EMBRYOLOGY LC6: Birth Defects and Prenatal Diagnosis PDF

Embryonic period/organogenesis OUTLINE - 3rd to 8th week of development - the risk of development of birth...

Embryonic period/organogenesis OUTLINE - 3rd to 8th week of development - the risk of development of birth defects or congenital anomaly is highest. This is the time that the I. BIRTH DEFECTS organs of the fetus are being developed. It does not mean that on or II. CAUSES after this period that the fetus will not develop any congenital III. RISKS anomaly if the mother is exposed either to environmental IV. TYPES OF ABNORMALITIES teratogens, drugs, medicines, or any other exposures. For example, if V. PREVENTION the mother is exposed to the patient with measles during the 3rd to VI. PRINCIPLES OF TERATOLOGY 8th week, the measles might cause congenital cataract to the fetus. VII. PRENATAL DIAGNOSIS The mother might not have the measles, but the baby might have a A. Non-invasive Technique congenital anomaly. B. Invasive Technique VIII. TREATMENT Fetal period - 9th week – birth I. BIRTH DEFECTS Birth defects are also called as: Congenital malformation / Congenital anomaly - Structural, behavioral, functional, metabolic disorders present at birth. The structural deformities in the skeletal or muscular system or on any organs in the body cannot be seen by the naked eye. The behavioral, functional, and other metabolic disorders can be seen when the baby will grow up, but it is already present at birth. It results in congenital defects like anomalies. - Approximately 3% of birth defects are leading causes of infant mortality - 5th leading cause of years of potential life lost prior age 65 - Major contributor to disabilities: congenital or birth defects. Other Figure 2. Risk of Birth Defects being induced contributors: noncommunicable diseases. - Non-discriminatory, frequencies of birth defects are the same of all The graph shows the times of gestation versus the risks of birth defects being races, same for Asians, Whites, Americans. It depends upon the induced. The most sensitive time is the embryonic period during the third to mother’s exposure. eighth weeks. The fetal period begins at the end of the eighth week and extends to term. During this time, the risk for gross structural defects being induced decreases, but organ systems may still be affected. For example, the II. CAUSES brain continues to differentiate during the fetal period, such that toxic exposures may cause learning disabilities or intellectual disability. The fact that most birth defects occur prior to the eighth week makes it imperative to 55%: Interaction of environment with genetic susceptibility initiate birth defects prevention strategies prior to conception. Unfortunately, 30%: Genetic factors (Hereditary from mother or father) most women do not appear for their first prenatal visit until the eighth week, 15%: Environmental factors which is after the critical time for prevention of most birth defects ○ Example: exposure of the mother to radiation or exposure to the medicines and drugs during pregnancy. IV. TYPES OF ABNORMALITIES 1. MALFORMATION: occur during formation of structures; period of organogenesis; all or none rule; physical characteristics caused by environmental and/or genetic factors acting independently or in concert. Most malformations have their origin during the third to eighth weeks of gestation Some complex combinations of defects, such as those observed in cases of heterotaxy, may have their origins where the embryonic axes are being specified as early as the second week. Example: the mother took a drug (thalidomide) during 3rd to 8th week of development; this will affect the long bones and the baby will have phocomelia. ○ Thalidomide – given as antinauseant (treat morning Figure 1. Graph of the major causes of birth defects sickness) and as a sedative to pregnant women. ○ Amelia - one or more limbs was absent ○ Phocomelia - lacking the long bones such that only a III. RISKS hand or foot was attached to the torso L-R axes period - Peak of the risk: 3rd week of development Page 1 of 5 [EMBRYOLOGY] 1.02&3 FIRST AND SECOND WEEK OF DEVELOPMENT – Dr. La Paz L. Peredo, MD 4. SYNDROME: Group of symptoms or anomalies occurring together that have specific common cause; risk of occurrence is known. Since the cause is known, we already know when this will occur, e.g. DOWN SYNDROME (aka Trisomy 21, a mutation in chromosome 21; producing extra copy of chromosome 21 [trisomy 21]) Figure 3. Examples of phocomelia. Limb defects characterized by loss of the long bones of the limb. These defects were commonly produced by the drug thalidomide. 