMAIT, and it is typically diagnosed on clinical manifestations of fetal haem­orrhage. Laboratory diagnosis can be used to confirm the presence of platelet antibodies in the maternal circulation and to perform HPA genotyping. As with haemolytic disease, the familial recur­rence rate is dependent on the paternal genotype. Families with homozygous dominant fathers have almost 100% recurrence rate. Given that the severity of clinical manifestations may increase with subsequent pregnancies, it is imperative to perform these investi­gations for accurate prenatal counselling. In heterozygous affected pregnancies, non- invasive fetal genotyping from maternal blood can now be performed to help guide management. The antenatal man­agement of this condition remains contentious, as its evolution over the last 25 years has been largely based on case series. The main aim of treatment is to prevent fetal thrombocytopenia with the use of IVIG therapy, immunosuppression with corticosteroids, or serial intrauterine platelet transfusions.

IVIG has previously been used to treat autoimmune condi­tions such as idiopathic thrombocytopenic purpura, but its exact mechanism of action remains unclear. Due to a lack of prospective randomized controlled trials, there is conflicting evidence in the lit­erature with regard to its efficacy in the prevention of ICH. Most centres typically give 0.5-1 g/kg intravenously to the mother on a weekly basis from 16 weeks' gestation. IVIG therapy is expensive and can be associated with side effects such as renal dysfunction, transmission of blood-borne diseases, febrile reactions, and severe headaches. As a result of the cost and associated adversities, some centres stratify IVIG treatment regimens according to the presence or absence of ICH in the previously affected child. Corticosteroids can be administered alongside IVIG therapy, with prednisolone being the corticosteroid of choice. In 2011, a Cochrane review of the antenatal interventions for FMAIT found that IVIG in combination with prednisolone was more effective than IVIG alone at raising the fetal platelet count in high-risk pregnancies (14). Serial intrauterine platelet transfusions have previously been used in the prenatal man­agement of FMAIT. They are associated with a significant risk of fetal loss and for this reason remain second-line therapy for the pre­vention of ICH associated with this condition.