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Malformatiile congenitale - istoric si actualitate

de dr. Eduard Crauciuc
medic primar obstetrica-ginecologie, doctor in stiinte medicale, Clinica a III-a Obstetrica-ginecologie, Spitalul "Elena Doamna" Iasi-Romania, Universitatea de Medicina si Farmacie "Gr.T.Popa"

www.crauciuc.rosau e-mail:crauciuc@xnet.ro





      Malformatiile congenitale au atras atentia din cele mai vechi timpuri, in special atunci cand se manifestau prin modificari morfologice neobisnuite. Stau marturie numeroase documente istorice, precum si reprezentari care sugereaza asocierea cu malforma]iile congenitale. Particularitatea unui punct de vedere cultural-istoric in ceea ce priveste malformatiile congenitale consta in faptul ca, prin intermediul unor documente din trecut si studiate in prezent, putem sa reconstituim drumul unei evolutii stiintifice, care a fost pentru teratologie deosebit de anevoios. Astfel am aflat despre erori si confuzii, care au trebuit eliminate, pentru ca omenirea sa poata renunta prin convingere si probitate stiintifica la reprezentarile fantastice si superstitioase.
      Teratologia (gr. theras - monstru) este stiinta care se ocupa de studiul malformatiilor congenitale, care reprezint\ anomalii structurale macroscopice care pot fi atribuite unei dezvoltari defectuoase intrauterine, prezenta si la nastere.
       Anomaliile congenitale includ nu numai defectele macroscopice, ci si cele microscopice, erori de metabolism innascute, retard mintal, anomalii celulare si moleculare etc. Sunt minore sau majore, unice sau multiple.
      De fapt, istoria teratologiei este o parte a istoriei culturii, cu numeroase puncte de legatura cu arta veche si medievala. Amintim in acest sens:
      1. Reprezentari fantastice: Ganesh - patronul negustorilor la indieni.;
      2. Reprezentari reale: diferite tipuri de oameni dubli: placute de ceramica din Babilon
      3. De la 1416 i.c. s-au descoperit documente sanscrite, scrieri ale lui Aristotel si Hipocrat, pasaje in Biblie care descriu malformatii; la 100 d.c. Galen a descris morfologia fatului; in Coran apar referiri la malformatii la 600 d.c.
      Renasterea implica o orientare a artelor catre legile anatomiei si modelele anticilor. Apare o colaborare intre oamenii de stiinta ai vremii si marii artisti: Marc Antonio della Torre si Leonardo da Vinci, Johann Stephan von Calcar si Andreas Vesalius, Michelangelo, Raffael, Paracelsus. In sec XV Leonardo da Vinci a efectuat masuratori embrionare si a reprezentat fatul in uter. In bibliotecile universitare din Oxford si Berlin au fost descoperite desene reprezentand malformatii inca din secolul XVI: autosid cu cap parazit si un pygopagus - Oxford 1552; gemeni uniti dorsal si ventral, dicephalus tribrachius, dicephalus dibrachius - Berlin 1554.
      In 1512 s-a descoperit un desen apartinand lui Durer reprezentand copii malformati. La Berlin se descopera scheletul unui dicefal toracopag. Profesorul Gert Horst Schumacher publica in cartea: "Monster und Damoned" Univ. Berlin - un exemplu de gigantism :"Anton cel lung" . In acelasi volum sunt descrise anomalii frecvente intalnite in obstetrica, datand din 1889: jonc]iune cranio-median\; thoracopagus; craniopagus frontalis; pygopagus; dicephalus dibrachius dipus; thoracopagus.
      Prezentam si cateva celebritati care au prezentat malformatii. In Siam - Thailanda - se nasc in 1811 gemeni uniti xiphosternopagi - fratii Chang si Eng, casatoriti la 32 ani; Chang va avea 6 copii, Eng - 5 copii; ajung si in instanta pentru neintelegeri; au decedat in 1874 (la varsta de 63 ani), dupa ce Chang se imbolnaveste de bronhopneumonie.
      Prevalena malformatiilor reprezinta studiul statistic al noilor -nascuti vii sau morti ce prezinta o anumita anomalie:
      - majora : 1,5 - 2,5 % din totalul nasterilor ( alti autori: 3-7%);
      - minore: 6-15%;
      - 1/5 - 4/5 din sarcini se pierd prin avort spontan datorita aberatiilor cromozomiale;
      o 10% an primele 5 saptamani;
      o 75% la sfarsitul embriogenezei;
      o 15% pana la termen.
      - 80% din totalul sarcinilor anormale se pierd an stadiul de embrion;
      - 18% din cei normali se pierd prin avort spontan;
      - avortul spontan reduce mult numarul fetilor malformati;
      - incidenta reala se pare ca este ceva mai mare.
      Distributia anomaliilor congenitale in raport cu factorii etiologici implicati:
      (Beckman, Brent 1986) se prezinta astfel :Defecte cromozomiale sau care implica o singura gena: 20-25%;
      1. Infectii congenitale (citomegalia, rubeola, toxoplasmoza, lues): 3-5%;
      2. Afectiuni ale mamei (alcoolism, diabet, epilepsie etc.): 4%;
      3. Droguri si medicamente cu efect teratogen:
<1%. Wilson (1959) a formulat urmatoarele principii:
      1. Este considerat agent teratogen orice factor care, actionand asupra produsului de conceptie, induce anomalii permanente ale formei sale.
      2. Susceptibilitatea unui embrion fata de agentii teratogeni depinde de stadiul de dezvoltare pe care l-a atins in momentul agresiunii. Susceptibilitatea este maxima in perioada de embriogeneza.
      3. Fiecare agent patogen prezinta o actiune particulara asupra metabolismului celular. Acelasi agent patogen poate induce efecte diferite in functie de perioada de dezvoltare. Agenti diferiti pot induce efecte similare daca ac]ioneaza in acelasi moment al dezvoltarii.
      4. Fenotipul tinde sa influenteze gradul afectarii teratogene.
      5. Un agent ce poate determina malformatii creste incidenta opririlor in evolutie ale sarcinilor.
      6. Un agent teratogen poate fi neutru pentru organismul mamei (rubeola).
      7. Gestatia include 3 perioade: ovulara (fecundatie-implantare); embrionara (s.2-8); fetala (dupa s. 8 de sarcina). Perioada embrionara este cu maxima susceptibilitate fata de actiunea agentilor teratogeni - perioada organogenezei.
      Agentii potential teratogeni sunt:
      1. Medicamentele: thalidomida, antagonisti de acid folic, izomeri ai Vit. A, unii steroizi sexuali(dietilstilbestrol).
      2. Agentii infectiosi: citomegalovirus, rubeola, lues, toxoplasma.
      3. Unele afectiuni ale mamei: alcoolism, boli cronice ale tesutului conjunctiv, diabet, hipotiroidia, tumori ovariene virilizante.
      4. Radiatii ionizante. (> 15-20 razi).
      5. Unele substante chimice: metilmercurul, ierbicidele.
      Medicamentele si drogurile ocupa primul loc intre agentii teratogeni.
      FDA (Food and Drugs Administration) - a impartit medicamentele si drogurile `n 5 categorii:
      1. Cat. A - fara riscuri: vitamine si preparate de Fe;
      2. Cat. B - fara riscuri semnificative: B-lactaminele, macrolidele, metronidazolul, antifungicele, nitrofuranii, terbutalina, heparina, insulina, meclizina, antiprostaglandinice.
      3. Cat. C - nu exista suficiente date care sa probeze existenta efectelor adverse: antiastmatice, beta-blocante, digitalice, furosemid, chinidina, metil-Dopa, verapamil, acyclovir, clorpromazina.
      4. Cat. D - riscurile administrarii in cursul sarcinii sunt mai mici decat beneficiile: citostaticele, anticonvulsivantele, barbituricele, antiinflamatoarele, amitriptilina, diazepamul, litiul, fenotiazinice, progesteronii.
      5. Cat. X - riscuri embrio-fetale probate si care depasesc orice beneficii: izoretinoina, unii antagono[ti ai acidului folic, hormonii steroizi (dietilstilbestrolul, estroprogestativele), clomifenul, thalidomida.
      Malformatiile congenitale reprezinta un capitol important din patologia prenatala, obstetricianul avand un rol activ atat in diagnosticarea precoce prenatala a unei posibile malformatii, cat si in determinarea riscului de recurenta in familiile afectate. Malformatiile congenitale, majore sau minore, pot fi incompatibile cu viata (intrauterina sau postnatala), pot fi tolerate, corectabile total sau partial, prezente de la nastere sau descoperite mai tarziu. Malformatiile majore sunt cele cu implicatii chirurgicale, estetice sau functionale si cu risc vital crescut. Malformatiile minore sunt cele fara implicatii chirurgicale, estetice sau functionale. Proportia malformatiilor creste cu varsta prin diagnosticarea formelor latente. Majoritatea malformatiilor sunt izolate pe diferite aparate si sisteme si au o etiologie multifactoriala. Restul sunt asociate (plurimalformatii) si au o etiologie genetica.
      Specificitatea teratogena depinde de capacitatea de metabolizare si neutralizare a agentilor teratogeni, varsta gestationala critica fiind primele doua luni. In transmiterea multifactoriala nu se cunosc exact: modul de transmitere la descendenti, natura factorilor de mediu sau numarul de gene implicate. Frecventa si recurenta malformatiilor cu transmitere multifactoriala este mult mai rara decat in cazul bolilor cu alt mod de transmitere.
      Rolul sfatului genetic este de a informa genitorii cu privire la cauza malformatiei, evolutia ulterioara a nou-nascutului si a riscului de deces, precum si posibilitatea corectiei chirurgicale. Este foarte importanta informarea genitorilor asupra diagnosticului prenatal si a riscului de recurenta .
      Recunoasterea si evaluarea factorilor de risc materno-fetali implicati in decesul perinatal este importanta si pentru medicul de familie, in scopul dispensarizarii si alegerii unei alternative favorabile ca evolutie si prognostic pentru mama si fat.