2. DISRUPTION: morphological alteration of already formed structures; destructive processes; amniotic bands; physical deformation Extremities have already formed, but there is alteration because of destructive processes like the presence of amniotic bands. Vascular accidents leading to transverse limb defects and defects produced by amniotic bands are examples of destructive factors that produce disruptions. Figure 6. Characteristics of Down Syndrome 5. ASSOCIATION: nonrandom appearance of 2 or more anomalies that occur together more frequently than by chance alone. Abnormalities just occur associated. Meaning there is another cause. The cause is not determined. Although they do not constitute a diagnosis, associations are important because recognition of one or more of the components promotes the search for others in the group. Figure 4. Limb abnormalities caused by amniotic bands. A) Cleft lip. B) Toe amputations. C) Finger amputations. Strands of ammion may be swallowed or become wrapped around structures causing various disruption-type defects. The origin of the bands of amniotic tissue is unknown. 3. DEFORMATION: result from the mechanical forces that mold a part of the fetus over a prolonged period; often involve the musculoskeletal (clubfeet); reversible postnatal; physical deformity - The extremities are already formed, but due to exposure to oligohydramnios (small amounts of amniotic fluid), but can be reversed after delivery. Figure 7. Examples of Vacterl association with left pulmonary Figure 5. Abnormal positioning of the lower limbs and clubfeet as examples of agenesis. A. Vestibular fistula with three openings in the vestibule, B. deformations. These defects are probably caused by oligohydramnios (too computed tomography of the chest agenesis of the left lung, little amniotic fluid). C. colostomy, D. club foot. Page 2 of 5 [EMBRYOLOGY] 1.02&3 FIRST AND SECOND WEEK OF DEVELOPMENT – Dr. La Paz L. Peredo, MD V. PRINCIPLES OF TERATOLOGY Teratogen Congenital Malformations Infectious Agents Teratogens/Teratogenic agents – any agent that has been identified to cause Rubella Virus Cataracts, glaucoma, heart defects, birth defects. hearing loss, tooth abnormalities 1. Susceptibility to teratogens depends on genotype of conceptus Cytomegalovirus Microcephaly, visual impairment, and the interaction with the environment intellectual disability, fetal death The parents already have these abnormalities present in their genes, increasing the possibility and risk for Herpes simplex virus Microphthalmia, microcephaly, retinal the fetus. dysplasia If the anomaly is in the gene or if the mother was exposed to environmental factors (x-ray, MRI, Varicella virus Skin scarring, limb hypoplasia, intellectual radiation, or virus), increasing the risk for the fetus to disability, muscle atrophy have the defect. Toxoplasmosis Hydrocephalus, cerebral calcifications, The maternal genome is also important with respect microphthalmia to drug metabolism, resistance to infection, and other biochemical and molecular processes that affect the Syphilis Intellectual disability, hearing loss conceptus. Physical agents 2. Susceptibility to teratogens varies with the X-rays Microcephaly, spina bifida, cleft palate, developmental stage at time of exposure limb defects ○ Exposure of mother to teratogen especially during the 3rd week to 8th week. Hyperthermia Anencephaly, spina bifida, intellectual ○ The most sensitive period for inducing birth defects is disability the third to eighth weeks of gestation, the period embryogenesis Chemical agents ○ Each organ system may have one or more stages of Thalidomide Limb defects, heart malformations susceptibility. For example, cleft palate can be induced at the blastocyst stage (day 6), during gastrulation (day Aminopterin Anencephaly, hydrocephalus, cleft lip and 14), at the early limb bud stage (fifth week), or when palate the palatal shelves are forming (seventh week) ○ Whereas most abnormalities are produced during Diphenylhydantoin (phenytoin) Fetal hydantoin syndrome: facial defects, embryogenesis, defects may also be induced before or intellectual disability after this period; no stage of development is Valproic acid Neural tube defects, heart, craniofacial, completely safe. and limb anomalies, seizures 3. Manifestation of abnormal development depends on dose Trimethadione Cleft palate, heart defects, urogenital and and duration of exposure to teratogens skeletal abnormalities The higher/longer the dose of exposure to the teratogen, the higher the risk of having the Topamax (topiramate) Cleft palate and/or cleft lip abnormality. Lithium