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= Drug Delivery through Placental Membrane for Management of Fetal Supraventricular Tachycardia =

Fetal Supraventricular Tachycardia Introduction
Drug Delivery through the placental membrane for the management of fetal supraventricular tachycardia is accomplished through the complete and simple diffusion of maternally administered therapeutic drugs. Transplacental drug delivery is the most common approach to gaining sinus rhythm. Supraventricular Tachycardia (SVT) is an abnormally fast heart rate that exceeds 200 bpm, it accounts for 60-80% of fetal tachyarrhythmias. A fetus’ heart develops after 3 weeks (first trimester) and the conduction system develops after 16 weeks (second trimester).

Physiology of Supraventricular Tachycardia
A typical sinus rhythm heartbeat is 60-100 beats per minute. The sinoatrial (SA) node, located in the right atrium, is the heart's natural pacemaker and controls the heart's rhythm. Electrical signals are sent from the SA node and cascade out to the left atrium. The electrical signal slows at the atrioventricular (AV) node which allows blood the fill the ventricles. The electrical signals begin each heartbeat as the atrium contract to pump blood into the ventricles. As the electrical signal cascades to the ventricles, the ventricles contract and pump blood to the rest of the body.

In the instance of irregular electrical impulses, ectopic beats fire off in the atria. SVT results from this abnormality in the electrical system of the heart. Ectopic beats are also known as premature atrial contractions (PACs) and send extra heartbeats through the atria. The heartbeat rapidly beats and does not have sufficient time for the ventricles to fill with blood before each contraction.

There are three main types of supraventricular tachycardias: Atrioventricular nodal reentrant tachycardia (AVNRT), Atrioventricular reentrant tachycardia (AVRT), and Atrial tachycardia.

Importance of Treatment
In the case of SVT in the first trimester, digoxin has been administered and successfully crossed the placental membrane. However, in the second and third trimesters, there is increased blood flow between the mother and fetus due to a higher placental surface area and decreased membrane thickness. This increased blood flow allows for an increase in placental drug transfer and fewer limitations in the treatment of fetal SVT. Fetal tachycardia can have many causes including infection, hypoxemia (low oxygen levels), hyperthyroidism (sharp increase in thyroid hormone), as well as excessive caffeine, alcohol, or drug consumption of the mother, which can be transferred transplacentally to the fetus.

The diagnosis and drug delivery methods for the management of SVT are important for the health of the fetus and mother. Delivering therapeutics across the placental membrane in cases of fetal SVT is useful for the conversion of SVT to sinus rhythm as fast and safely as possible. If the SVT is not managed in time, the fetal tachyarrhythmias can result in fetal heart failure, non-immune hydrops fetalis, Ballantyne syndrome, and perinatal mortality. Diagnosis of fetal SVT can be obtained through echocardiography.

Management of Fetal Supraventricular Tachycardia
The decision of treatment for fetal SVT is at the doctor's discretion and will account for the maternal and fetal risks and benefits. Gestational age, presence of hydrops, type of arrhythmia, and risk of prematurity are all taken into consideration. The first line of treatment for fetal SVT is through the transplacental transfer of antiarrhythmic agents administered to the mother. The first antiarrhythmic drug of choice is Digoxin. Digoxin can increase myocardial contractility by concentrating on the heart's electrical activity, which controls contractility.

When administered, digoxin rapidly crosses the placenta and binds to the sodium/potassium ATPase found in the cardiac myocyte plasma membrane. It binds to inhibit this sodium-potassium pump, which increases the intracellular sodium and calcium content. An increase in sodium and calcium contact will increase cardiac contractility. With an increase in contractility, the ventricles can more successfully empty blood and slow the ventricular rate to a normal sinus rhythm. Amiodarone, sotalol, and flecainide are a second line of treatment if digoxin administration is insufficient.

Placental Structure
The placenta is a round-oval shape that acts as a physical connection between the mother and fetus. The placental structure is complicated, the chorionic villi are the main unit of the placenta. The chorionic villi are vascular projections of fetal tissue as blood vessels, also called villi. The villi enable the delivery of nutrients and drugs from the maternal blood to the fetus. The villi are surrounded by chorion. Oxygen and carbon dioxide transport are facilitated by the chorion between the mother and the fetus. The two cellular layers that comprise the chorion are the outer syncytiotrophoblast and the inner cytotrophoblast.

The cytotrophoblasts form outgrowths and expand into the syncytiotrophoblast to form primary or anchoring chorionic villi. The primary villi expand like a tree into a large space called the intervillous space. The intervillous space is where maternal blood flows, containing the nutrients and other substances that are transferred to the fetus. In addition to the intervillous space aiding a delivery, the umbilical vein and arteries carry the substance to the fetus. This intricate network of connections is the driving force of delivery to the fetus.

Substances, whether that be nutrients or drugs, are transported through the intervillous space to the syncytiotrophoblast in the maternal blood, to the chorionic villi in the fetal connective tissue, and through the umbilical network into the fetal bloodstream.

Transplacental Drug Delivery Mechanisms
Transplacental nutrient and drug delivery is facilitated by passive diffusion, facilitated diffusion, active transport, and pinocytosis. Placental drug delivery is facilitated by passive diffusion. There are also three drug classes of transfer the placenta recognizes complete transfer which is type 1 drugs, exceeding transfer which are type 2 drugs, and incomplete transfer which are type 3 drugs.

Complete Transfer
Digoxin is in the cardiac glycoside class of drugs and undergoes complete transfer across the placenta. The complete transfer is when the drug will rapidly cross the placenta and readily bring maternal and fetal concentrations in the blood to equilibrium. Complete and targeted drug delivery systems are advantageous when managing SVT because they concentrate the drug at the desired site, ensure patient compliance, and have fewer drug-related side effects. A complete transfer is the most common drug delivery method for the management of SVT.

