W11 Teratology and the Placenta (Nunn).pdf

Teratology and the Placenta Sheila Nunn Professor of Anatomy Email: [email protected] Please email me any questions or to set up a 1:1 WebEx meeting to clarify concepts Recommended text: Langman’s Medical Embryology. Author T. W. Sadler. 14th Edition. Chapters 8 and 9 Objectives 1. 2. 3. 4. 5. Def...

Teratology and the Placenta Sheila Nunn Professor of Anatomy Email: [email protected] Please email me any questions or to set up a 1:1 WebEx meeting to clarify concepts Recommended text: Langman’s Medical Embryology. Author T. W. Sadler. 14th Edition. Chapters 8 and 9 Objectives 1. 2. 3. 4. 5. Define what a teratogen is. Explain which period of development is most at risk from teratogen. List the main activities of the placenta. Explain placental circulation. Illustrate the placental membrane barrier and discuss the transfer of materials between fetal and maternal blood. 6. Know the substances that can and cannot pass through the placental barrier. 7. Discuss the effects of drugs, viruses and other teratogens that can cross the placental barrier on the developing embryo/fetus. • What is teratology? • Teratology = (Gr. teratos; monster) • The study of birth defects, congenital abnormalities, and their causes • Major congenital abnormalities are seen in approximately 3% of live births; additional can be detected after birth • The causes of birth defects fall into three categories: 1. Those that are caused by environmental factors (15%), 2. Those caused by genetic factors (30%), and 3. Those caused by an interaction of the environment with a person’s genetic susceptibility (55%), and for most of these congenital malformations, details of their origin are unknown To be covered in your genetics curriculum Am I likely to have a Congenital Malformation? • Single minor malformations are observed in approximately 14% of newborns. • These malformations are usually of no clinical consequence and may include features such a single palmar crease or ear tags. • Specific minor malformations may suggest the possibility of an associated major malformation. For instance, the finding of a single umbilical artery should suggest the possibility of associated congenital heart problems. • The greater the number of minor malformations, the greater the likelihood of an associated major malformation. The Importance of Timing of Teratogenic Insult • During the first two weeks of gestation, teratogenic agents usually kill the embryo rather than cause congenital malformations • Teratogens have their greatest effects in early pregnancy, particularly in the embryonic stage (3-8 weeks) as this is when organ systems are starting to be formed and are at most risk of damage. • In the fetal period (9-36 weeks), most of the systems have already developed and only need to mature, meaning that they are at less risk of teratogenic damage. • Teratogens can easily be transferred across the placenta during the pregnancy. • Teratogens can be found in many drugs; illicit and pharmaceutical. As a result, extra attention should be given to the medications a pregnant woman is prescribed to prevent harm to the developing fetus. Examples of Teratogens Causing Congenital Malformations To be covered in later modules e.g., reproductive Congenital Rubella Syndrome • Congenital rubella or German measles consists of the triad (three features) of cataracts, cardiac malformations (patent ductus arteriosus), pulmonary stenosis (narrowing) and deafness when the developing embryo is exposed to the virus during the embryonic period. Congenital Cytomegalovirus infection • Most common viral infection of the fetus • Exposure later in the pregnancy results in: o Intrauterine growth retardation o Micromelia (short extremities) o Chorioretinitis (inflammation of the choroid (thin pigmented vascular coat of the eye) o Blindness o Microcephaly (small head usually is the result of a problem with brain development) o Hepatosplenomegaly • Infants who appear normal at birth may later develop hearing loss and intellectual disability Reader Preferences Toxoplasmosis • This is caused by the protozoan parasite Toxoplasmosis gondii • Poorly cooked meat; feces of domestic animals, especially cats; and soil contaminated with feces can carry the virus • Features that may be present at birth include: ➢Microcephaly (small head) ➢Macrocephaly (large head), or ➢Hydrocephalus (an increase in cerebrospinal fluid in the brain). • Infants who appear normal at birth may later develop visual impairment, hearing loss, seizures, and intellectual disability Zika Virus • Zika virus causes congenital Zika syndrome (CZS) • Infection is spread primarily by mosquitoes, but cases of sexual transmission have been reported. • Features include: ➢Severe microcephaly with overlapping cranial sutures and redundant scalp skin ➢Thinning of the cerebral cortex with abnormal gyri and subcortical calcifications; ➢Microphthalmia (small eye/s) and coloboma (part of the tissue that makes up the eye is missing) ➢Joint contractures (arthrogryposis) and ➢Neurological issues which may include motor and cognitive deficits Ionizing Radiation • Radiation consisting of particles, X-rays, or gamma rays with sufficient energy to cause ionization in the medium through which it passes • Can injure the developing embryo due to cell death or chromosomal injury. The severity of damage to the embryo depends on the dose absorbed and the stage of development at which the exposure occurs. • There is no proof that human congenital malformations have been caused by diagnostic levels of radiation. However, attempts are made to minimize scattered radiation from diagnostic procedures such as x-rays that are not near the uterus. All women of childbearing age are asked if they are pregnant before any exposure to radiation Thalidomide • Marketed as a sedative and anti-hypnotic in 1957. Then used to give effective relief from morning sickness during early pregnancy. • The characteristic features of this syndrome include limb abnormalities • Phocomelia remains the most striking limb deformity. Severe shortening of the limb/s, due to proximal elements (long bones) being reduced or missing and leaving distal elements (handplate) in place • Also causes malformations of other organs including absence of the internal and external ears, hemangiomas (noncancerous growths of blood vessels., congenital heart disease, and congenital urinary tract malformations