Teratogenic+Effects+of+Phenytoin+and+Varicella

By Kristi Walker, Hilgrove Lightbourne and Erica Misner =__**Phenytoin**__=

A teratogen is something that the mother is exposed to during pregnancy that can cause or increase the risk of birth defects. Examples are prescription medications, herbal drugs, illegal drugs, chemicals, and viruses. The fetus may be affected by a teratogen as early as 10-14 days after conception (Lucile Packard Children’s Hospital at Stanford, 2012). For the teratogen to cause a problem it must be able to cross the placenta. Heparin is one medication that cannot cross the placenta so it cannot be teratogenic. About 7% of congenital defects are caused by teratogens. If a women is planning on getting pregnant she should talk to her doctor about any medications she may be on, including herbal medications so that the doctor can explain the possible problems. She should also avoid people infected with certain diseases, such as varicella during the pregnancy to avoid catching the disease and causing problems to the fetus (Chung, 2004). Normal human embryo development begin with the process called fertilization, in which a sperm and an egg bind together fusing their nuclei; thus making a diploid human zygote. The zygote then begins to go through a process called cleavage in which the cells are beginning to divide. Eventually forming a 16-32 solid ball of cells called morula. The outer cells of the morula divide and form the tropectoderm and the inner cell mass. The inner cell mass will give rise to all the tissues of the embryo’s body as well as to the extra embryonic tissues such as the allantois and amnion. The morula begins to form a fluid filled cavity called the blastula. The fluid is formed from the secretion by the tropectoderm cells, which results in a separation of the inner most cells from the tropectoderm causing the morula to be charged into a blastocyst. Before the blastocyst reaches the uterine wall, it hatches out of the zona pellucida and attaches to the uterine wall. The trophoblast cells (tropectoderm) begin to proliferate and invade into the uterine epithelium by digestion of the uterine cells. Upon contact with the endometrium the uterus the cytotrophoblast forms the syncytiotrophoblast and human chorionic gonadotropin production begin. The syncytiotrophoblast cells further invade the endometrium by secreting hydrolytic enzymes. It nearly surrounds the cytotrophoblast cells of the blastocyst at day 10 of development (Early Development, 2009) due to the depth of the blastocyst in the uterine wall. The syncytiotrophoblast then becomes supplied with maternal blood vessels to take nutrition and exchange waste with the mother. The fusion of the embryonic chorion, uterus epithelium and vascular tissue give rise to the placenta. The epiblast begins to split to form the amniotic cavity. The cavity fills with fluid and cushions the embryo throughout gestation.
 * __Introduction__** 
 * __Normal Development__**

Next gastrulation happens and a primitive streak form giving rise to the 3 tissue layers ectodetm, endoderm, and mesoderm. Gastrulation is triggered at the posterior end of the embryo with the formation of a structure called the node. The node acts as a signaling center to regulate the formation and movement of epithelial cells. A primitive streak forms from a specific region of the epiblast along the posterior axis of the embryo. The forward migration of the posterior epiblast cells occurs as their cells-cells contact breaks down, and they release enzymes that digest the basement membrane which allows them to migrate into the space between the epiblast and endoderm( Early Development, 2009). The epiblast cells also spread laterally inducing the formation of the mesoderm and the notochord. The anterior epiblast is responsible for generating the neuroectoderm and the ectoderm that covers the surface of the embryo. Ectodermal tissues that lie dorsal to the notochord will generate the neural plate, which will form the neural tube of the embryo. After gastrulation, there is a process called organogenesis that is responsible for taking the three germ layers and differentiating them into specialized cells and eventually organs. For instance, the ectoderm give rise to the central nerves and peripheral nerves system, skin, cornea and lens of the eyes, epithelium that lies in the mouth and nasal cavities, neural crest (which gives rise to the various facial structures, melanocytes, and the nerves of the spinal cord. The mesoderm is responsible for making the skeletal, smooth and cardiac muscles, the urogenital system structures, bone marrow, connective tissue etc. finally the endoderm give rise to the epithelium of the digestive and respiratory tract, as well as the reproductive structures of the fetus.

