Fetal drug therapy

5.1

Introduction

The intention of most drugs prescribed during pregnancy is to treat a condition affecting maternal health. Careful attention is placed on the appropriate selection of the medication and its dose that would reduce transplacental drug transport and minimize consequences of fetal drug exposure. However, this chapter will focus on the administration of drugs intended to treat medical conditions afflicting the fetus, rather than the mother. In order to achieve therapeutic drug concentrations in the fetus, efforts are made to circumvent the placenta's function as a barrier. In this case, it is imperative to reduce maternal exposure to a medication that she does not need and consequently might adversely affect her well-being.

The first section of this chapter will discuss a number of medical indications for which fetal drug therapy might be warranted. As the focus is on pharmacological therapy, the reader is referred to other sources for details regarding fetal medical interventions such as prenatal repair of myelomeningocele [ ], blood transfusions to treat fetal anemia [ ], and others [ ].

The second part of this chapter will describe strategies for fetal drug delivery, including transplacental transfer following maternal administration, direct fetal injection, gene therapy, stem cell transplantation, and nanomedicine. This chapter will conclude with a brief discussion of the ethics associated with this challenging subject (see also Chapter 8 which discusses the ethics of clinical pharmacology in pregnancy).

5.2

Indications for fetal therapy

Table 5.1 lists some common indications for fetal therapy and details regarding these conditions are provided below (see also Table 5.2 ). Nevertheless, as this table is not comprehensive, this section will identify a number of additional settings where fetal drug therapy may be beneficial.

Among the most common pharmacological interventions for fetal therapy is the administration of antenatal corticosteroids in anticipation of preterm delivery to promote fetal lung maturation . Dexamethasone and betamethasone are the most common drugs prescribed for this purpose and have demonstrated clinically significant reductions in respiratory distress syndrome, neonatal mortality, cerebroventricular hemorrhage, necrotizing enterocolitis, intensive care admission, and systemic infections in the first 48 h of life [ , ].

Magnesium sulfate is commonly used in obstetric practice for seizure prophylaxis in preeclampsia, but growing evidence supports its role of neuroprotection in low birth weight children [ ]. Randomized placebo-controlled trials of antenatal administration of magnesium sulfate have consistently demonstrated a decreased risk of cerebral palsy and severe motor dysfunction in preterm infants [ ]. Long-term cognitive, behavioral, growth, and functional advantages were not observed at school age [ ].

Fetal cardiac arrhythmias affect at least 2% of low-risk pregnancies and as much as 16.6% of high-risk pregnancies [ , ]. Although intermittent extrasystoles can be common and may not require treatment, sustained fetal arrhythmias demand vigorous attention because this can lead to hydrops within 48 h, a condition with poor prognosis [ ]. Hydrops can impair transplacental transport, thereby necessitating fetal injection of a medication [ ]. The most common fetal arrhythmias are supraventricular tachycardia, atrial flutter, and severe bradyarrhythmia associated with complete heart block [ ]. Drugs used to treat fetal tachycardia include digoxin, flecainide, sotalol, procainamide, propranolol, amiodarone, and adenosine; questions remain regarding the use of steroids and sympathomimetics for bradycardia caused by heart block [ ]. Attentive monitoring of response to most antiarrhythmic drugs is needed due to narrow therapeutic margins, and certain drug–drug interactions, as in the case of verapamil and digoxin, could lead to significant maternal toxicity and even fetal death [ , ]. Maternal side effects to fetal antiarrhythmic therapy include palpitations, second-degree atrioventricular block, Wenckebach phenomenon, and hypotension [ ].