Tetracycline, Phenytoin and Chemotherapeutic Agents • Tetracycline is an antibiotic that can cross the placental membrane and is deposited in the embryo in bones and teeth. • Results in yellow staining of the primary or deciduous teeth and diminished growth of the long bones • Phenytoin (anticonvulsant agent) causes the fetal hydantoin syndrome. • Results in intrauterine growth retardation, microcephaly, mental retardation, distal phalangeal hypoplasia, and specific facial features e.g., midfacial hypoplasia and increased risk of cleft lip • Anti-neoplastic or chemotherapeutic agents are highly teratogenic as these agents inhibit rapidly dividing cells. These medications should be avoided whenever possible but are occasionally used in the third trimester when they are urgently needed to treat the mother. Fetal Alcohol Syndrome • Infants born to alcoholic mothers demonstrate prenatal and postnatal growth deficiency, intellectual disabilities, heart defects and other congenital malformations • Facial features associated with fetal alcohol syndrome including short palpebral fissures, maxillary hypoplasia, a smooth philtrum, (and congenital heart disease). • Moderate alcohol consumption consisting of 2 to 3 oz. of hard liquor per day may produce the fetal alcohol effects. Binge drinking also likely has a harmful effect on embryonic brain developments at all times of gestation Mechanical Forces • Mechanical forces can also act as teratogens • Malformations of the uterus may restrict fetal movements and be associated with congenital dislocation of the hip and clubfoot • Amniotic bands are fibrous rings and cause intrauterine amputations or malformations of the limbs as well Title of Lecture is Teratogens and the Placenta • ……. , so how does the placenta link to teratogens? • To answer this question, we need to discuss formation and function of the placenta • The placenta is a fetomaternal organ 1. Fetal part: develops from the chorionic plate 2. Maternal part: develops from the endometrium (more precisely the decidua basalis) • The placenta and the umbilical cord are a transport system for substances (beneficial and potentially harmful) between the mother and the fetus Where we left off development of the placenta • Cells of the syncytiotrophoblast continue to penetrate deep into uterine wall • They erode the endothelial lining of maternal capillaries (sinusoids) • The lacunae then become continuous with the sinusoids • Result is that maternal blood enters the lacunar system, establishing the uteroplacental circulation sinusoids So How Does Development of the Placenta Proceed? • You know that the extraembryonic mesoderm that lines the inside of the cytotrophoblast now known as the chorionic plate • Connecting stalk only place where extraembryonic mesoderm crosses chorionic cavity • Trophoblast layer develops primary villi, which are a proliferation of the cytotrophoblast cells surrounded by the syncytium 13-days post-fertilization • Next the mesodermal cells penetrate the core of the primary villi and grow towards the decidua basalis: and a secondary villus is formed. • These mesodermal cells then differentiate to form a villus capillary system: a tertiary villus is thus formed. • Capillaries in the tertiary villi now make contact with capillaries that are developing in the mesoderm of the chorionic plate and the connecting stalk • These vessels will establish contact with the intraembryonic circulatory system that is forming Maternal tissue (spiral arteries) Developing fetus • Cytotrophoblastic cells reach deeper into the endometrium. They make contact with other cytotrophoblastic cells to form the outer cytotrophoblastic shell. Eventually surrounds the entire trophoblast with the result that the fetus is firmly attached to maternal endometrial tissue • We can now get transfer of substances across the placental barrier. How is this accomplished? Placental Circulation Maternal Side • Highly oxygenated and nutrient rich maternal blood, flows into an intervillous space from the spiral endometrial arteries in a pulsatile manner and spurts toward the chorionic plate (CP) • As the pressure dissipates, blood flows slowly over the villi to allow exchange of gases, nutrients, and metabolic products • Blood, which has collected the waste products that has passed across the placental barrier from the embryo/fetus, returns through the endometrial veins to the maternal circulation CP Placental Circulation Embryo/Fetal side • Poorly oxygenated blood leaves the fetus and passes through the umbilical arteries towards the placenta. • These divide in the villi to form an extensive arterio-capillaryvenous system which brings fetal venous blood close to maternal blood. Thus, no mixing of blood occurs. • Once exchange occurs across the placental barrier, highly oxygenated and nutrientrich blood returns to the fetus via the umbilical vein. Functions of the Placenta • . • Remember the embryonic/fetal circulation is at all times separated from the maternal circulation • YOU CAN SEE THAT NOT EVERYTHING THAT PASSES ACROSS THE BARRIER IS GOOD FOR THE EMBRYO/FETUS Some Examples of the Benefit of the Placental Barrier 1. Exchange of gases, nutrition, and electrolytes • O2, CO2, by simple diffusion. Even shortterm interruption of the oxygen supply is fatal to the fetus. 2. Transmission of maternal antibodies • Maternal IgG begins to be transported from the mother to the fetus at about 14 weeks. In this matter, the fetus gains passive immunity 3. Hormone production • Progesterone • Estrogen • Human chorionic gonadotropin /hCG • Somatomammotropin/placental lactogen Harmful Substances that can cross the Placenta • Synthetic estrogen diethylstilbestrol (DES): crosses placenta easily, can cause carcinoma of the vagina and abnormalities of the cervix and uterus in the female, and in the testes of males who were exposed to DES during their intrauterine life. • Many viruses cross the placenta without difficulty. Already discussed earlier in the lecture • Most drugs: cross without difficulty resulting in serious damage to embryo/fetus. Heroin and cocaine can cause fetal habituation • MOST BACTERIA ARE TOO LARGE SO DO NOT CROSS THE PLACENTAL BARRIER • In some cases, this transplacental transfer may be beneficial and drugs may be deliberately administered to the mother in order to treat specific fetal conditions. For example, steroids may be given to the mother to promote fetal lung maturation