Heart malformations 4. Teratogens act in specific ways on developing cells and tissues Selective serotonin reuptake Heart malformations, neural tube defects, initiate abnormal embryogenesis (pathogenesis). inhibitors (SSRIs) anal atresia. facial clefts, and many other Mechanisms may involve inhibition of a specific defects biochemical or molecular process; pathogenesis may involve cell death, decreased cell Ondansetron Facial cleft, heart defects proliferation, or other cellular phenomena. Opioids (codeine, hydrocodone, Neural tube defects, heart defects, 5. Manifestation of abnormal development are death, oxycodone) gastroschisis malformation, retardation Amphetamines Cleft lip and palate, heart defects *The conditions always depend on how the fetus will react or be Table 1. Teratogens Associated with Human Malformations affected. Sometimes, slight retardation and malformation, the worst is death. VI. PREVENTION For example, measles. Once the fetus is exposed even if the mother is not affected, the baby may be born with cataract or any other anomalies, worst fetal death. SUPPLEMENTATION salt with iodine: to prevent mental retardation folate/folic acid: to prevent neural tube defects. Avoid alcohol and smoking to prevent mental retardation and other physical abnormalities. Metabolic control prior to conception such as obesity, diabetes mellitus to prevent neural tube defects and other congenital defects. Precaution on use of drugs because the placental barrier is not a complete barrier. Example is anti-seizure drugs, which can pass the Page 3 of 5 [EMBRYOLOGY] 1.02&3 FIRST AND SECOND WEEK OF DEVELOPMENT – Dr. La Paz L. Peredo, MD placental barrier and will cause neural tube defects and mental ○ AFP screening, combined with testing other second retardation. trimester markers (e.g., human chorionic gonadotropin Fat-soluble drugs are more likely to cross placental barriers. [hCG], unconjugated estriol, and inhibin A) can increase the detection rate for birth defects using these serum screening studies. VII. PRENATAL DIAGNOSIS c. Noninvasive prenatal screening Goal: provide women-at-risk information that gives opportunity to Positive (+) results require confirmation by invasive technique make informed choices about their pregnancy *If there is a detection of abnormality upon non-invasive screening or *During prenatal check-up, make a good prenatal history and give right the result becomes positive, proceed to invasive technique. information to the mother to be informed and make choices. Not the option to not continue the pregnancy, but guide them on what to do in INVASIVE TECHNIQUE case there are anomalies. Set of ultrasound guided technique Performed by a trained healthcare worker HIGH RISK PREGNANCY: Performed to confirm positive noninvasive screening tests Advanced maternal age (35 years and above) Results are after 1-2 weeks, unlike the immediate result of the previous family history of genetic problem non-invasive Presence of maternal disease - DM Also done if the pregnancy is HIGH-RISK like: Abnormal UTZ or serum screening test ○ Advanced maternal age 35 years up monitor if candidates of invasive technique ○ Previous family history of genetic problem ○ Presence of maternal disease- DM, hypercholesterolemia NON-INVASIVE TECHNIQUE ○ Abnormal UTZ or serum screening test a. Ultrasonography Best done during the first trimester – 3rd week a. Amniocentesis Measure the fetal skeletal a needle is inserted transabdominally into the amniotic relatively noninvasive technique that uses high- frequency cavity (identified by ultrasound) sound waves reflected from tissues to create images. approximately 20 to 30 mL of amniotic fluid is withdrawn. may be transabdominal or transvaginal, with the latter take a sample of the amniotic fluid producing images with higher resolution after the first trimester, usually on the 16th week or 20th Important parameters revealed by ultrasound include: week 1. characteristics of fetal age and growth Takes about 2 weeks 2. presence or absence of congenital anomalies 3. status of the uterine environment, including b. Chorionic villi sampling the amount of amniotic fluid inserting a needle transabdominally or transvaginally into 4. placental position (anterior, posterior or the placental mass and aspirating approximately 5 to 30 placenta previa) and umbilical blood flow mg of villus tissue 5. presence of multiple gestations Takes about 3 days c. Cordocentesis or percutaneous umbilical blood sampling Sample is taken from the blood of umbilical cord Figure 9. Ultrasounds showing measures used to assess embryonic and fetal Figure 8. Examples of the