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1、1,CONGENITAL FETAL ANOMALIES,2,Terminology,Congenital means exist since birth,whether clinical evidences are obvious or not obvious.Anomaly means a deviation from the normal.Malformation means faulty development of a structure,3,Types of congenital anomalies:Physical structural defects:Single struct
2、ure is affected.Multiple structures are affected.Non-structural defectsInherited metabolic defectsFunctional and behavioral deficits e.g.congenital mental retardation.,Incidence:Major congenital anomalies:affects about 2 to 5%of all newborns.Minor anomalies occur in higher percentage of newborn(abou
3、t 10%).The risk of recurrence of congenital malformations with the same patient is very important in genetic counseling.Most of congenital anomalies are single primary developmental anomalygeneral empirical average figure of 2 to 5%,to the apparently known healthy parents with one affected child.Mor
4、e accurate figures could be calculated only when the etiology is due to a defect in a single gene and according to the laws of inheritance e.g.hemophilia,4,Etiology of Congenital Anomalies,Unknown cause(60%):The causes of malformations are not identifiable in the majority of cases.Multifactorial fac
5、tors(20%):Multifactorial etiology denotes the presence of an interaction between genetic predisposition and non-genetic intrauterine factors.Common examples include neural tube defects,certain forms of hydrocephaly,facial clefts,cardiac anomalies,and imperforate anus.,5,Genetic basis:Thousands of kn
6、own genetic diseases that may affect humans as all inherited disordersAre passed from one generation to another.Genetic diseases may be secondary to either of the following:Secondary to a single mutant genes(7.5%):Mendelian single gene disorders that carries a risk of causing congenital malformation
7、s.Autosomal dominant and recessive disorders:About 3000 disorders are inherited in humans due to single gene disorder.e.g Hemoglobinopathies.sickle cell disease,thalassemia&Renal disorders:polycystic kidney disease.Sex chromosomal traits(X-linked diseases):There is no male to male transmission e.g.h
8、emophilia,muscular dystrophy.,6,Secondary to chromosomal anomalies(6%).Abnormality of chromosome number(numerical abnormalities):Triplicate number of portion or an entire chromosome:clinically-Autosomal abnormalities:e.g.Trisomies e.g.trisomy 21,18 and 13.Trisomy 13 and 18 are fatal.-Sex chromosome
9、anomalies:The most common are Turners syndrome(45,X),Kleinfelters syndrome(47,XXY).Monosomies:Single number of chromosome:monosomy X.e.g.X-linked mental retardation(fragile X syndrome).Abnormality of chromosome structure:Deletions,translocations,inversions.,7,Exogenous influences Teratogen exposures
10、:Teratogenesis mostly occurs before the tenth week of intrauterine life(the period of embryogenesis).,Intrinsic insults:Maternal infections:rubella virus,cytomegalovirus,toxoplasmosa gondi,human parovirus B19 infection,and syphilis.Noninfectious systemic e.g.diabetes mellitus,phenylketonuria,and sei
11、zure disorders.Functional virilizing lesions of the ovary and adrenal glands.,Extrinsic insults:Environmental agents:organic solvents,pesticides,anesthetic gases and heavy metals like lead,lithium,and organic mercury.Drug exposure and medications:Examples of known human teratogenic medications:Hormo
12、nal agents:Progesterone,androgenic hormones causing masculinization of the female fetus and thyroid and antithyroid drugs.Thalidomide causing phocomelia and other limb congenital malformations.Physical injury:Exposure to high doses of ionizing radiation produces gene mutation,chromosomal aberrations
13、 and abnormalities.,8,The Food and Drug Administration“FDA”lists five categories of tabling for drug use in pregnancy Controlled studies in women failed to demonstrate a risk to the fetus in the first trimester,and the possibility of fetal harm appears remote.Animal studies do not indicate a risk to
14、 the fetus,there are no controlled human studies,or animal studies do show an adverse effect on the fetus,but well controlled studies in pregnant women have failed to demonstrate a risk to the fetus.Studies have shown the drug to have animal teratogenecity or embryocidal affects,but no controlled st
15、udies are available in either animals or women.Positive evidence of human fetal risk exists,but benefits in certain situations(e.g.,serious diseases for which safer drugs are ineffective)may make use of the drug acceptable despite its risks.Studies in animals or humans have demonstrated fetal anomal
16、ies and the risk clearly outweighs any possible benefit.,9,10,Prevention Of Having An OffspringWith Congenital Anomalies,11,I.General guidelines:Control of medications during pregnancy:Minimize drug exposure.Detection and control of relevant maternal diseases.Genetic counseling.Prenatal diagnosis of
17、 genetic conditions and selective termination of the affected pregnancy or in-utero treatment if possible.Discourage consanguineous marriages when appropriate e.g.closed family,previous inheritable malformation in the family.,12,Pre-Pregnancy Assessment,Genetic counseling:A pre-pregnancy information