Simple Diffusion
The complete transfer of digoxin across the placental membrane occurs through simple diffusion. Simple diffusion is when small non charged particles move from an area of high concentration to an area of low concentration through phospholipids to enter or leave the cell. The placental transfer is governed by the net flux of the mother to fetus and is the result of a concentration difference.

In relation to the placental transfer, diffusion is dependent on the concentration gradient through the placenta for passive movement from high to low concentrations without energy input. Fick’s law of diffusion governs the placental transfer from mother to fetus. Fick’s law states that the rate of a molecule moving through a material is proportional to the concentration gradient of a material and inversely proportional to the material thickness. In this case, the material is the membrane thickness of the placenta.

As gestation continues, the surface area of the villous and the placental blood flow increases. In addition, the membrane thickness decreases and the cytotrophoblast layer dissipates. With these structural changes, the conditions are more favorable for the passive diffusion of drugs and nutrients from the mother to the fetus. The diffusion is facilitated by either water channels in the membrane or transcellular in the syncytiotrophoblast layer.

This simple diffusion mechanism can be translated quantitatively. Where D is the diffusion coefficient, is determined based on four physiochemical drug properties:

Molecular Weight
D increases inversely to the radius of a material according to the Stokes-Einstein equation. A higher molecular weight is related to a larger material radius and a smaller diffusion coefficient.

Lipid Solubility
Lipid soluble molecules and small non-charged molecules can diffuse from an area of high to a low concentration between phospholipid membranes. The placenta is a phospholipid membrane.

Degree of Ionization
The degree of ionization (pKa) and the pH of maternal blood controls how much a drug is ionized. If the drug’s pKa and the pH of the solution it is dissolved in are equivalent, then 50% of the drug is ionized and the other 50% is non-ionized. The non-ionized fraction of a drug is the only part of a partially ionized drug that can cross the placental membrane.

Protein Binding
Free and unbound fractions of a drug can cross the membrane. Drugs with higher plasma protein binding avert transport across the placenta. Drugs that have dissociated from plasma proteins readily enter the syncytiotrophoblast membrane.

Exceeding Transfer
Exceeding transfer is the drug delivery mechanism for type 2 drugs. These drugs are transferred incompletely across the placenta, they are greater in concentration in fetal blood than in maternal blood. Exceeding transfer is not a common method for the management of SVT.

Incomplete Transfer
An incomplete transfer is the drug delivery mechanism for type 3 drugs. These therapeutic drugs are higher in concentration in maternal blood and lower in fetal blood because they do not transfer completely across the placenta.

Case 1
A 26-year-old woman at 26 weeks of gestation was referred to a hospital for investigation and treatment of fetal tachycardia with Husain, et al. There was a noted loss of fetal movement for 1-day durations and a persistent fetal tachycardia of 200bpm. The echocardiogram revealed an atrioventricular reentrant circuit, the fetus was diagnosed with AVRT. Transplacental antiarrhythmic therapy with digoxin was decided as treatment. For 2 days the mother was administered 0.25 mg digoxin every 8 hours, resulting in sinus rhythm. On the third day, 0.25 mg was administered once and a recurrence of AVRT was present. Due to favorable conditions with the first dosing, 0.5mg was administered twice a day for two days. While the fetal heart rate stabilized, the mother experienced digitalis toxicity. The therapy was halted for one day and then the dose was decreased to 0.25 mg twice a day and the fetal heart rate remained normal. The mother was discharged and during follow-up visits, the fetus and mother presented with normal heart rates.

Case 2
A 26-year-old woman at 28 weeks of gestation was admitted for fetal tachycardia with a persistent heart rate of 250 bpm. Digoxin was administered with a loading dose of 500 mcg followed by 250 mcg every 6 hours for 2 doses. There was no fetal response after digoxin administration for 24 hours. On day 2, flecainide was administered instead at 100 mg every 8 hours. There was no fetal response after 36 hours of administration. On day 4, digoxin was re-administered in addition to flecainide at a daily dose of 250 mcg. Hydrops, pericardial effusion, and pleural effusion were noted and treated. Due to maternal flecainide toxicity, amiodarone was administered at 600 mg every 8 hours with digoxin at 125 mcg daily. On day 6, due to continued fetal SVT, amiodarone was administered at 800 mg every 8 hours. On day 10, the fetal response was noted. due to this response, digoxin was discontinued and amiodarone was tapered off. The fetus was monitored for 2 days before discharge and a normal fetal heartbeat was consistent.

Amniotic Sac Drug Delivery
The amniotic sac and amniotic fluid form around week 4 of gestation. The amniotic sac membrane, also known as the chorioamnion (CA) membrane, holds amniotic fluid which in conjunction acts as another protective barrier around the placenta. The CA membrane has 2 layers, the amnion which is on the fetal side, and the chorion which is on the maternal side. Drugs administered such as digoxin will have to travel through both layers to reach the placenta.

Penetration Enhancers
Chemical penetration enhancers (CPEs) decrease barrier resistance by penetrating the skin and other membranes. CPEs have been evaluated to increase transport across the CA membrane. A study conducted by Karande et al. concluded that CPEs can have the same effect on the CA membranes as they to the skin. Two CPE mechanisms were detected that enhance drug delivery through the amniotic sac to the placenta. CPEs can extract lipids from the stratum corneum (SC) and also present a fluidizing characteristic of the lipid bilayers. Based on this study, it was concluded that penetration enhancers can also increase mass transport through the CA membrane which is beneficial in cases of SVT when management is time-dependent.

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