Congenital adrenal hyperplasia is most often due to a 21-hydroxylase deficiency (CYP21A2) [ ]. Decreased cortisol production results in excess androgen synthesis, which causes virilization of female genitalia. In the future, genetic testing could play a stronger role in the prenatal counseling of this condition, as the extent of virilization may be linked to fetal genotype [ ]. In utero treatment with dexamethasone reduces the abnormal levels of androgens, and this therapy prevents the devastating consequences of wrong sex assignment in affected females. Differentiation of external genitalia occurs between 7 and 12 weeks of gestation, so therapy in at-risk pregnancies must begin earlier, preferably by the fifth week [ ]. Cell-free DNA testing can provide noninvasive determination of fetal sex at as early as 5 weeks of gestation, thereby enabling rapid discontinuation of dexamethasone for male fetuses [ , ]. Chorionic villus sampling (CVS) can be performed at 10–12 weeks, at which point therapy can be halted for unaffected females [ ]. Dexamethasone treatment (three times daily) will continue throughout pregnancy for an affected female fetus. Maternal side effects of fetal dexamethasone therapy include edema, striae, excess weight gain, Cushingoid facial features, facial hair, glucose intolerance, hypertension, gastrointestinal problems, and emotional irritability [ , , ].

Congenital hypothyroidism , which affects approximately 1 out of every 4500 pregnancies, is usually a secondary condition caused by treatment of maternal hyperthyroidism, such as Graves' disease [ ]. Fetal goiter can interfere with fetal swallowing and lead to polyhydramnios and premature rupture of membranes. Furthermore, fetal goiter can cause tracheal compression and asphyxia at birth [ , ]. Fetal hypothyroidism can be successfully treated with levothyroxine. Levothyroxine is administered via intraamniotic injection due to its low transplacental transfer [ , ].

Fetal hematological disorders that can be treated include alloimmune thrombocytopenia and erythrocyte alloimmunization. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) has an incidence rate of 1 in 1500 and is caused by a maternal antibody-mediated response against a fetal platelet–specific antigen; this may lead to in utero intracranial hemorrhage [ ]. Women at risk for a pregnancy with FNAIT are usually only identified after having a previous child with the disorder, but maternal administration of intravenous gamma globulin can successfully increase fetal platelet counts [ , ]. Erythrocyte alloimmunization —the reaction of maternal antibodies with fetal erythrocyte antigens—can lead to hemolysis, fetal anemia, and hydrops fetalis [ ]. Antepartum anti-D immunoglobulin given to Rh-negative women carrying an Rh-positive fetus reduced the incidence of Rh immunization during pregnancy from 1.8 to 0.14% [ ]. Intravenous immunoglobulin treatment in pregnant women with a fetus at risk for hemolytic disease may lower the demand for intrauterine transfusions [ ]. It should be noted that there are other types of red-cell alloimmunization besides anti-RhD without prophylactic immune globulins yet available [ ].

In addition to the aforementioned indications, there are a number of fetal conditions for which experimental therapeutics are in various stages of testing. Polyhydramnios (excess amniotic fluid) affects approximately 1% of pregnancies, of which 55% are idiopathic and 25% are related to fetal diabetes [ , ]. Amnioreduction and betamethasone are used in the management of severe polyhydramnios [ ]. Although indomethacin likely decreases fetal urine production in mothers with severe refractory symptoms, it is not recommended for reducing amniotic fluid because of its associated neonatal risks [ , ]. Randomized controlled trials are essential to evaluate the safety and efficacy of novel treatments. For example, preliminary studies had suggested some advantages of sildenafil as an option for intrauterine growth restriction [ ], but larger trials failed to show improved outcomes and the studies were terminated early due to increased mortality in the treatment arm [ ]. On the other hand, it is clear that smoking cessation lowers rates of low birth weight and preterm birth [ ]. Injection of picibanil into the pleural cavity for pleurodesis appears promising for the treatment of early second trimester, nonhydropic fetal chylothorax [ , ]. Digoxin and furosemide have been injected into fetal intravascular space to treat idiopathic nonimmune hydrops fetalis [ ], and infection-induced nonimmune hydrops fetalis has been treated with transplacental antiviral or antibiotic therapy [ ]. Fetal malignancies are rarely diagnosed in utero [ ], but this may represent a future area of potential fetal chemotherapy. There are also several examples of maternal prescriptions with direct or indirect fetal benefit, including tocolytics preventing preterm birth, penicillin to treat syphilis [ ], spiramycin for toxoplasmosis [ ], antibiotics before delivery to reduce neonatal sepsis [ ], and the reduction of maternal–fetal HIV transmission rates by the use of highly active antiretroviral therapy [ ].

5.3

Strategies to achieve fetal drug therapy