18、 given to couples with family history of congenital and inherited disorders,helping them to make a decision regarding future childbearing.The correct advice provides accurate information concerning the recurrence risks.General screening programs:The aim is to identify some of the common genetic diso
19、rders in a community.Adult screening programs in selected high-risk groups:Common examples of autosomal recessive disorders:sickle cell anemia,thalassemia major.Gravidas over 35 years:Cytogenic studies on fetal cells obtained by amniocentesis or chorionic villus sampling.Neonatal screening programs:
20、Some of the disorders that are in needs for immediate identification after delivery and to be screened soon after delivery are phenylketonuria,congenital hypothyroidism,sickle cell disease and galactosemia.,13,Pre-natal Diagnostic Procedures,History TakingAbnormal findings during routine examination
21、Abnormal findings during routine investigationsSpecific Antenatal diagnostic procedures,14,History Taking,leading questions of special significance:Maternal age.Personal or family history of congenital anomalies e.g.familial disorders in the blood relatives.The ethnic origin.Significant maternal dis
22、eases:diabetes mellitus,infections,and acute maternal illness.,15,Suspicious Findings On Clinical Examination,A higher incidence of congenital anomalies are detected in association with:Oligohydramnious:renal dysplasia,renal agenesis,bladder outlet obstruction and intrauterine growth retardation.Pol
23、yhydramnios:Central nervous system anomalies:anencephaly,hydrocephaly.Gastrointestinal malformations:Tracheoesophageal fistula,duodenal atresia.Threatened abortion.Unexplained IUGR.,16,Suspicious Findings On Routine Investigations,Suspicious findings on ultrasound screening:Early IUGRIUGROligohydram
24、niosHydramniosRestricted fetal movements,17,Abnormal maternal serum alpha-fetoprotein(MSAFP),MSAFP is elevated(2.5 MOM)Fetal anomalies such as neural tube defects,abdominal wall defects e.g.omphalocele,esophageal or intestinal obstruction,cystic hygroma,urinary obstruction,renal anomalies:polycystic
25、 kidneys,osteogenesis imperfecta,Turners syndrome,and Rh disease.Obstetrical complications such as low birth weight,oligohydramnios,multifetal gestation.MSAFP is abnormally low(0.2 MOM)Chromosomal trisomies of the fetus.The values are low in only one third of Downs syndrome,Gestational trophoblastic
26、 disease,and fetal death.The triple test:Specified combinations of maternal serum assay of AFP,unconjugated oestriol(uE3)and hCG.Special tables are used to interpret the results.,18,19,Specific Prenatal Techniques,Non-invasive techniques:Malformation ultrasound scan2D Vs3D and 4D scansMRI.Invasive t
27、echniques:AmniocentesisChorionic villous sampling(CVS),Cordocentesis,Fetoscopy Tapping of fluid filled fetal structure e.g.collection of fetal urine for assessment of the renal function.,20,Anomaly Scans,Structural Assessment:Systematic documentation of the essential fetal anatomy:head,neck,chest,ab
28、domen,limbs,external genitalia,Assessment of amniotic fluid volume.The umbilical cord and its vessels.Measurements are calculated(Biometry):The most significant measurements are BPD(biparietal diameter),OFD(occipto-frontal diameter),HC(head circumference),and femur length.Serial measurements are use
29、d to evaluate the growth pattern of organs.,21,22,23,Amniocentesis,It is the most frequently and the established invasive procedure to be performed.The samples contain:Fetal somatic cells that can identify the cytogenetic constitution of the fetus.Fluid that can be used to assess variety of biochemi
30、cal processes.Indications of amniocentesis Chromosomal abnormality,open neural tube defect,inborn error of metabolism.,24,12 weeks,14 weeks,16 weeks,40 ml,100 ml,185 ml,25,26,27,Fetal Loss0.5%Failed Amino.1.0%Culture Failure0.5%,Problems,28,Chorionic Villous Sampling(CVS),The aim is to obtain chorio
31、nic cells(fetal in origin)for laboratory study.Advantages of(CVS)over amniocentesis:Fetal cells could be obtained at an earlier gestational age.Lengthy culture procedures are unnecessary,as chorion cells divide very rapidly.A decision for termination,if necessary,could be taken at an earlier stage o
32、f pregnancy with greater safety and less legal and religious concerns.,29,30,31,CVS-Complications,Fetal loss 1%Unsuccessful CVS 1 5%(Depends on operator experience and accessibility of placenta)Ambiguous results/maternal cell contamination 1-2%Culture failure 1-2%,32,Factors Affecting Rate ofFetal L
33、oss Following CVS,Experience of operatorNumber of attemptsTime of samplingManipulation requiredRoute of CVSWho Report 1991,33,PercutaneousUmbilical Cord Blood Sampling Cordocentesis,The aim is to obtain fetal blood,using ultrasound directed needling of the umbilical cord.The needle is directed to en