Basic embryogenesis to the point of uteral implantation (Early Development, 2009)

When the seizure medicine phenytoin is given during pregnancy it can cause a wide range of congenital abnormalities. Phenytoin and other anti-convulsive medications can be embryo toxic due to them forming intermediate oxide metabolites. Some of the abnormalities caused by phenytoin are cognitive impairment, genitourinary defects, cleft lip and palate defects, and congenital heart defects. Exposure before day 35 can lead to a cleft lip and a cleft palate can occur before day 70. If exposed before day 42 heart defects can occur. These days are referencing the days after the first day of the last menstrual cycle. After the first trimester exposure only effects brain development (Nulman, Laslo, & Koren, 1999). Prenatal growth retardation, distal limb defects, and embryonic dysrhythmia are some of the other abnormalities that can occur (Azarbayjani & Danielsson, 2002). Fetal hydantoin syndrome is a syndrome that can occur in about 10% of births when the mother takes phenytoin during her pregnancy. It resembles Fetal Alcohol Syndrome. Babies that are born with this syndrome can have ocular hypertelorism, a flat nasal bridge, and distal digital hypoplasia with nail hypoplasia (Santis, Carducci, Cavaliere, Santis, Straface, & Caruso, 2001). Microcephaly and brain abnormalities are two of the other problems sometimes seen. Children that have this syndrome can have abnormal facial features that include a large mouth, deformed ears, crossed eyes, drooping eyelids, down-slanted eyes and widely spaced eyes. Some children may also have more hair on their face and body and they can have a short or webbed neck (Genetic and Rare Diseases Information Center, 2011). Another possible problem seen in some babies is a defect in coagulation within 24 hours after birth. Vitamin K can be given before or after delivery to correct or prevent this from happening.
 * __Phenomenon Resulting from the Teratogen__**

Epilepsy has been reported to double and possibly triple the incidence of congenital abnormalities among children born to epileptic mothers. Although epilepsy could be a factor in birth defects developed there is a higher incidence of defects in babies when the mothers had taken anti-convulsants. The study done by Santis, Carducci, & Cavaliere in 2001 found that the risk of birth defects was greater in mothers who had multiple therapies compared to monotherapy of phenytoin ( PHT) treatment. Fetal hydantoin syndrome occurs in roughly 10% of children born to women with epilepsy who had received phenytoin during pregnancy (Santis, Carducci,& Cavaliere, 2001). Phentyoin mechanisms are characterized by episodes of embryonic arrhythmia, episodes of hypoxia, production of reactive oxygen species, vascular disruption, hemorrhages, necrosis of embryonic tissues, and malformation in development (Azarbayjani & Danielsson, 2002). Due to the high effect on birth defects by multiple therapies of phenytoin, PHT, it is suggested that mothers taking PHT who are in their fertile years receive pre-conception counseling, folic acid supplement, control of seizure activity, and a monotherapy of phenotyoin in the lowest effective dose(Santis, Carducci,& Cavaliere, 2001).
 * __Mechanisms of Phenytoin__**

Azarbayjani and Danielsson, 2002, studied the effect of PHT teratogenicity on drug-induced embryonic arrhythmia. It was purposed that arrhythmia creates a link between PHT and its ability to inhibit I­K, a potassium channel, which results in occasional embryonic ischemia and the formation of reactive oxygen species (ROS). One of the current theories about the teratogenicity of PHT is linked to its chemical properties through the action exerted on voltage dependent channels, changing the activity of basic mediators in excitability of neurons and cardiac cells (Azarbayjani & Danielsson, 2002). Current studies using voltage clamping to inhibit the delayed potassium channels, IK, and the newly discovered possibility of blocking the fast activating component of IK, Ikr, to determine effects on the sodium channels. Ikr is the main cardiac repolarization channel encoded by HERG, or the human ether-a-go-go related, gene and is prominent in the regulation of heart beat prior to formation of the embryonic cardiac conduction system and the innervations of the heart (Azarbayjani & Danielsson, 2002). PHT and Ikr inhibitor drugs have been found to cause embryonic arrhythmia beginning when the embryonic heart begins beating in the 5th to 9th weeks. The toxigenicity of Ikr can be explained by the embryo’s arrhythmia causing oxygen supply to be episodically interrupted. Azarbayjani & Danielsson, 2002 results showed that the induced episodes of interrupted oxygen supply cause the same birth defects preceded by vascular disruption and hemorrhage as a single dose of PHT or Ikr blocker. These episodic losses of oxygen lead to orofacial clefts that are preceded by vascular disruption and hemorrhages.