effectiveness of ultrasound in imaging the embryo and growth. A. Crown-rump (C-R) length in a 7-week embryo. B. Biparietal (B-P) fetus. A. 6-week embryo. B. Lateral view of the fetal face. C. Hand. D. Feet. diameter of the skull. C. Abdominal circumference. D. Femur length (F-L). b. Maternal Serum Screening Check serum of mother VIII. TREATMENT In 30th week, the fetus secretes Alpha Fetoprotein AFP levels increase in amniotic fluid and maternal serum: ○ neural tube defects and several other abnormalities, a. Fetal medical: Treatment is given to the mother which will be including omphalocele, gastroschisis, bladder exstrophy, passed to the fetus amniotic band syndrome, sacrococcygeal teratoma, and intestinal atresia b. Fetal surgery - open/fetoscopic AFP levels decrease in: Done especially to the cardiac problem/blood vessel ○ Down syndrome, trisomy 18, sex chromosome problem/cranial cases abnormalities, and triploidy Through an open surgery or fetoscopic surgery Page 4 of 5 [EMBRYOLOGY] 1.02&3 FIRST AND SECOND WEEK OF DEVELOPMENT – Dr. La Paz L. Peredo, MD Performed by trained medical specialist and only if there a. Deformation is no other remedy b. Disruption Last choice of treatment c. Association d. Syndrome c. Stem cell transplantation and Gene therapy 3. What supplement prevents neural tube defects? Still under research a. Vitamin B1 hematopoietic stem cells or progenitor germ cells are b. Vitamin B6 used c. Vitamin B9 d. Vitamin B12 d. Fetal transfusion 4. What drug can cause phocomelia or limb defects, heart In cases of fetal anemia produced by maternal malformations, and amelia (total absence) or meromelia (partial antibodies or other causes, blood transfusions for the absence of extremities) when taken during pregnancy? fetus can be performed. Ultrasound is used to guide a. Topamax insertion of a needle into the umbilical cord vein, and b. Thalidomide blood is transfused directly into the fetus. c. Valproic acid d. Amphetamines *NEVER FORGET THIS ONE: 5. Over ⅓ of reproductive women experience this phase prior conception that puts risks such as neural tube and heart defects to the infant. a. Pre-pregnancy obesity b. Pre-pregnancy malnutrition c. Pre-pregnancy diet d. Pre-pregnancy excessive weight training 6. What kind of unprohibited activity during pregnancy can cause intellectual disability in kids, which is also associated to Ventricular septal defect (VSD) or a hole in the heart? a. Smoking tobacco b. Alcohol intake c. Fat-soluble drug intake d. Excessive weight training 7. It is a morphological alteration of already formed structures, which can be produced by amniotic bands. a. Deformation b. Disruption c. Association d. Syndrome 8. What agents are pregnant mothers susceptible to if the anomaly is in the gene or if the mother was exposed to environmental Figure 10. The Menstrual Cycle. factors, there is a higher risk for the fetus to have a defect? a. Infectious agents b. Chemical agents REFERENCES c. Radioactive agents d. Teratogenic agents Sadler, T. W., et.al. (2019). Langman's medical embryology (14th ed.). Lippincott 9. During the maternal serum screening in the 30th week, the fetus Williams & Wilkins. secretes what protein to screen and test the fetus’ risks for having Katzung, B. G. (2017). Basic and clinical pharmacology (14th ed.). McGraw-Hill genetic or birth defects? Education. a. Steroid hormones Tagnawa Trans b. Beta Fetoprotein Images: c. Alpha Fetoprotein Pawar, N., Singh, A., Gupta, A., & Tanger, R. (1970, January 1). Figure 1 d. Glycoprotein from VACTERL association with left pulmonary agenesis in an infant: 10. It is an invasive technique that removes a sample cell from a Semantic scholar. undefined. Retrieved November 19, 2022, from pregnant mother’s amniotic fluid to screen whether the fetus has a https://www.semanticscholar.org/paper/VACTERL-association-with-left- genetic or chromosomal condition. pulmonary-agenesis-in-Pawar-Singh/89bdc218a3a85e1ac30daaa1c905 a. Chorionic villi sampling 1ca02c145e71/figure/0 b. Gene therapy Bull, M. J., & Author AffiliationsFrom the Division of Developmental c. Cordocentesis Pediatrics. (n.d.). Down syndrome: Nejm. New England Journal of d. Amniocentesis Medicine. Retrieved November 19, 2022, from https://www.nejm.org/doi/full/10.1056/NEJMra1706537 Answers: 1. A, 2. C, 3. C, 4. B, 5. A, 6. B, 7. B, 8. D, 9. C, 10. D TEST YOUR KNOWLEDGE 1. When is an unborn baby most at risk of developing birth defects? a. First trimester b. Second trimester c. Third trimester d. None of the above 2. It is a nonrandom appearance of 2 or more anomalies that occur together more frequently than by chance alone. Page 5 of 5