34、ter an umbilical vessel at the cord root.Possible indications of cordocentesis:Diagnostic:Fetal karyotype.Other blood tests:Coagulation factors,hemoglobin composition,blood cells and platelets,Respiratory gases.Cases with isoimmunization:Fetal blood type and Rh status,coombs antibody testing,complet
35、e blood cell countTherapeutic:Transfusion of compatible donor blood.Fetal Loss in 1%of the cases.,34,Laboratory Investigative Procedures,Chromosome analysis:simple cytogenic techniques special culture and examination for minor chromosome aberrations Biochemical analysis:Bilirubin in rhesus isoimmuni
36、zation:normally it is excreted in fetal urine.Microvillar enzymes from the fetal gut for cystic fibrosis.Alpha-fetoprotein:nearly all of AFP is fetal in origin.,35,Laboratory Investigative Procedures,DNA analysis:Polymerase chain reaction(PCR)Chorionic villi.Amniotic fluid or fetal blood.Molecular g
37、enetics is the study of the structure of the genes.Its value in the obstetric practice is related to the study of inherited disease.Fetal Gender Determinationrisk of a serious X-linked hereditary disorders,for which no specific prenatal diagnostic test is readily available.The aim is termination of
38、pregnancy if the fetus is of the exposed type of the X-linked disorder.Fetal infectionTesting either the amniotic fluid or the chorionic villi or fetal blood.Testing for possible fetal viral infection is indicated in cases of maternal virus infection.Hematological analysis:haemoglobinopathies,coagul
39、ation disorders,and fetal blood grouping,36,What to Do when a CFA is Discovered?,Termination of pregnancy:Cultural background and religious beliefs play a role in the decision,Indicated with malformations incompatible with life to e.g.anencephaly,and multiple malformations with poor prognosis.,Couns
40、eling,37,What to Do when a CFA is Discovered?,Prenatal therapy or surgery,available for few conditions only:Medical treatment:Intrauterine heart failure and supraventricular arrhythmias:maternal medication of digoxin and propranolol.Congenital adrenal hyperplasia:dexamethasone to the mother to reduc
41、es accumulation of androgenic steroids and to lessens virilization of female fetus.Surgical treatment:Isoimmune anemias:(e.g.due to Rhesus disease)In utero treatment by intravascular or intraperitoneal transfusion.Obstructive hydrocephalus:attempts at intrauterine ventriculo-amniotic shunts are bein
42、g tested.Urinary tract obstruction:implanting a catheter from the fetal bladder to the amniotic cavity.Gene therapy:still experimental.,Counseling,38,What to Do when a CFA is Discovered?,Planning the best circumstances for delivery.Congenital anomalies requiring urgent surgical procedures and specia
43、l care after delivery:Gastrointestinal tract obstruction:pyloric stenosis,esophageal atresia,intestinal atresia,duodenal atresia,jejuno-ileal atresia,colonic atresia,ano-rectal malformations.Urinary tract obstruction.Congenital diaphragmatic hernia.Exomphalos and extrophy(bladder cloaca).Open neural
44、 tube defects.Congenital adrenal hyperplasia.,Counseling,39,Postnatal Diagnosis Of Congenital Fetal Malformations,Many cases of congenital malformation,even in the current obstetric practice are detected only after delivery.Routine examination of all newborns immediately after birth and few days lat
45、er is essential component in the routine practice.,40,Some Congenital Fetal Anomalies,Anomalies of the Nervous SystemAnomalies of the GITAnomalies of the Genito-urinary TractCardiovascular AnomaliesAnterior Abdominal wall defectsDiaphragmatic herniaDowns Syndrome Non Immune Hydrops Fetalis,41,Preven
46、tion of CNS Anomalies,Correction of dietary habits:Certain dietary patterns are deficient in folic acid,and need to be modified.Peri-conceptional folate administration.Peri-conceptional control of DM Special tests during pregnancy in high-risk individuals for early detection of such anomalies.,42,An
47、encephaly,Anencephaly is a lethal anomaly due to the absence of The membrane-ossifying bones of the cranial vault and consequently the skull and scalp.The cerebral hemispheres,underlying the above structuresIt is more common in girls.Antenatal diagnosis:Clinical features:Polyhydramnios and abdominal
48、 palpation(absence of head).Investigations:Raised plasma and amniotic fluid-fetoprotein levels and ultrasound features.Management of anencephalic pregnancy:Elective abortion.Vaginal delivery:there is an increased incidence of face presentation and shoulder dystocia,43,44,Hydrocephalus,Hydrocephalus
49、is an excess of cerebrospinal fluid within the ventricles,and the subarachnoid space.Congenital cerebral malformations:e.g.Arnold-Chiari malformation.Congenital fetal infections e.g.toxoplasmosis,cytomegalovirus.Intrauterine intracranial hemorrhage.Certain forms are multifactorial origin.Obstruction
50、 of the aqueduct of Sylvius which may be due to genetic disorders as trisomy 21,infection as toxoplasmosis and cytomegalovirus,intracranial tumors,and intracerebral hemorrhage.Chromosomal abnormalities:triploidy,trisomy 18,and X-linked trait.,45,Antenatal diagnosis of hydrocephalus:Clinical:Polyhydr