Patients with a mutation in the HERG gene or with ischemic heart disease are more likely to be predisposed for epilepsy. PHT has been discovered to have arrhthymogenic potential. For these patients research has shown that following intravenous administration of PHT it develops high concentrations of arrhythmia potential(Azarbayjani & Danielsson, 2002). Embryonic arrhythmia followed by hemorrhages after 24 hours of treatment by PHT was found to occur before orofacial clefts and distal digital defects occurred in embryos. According to Azarbayjani & Danielsson, 2002 HERG is partially responsible for decreased pH, which has been recently shown affect kinetics and deactivation of the Ikr. Reactive oxygen species, ROS, are produced in the mechanisms of the phenytoin. ROS has been recently under scrutiny for possibly having a part in malformations that are induced following episodes of embryonic arrhythmia or hypoxia. Azarbayjani & Danielsson, 2002, found that the major cause of damage is done by the replacement of the amount of oxygen and not the flow. Vascular disruption was found to be an additional effect caused by ROS’s damage to the endothelium.


 * __Timing of Impac__**

The exposure a fetus has to a drug may vary depending on the gestational state as well as the ability of the mother or fetus to eliminate the drug. The susceptibility of a fetus to overcome the drug effects depends on the interaction of the drug within the body as well as the strength of the drug depending on the individual immunology (Morgan & Mihaly, 2002). Since phenytoin is used to control/prevent seizure, it is possible that affected fetuses are the result of long term exposure of the mother to the drug which can lead to major birth defects especially with the shift of hormones that occur during pregnancy. It is also important to consider whether the mother or father have a history of circulatory issues due to the possible effect flow of circulation can have on the diffusion of the blood to the fetus. Women who had or have being taking the drug are usually recommended to take larger amounts which can also lead to birth defects.

The effect phenytoin has on pregnancy is to decrease folate metabolism. This decrease in folate has been speculated to be associated to navel tube defects in the fetus (Brewer & Waltman, 2003). The neural tube usually develops between days 18 to 30 after conception which is the time when the first organ: the heart is formed (med.upem.edu).

The frequency of congenital malformation is increased in pregnancies in which uncontrolled seizures occurs frequently during the first and part of the second trimester in which the fetus is most vulnerable to malformation from phenytoin. In the third trimester, seizures put the fetus in a hypoxic environment which can further lead to more complications within the pregnancy.

Fetal hydantoin syndrome is associated with phenytoin, which can lead to craniofacial malformation. It is speculated that the malformations caused by the drug is due to an increase in retinoic acid which regulates the expression of laminin beta 1 and growth factors IGF-2, TGF alpha and Beta. These genes are responsible for the normal formation of the craniofacial region (Van Wae, Bennett, Finnell, 1999).

Many of the abnormalities that occur do not have a treatment. When the child is born with a cleft lip or cleft palate there are surgery options to treat the problem. If they have developmental problems they may receive a special education and other services to help them function in society (GARD, 2011). When the child is born with heart and genitourinary defects there may be surgeries to correct some of the defects, but not all of the defects can be fixed with an operation. Overall the treatment options are limited and therefore it is best to talk to your doctor before getting pregnant if taking this seizure medication.
 * __Possible Treatments__**

=__**Varicella**__= Normal human embryo development begin with the process called fertilization, in which a sperm and an egg bind together fusing their nuclei; thus making a diploid human zygote. The zygote then begins to go through a process called cleavage in which the cells are beginning to divide. Eventually forming a 16-32 solid ball of cells called morula. The outer cells of the morula divide and form the tropectoderm and the inner cell mass. The inner cell mass will give rise to all the tissues of the embryo’s body as well as to the extra embryonic tissues such as the allantois and amnion. The morula begins to form a fluid filled cavity called the blastula. The fluid is formed from the secretion by the tropectoderm cells, which results in a separation of the inner most cells from the tropectoderm causing the morula to be charged into a blastocyst. Before the blastocyst reaches the uterine wall, it hatches out of the zona pellucida and attaches to the uterine wall. The trophoblast cells (tropectoderm) begin to proliferate and invade into the uterine epithelium by digestion of the uterine cells. Upon contact with the endometrium the uterus the cytotrophoblast forms the syncytiotrophoblast and human chorionic gonadotropin production begin. The syncytiotrophoblast cells further invade the endometrium by secreting hydrolytic enzymes. It nearly surrounds the cytotrophoblast cells of the blastocyst at day 10 of development (Early Development, 2009) due to the depth of the blastocyst in the uterine wall. The syncytiotrophoblast then becomes supplied with maternal blood vessels to take nutrition and exchange waste with the mother. The fusion of the embryonic chorion, uterus epithelium and vascular tissue give rise to the placenta. The epiblast begins to split to form the amniotic cavity. The cavity fills with fluid and cushions the embryo throughout gestation.
 * __Normal Development__**

Next gastrulation happens and a primitive streak form giving rise to the 3 tissue layers ectodetm, endoderm, and mesoderm. Gastrulation is triggered at the posterior end of the embryo with the formation of a structure called the node. The node acts as a signaling center to regulate the formation and movement of epithelial cells. A primitive streak forms from a specific region of the epiblast along the posterior axis of the embryo. The forward migration of the posterior epiblast cells occurs as their cells-cells contact breaks down, and they release enzymes that digest the basement membrane which allows them to migrate into the space between the epiblast and endoderm( Early Development, 2009). The epiblast cells also spread laterally inducing the formation of the mesoderm and the notochord. The anterior epiblast is responsible for generating the neuroectoderm and the ectoderm that covers the surface of the embryo. Ectodermal tissues that lie dorsal to the notochord will generate the neural plate, which will form the neural tube of the embryo. After gastrulation, there is a process called organogenesis that is responsible for taking the three germ layers and differentiating them into specialized cells and eventually organs. For instance, the ectoderm give rise to the central nerves and peripheral nerves system, skin, cornea and lens of the eyes, epithelium that lies in the mouth and nasal cavities, neural crest (which gives rise to the various facial structures, melanocytes, and the nerves of the spinal cord. The mesoderm is responsible for making the skeletal, smooth and cardiac muscles, the urogenital system structures, bone marrow, connective tissue etc. finally the endoderm give rise to the epithelium of the digestive and respiratory tract, as well as the reproductive structures of the fetus.

When a mother is infected with the virus varicella during pregnancy it can cause a wide variety of problems throughout the pregnancy. In the first two trimesters 12% of the fetuses infected with varicella will develop congenital varicella syndrome. Between 3 to 8% of mothers will experience a spontaneous abortion. Clinical symptoms seen in babies born with this syndrome are skin lesions, neurological defects, limb hypoplasia, and different eye diseases, such as microphthalmia, cataracts, and optic atrophy. Some other problems that can be seen are muscle hypoplasia, mental retardation and gastrointestinal, genitourinary and cardiovascular problems. Some of the neurological defects seen are spinal cord atrophy, limb paresis, seizures, microcephaly, Horner’s syndrome, and dysphagia. When a baby is born with congenital varicella syndrome they have up to a 30% chance of death within the first few months of life. Another possible problem is neonatal varicella, which is seen when the mother is infected with chickenpox during the last 3 weeks of pregnancy. If the baby develops neonatal chickenpox it can be life-threatening. Up to 23% of reported cases are fatal, with most being when the neonate is infected 5 to 10 days after delivery. When the neonate presents with this they most likely will have the typical skin rash seen with chickenpox. When a baby dies from neonatal varicella and an autopsy is performed the rash will be seen in the mouth along with necrotizing hepatitis, hemorrhagic-necrotizing pneumonia and necroses of the intestinal mucous membranes, adrenal glands, spleen and brain. (Sauerbrei, 2010). Another syndrome is fetal varicella syndrome that is seen in less than 2% of babies born after the mother was infected with varicella between 7 and 28 weeks of pregnancy. The symptoms are similar to the other syndrome, but also include missing skin on their limbs, low birth weight and malformed digits (Ramachandra, Metta, Haneef, & Kodali, 2010). Chickenpox is caused by varicella-zoster virus, VZV, and is spread by respiration or direct contact with an open wound. For many people chickenpox symptoms are very mild but in pregnant women the virus can lead to serious maternal and fetal diseases. The VZV can move into the bloodstream and be passed on to the fetus by either transplacental spread or by ascending infection from open sores in the birth canal (Sauerbrei, 2010). The effect on the fetus is dependent on the time of maternal infection. If no antiviral treatment is saught mortality is high, but recent studies have purposed that the mortality rate for both pregnant and non-pregnant has decreased due to antiviral therapies and more efficient respiratory management. But risk of death is higher in those who are pregnant, than those who are not.
 * __Phenomenon Resulting from the Teratogen__**
 * __Mechanisms Involved__**

The time in which the VZV onsets in the mother determines when maternal antibodies will be passed to the embryo and therefore will determine the severity of symptoms. Fetuses that get exposed within 6-20 days of infection will develop VZV but the disease will not be fatal due to a higher number of maternal antibodies decreasing the risk of complications (Sauerbrei, 2010). VZV with a fatal course in fetuses develops when the mother forms a rash on either the fourth or fifth day before delivery to two days after delivery because the fetuses will not have received the maternal antibodies.The acquired immune response has not fully developed in fetuses and therefore cannot aid in the defense against VZV. Fatal cases of VZV are more likely to occur between five and ten days after delivery, while milder cases occur if VZV onset occurs four days after birth (Sauerbrei, 2010).

Mothers and infants with VZV are kept in isolation. According to Sauebrei (2010) although not completely full proof some measures to avoid impact by VZV include moving the delivery date back to allow maternal antibodies to pass into the placenta, aciclovir may be administered intravenously for seven days to the mother within 24 hours of rash appearance and four to five days before delivery, and passive immunization of the infant to modify the course of VZV. Although these options do not prevent the disease they may decrease the risk of death within infants.


 * __Timing of Impact__**

Varicella usually results in congenital varicella syndrome (CVS) in which the virus attacks the fetus bones and skin. The virus usually is most active during weeks 13-20 of gestation (Smith & Arvin, 2009). The pathogenesis of CVS is attributed to disseminated infection in utero and poor latency of the host-virus complex. CVS can also play a role as a neurotropic virus which can cause defects in the spinal cord and ganglia, which leads to denervation of the limbs buds and hypoplasia.

If the mother has been exposed to varicella virus during pregnancy and she has not had chickenpox before she should be tested for virus-specific IgG antibodies. If she is negative or if her status is unknown she should be given varicella-zoster immune globulin within 72-96 hours. The dose is 125 U/10kg intramuscularly, with the maximum dose being 625U. This will not prevent the infection, but it will reduce the severity of the infection and the risk of fetal infection. When the mother presents with a rash 4-5 days before delivery it is best to administer the antiviral medication aciclovir at a dose of 800mg for 5 days orally or 10-15 mg/kg 3 times a day for 7 days intravenously. This should be done within 24 hours of the rash appearing (Sauerbrei, 2010). If fetal varicella syndrome is suspected after doing an amniocentesis and fetal blood work and the there is a great risk of defects termination of the pregnancy may be recommended. When the baby has scars and defects of the limbs plastic surgery may be used to correct the problems (Ramachandra et al., 2010). In the case of metal retardation and other neurological defects the child should be provided a special education and other supportive services.
 * __Possible Treatments__**

A teratogen is something that the mother is exposed to during pregnancy that can cause or increase the risk of birth defects. The fetus may be affected by a teratogen as early as 10-14 days after conception (Lucile Packard Children’s Hospital at Stanford, 2012). For the teratogen to cause a problem it must be able to cross the placenta barrier. Approximately 7% of congenital defects are caused by teratogens. If a women is planning on getting pregnant she should talk to her doctor about any medications she may be on, including herbal medications so that the doctor can explain the possible problems. She should also avoid people infected with certain diseases, such as varicella during the pregnancy to avoid catching the disease and causing problems to the fetus (Chung, 2004).
 * __Conclusion__**

Phenytoin causes cognitive impairment, genitourinary defects, cleft lip and palate defects, and congenital heart defects, cleft lip and palate, and fetal hydantoin syndrome. Greater risk lies in mothers who have multiple therapies compared to monotherapy of phenytoin. It is suggested that mothers taking PHT who are in their fertile years receive pre-conception counseling, folic acid supplement, control of seizure activity, and a monotherapy of phenotyoin in the lowest effective dose(Santis, Carducci,& Cavaliere, 2001). Phentyoin mechanisms are characterized by episodes of embryonic arrhythmia, episodes of hypoxia, production of reactive oxygen species, vascular disruption, hemorrhages, necrosis of embryonic tissues, and malformation in development (Azarbayjani & Danielsson, 2002).

Chickenpox is caused by varicella-zoster virus, VZV, and is spread by respiration or direct contact with an open wound. For many people chickenpox symptoms are very mild but in pregnant women the virus can lead to serious maternal and fetal diseases. Clinical symptoms of VZV seen in babies born with this syndrome are skin lesions, neurological defects, limb hypoplasia, and different eye diseases, such as microphthalmia, cataracts, optic atrophy, muscle hypoplasia, mental retardation, gastrointestinal, genitourinary and cardiovascular problems, spinal cord atrophy, limb paresis, seizures, microcephaly, Horner’s syndrome, and dysphagia. The time in which the VZV onsets in the mother determines when maternal antibodies will be passed to the embryo and therefore will determine the severity of symptoms.

__**Resources:**__

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Saurerbrei, A. (2010). Review of varicella-zoster virus infections in pregnant women and neonates. //Health,// 2, 143-152.