      Congenital malformations have raised great interest since the old times, especially if they are represented by unusual morphological changes. In this respect, there are numerous historical documents, as well as representations which suggest the association with congenital malformations. The particularity of a cultural-historic point of view, as concerns congenital malformations, consists in reconstructing - with the help of documents from the past studied in the present - a scientific evolution, and this reconstruction process was quite difficult for teratology. It was in this way that we learned about errors and mistakes, which needed eliminating in order for mankind to be able to give up, by means of scientific evidence, any superstitious and fictional representations.
      In fact, the history of teratology is a part of the history of culture, with many connections to old and medieval art.
      The teratology (gr. theras - "monster") is the science concerned with the study of congenital malformations, of their manifestations and occurrence, as well as of the mechanisms of prenatal abnormal developme knowledgment of congenital malformations, they are structural macroscopic anomalies which may account for a defective intrauterine development, present at birth as well.
       Congenital anomalies: they include not only macroscopic defects, but also the microscopic ones, such as innate metabolic faults, mental retard, cellular and molecular anomalies, and so on. They may be minor or major, unique or multiple.
      Soma examples:
      1. Fictional representations: Ganesh - the Indian merchants' patron.;
      2. Real representations: different types of double people: ceramic plates of Babylon ;
      3. In 1416 B.C. were discovered Sanskrit documents, writings of Aristotle and Hippocrates, fragments in the Bible which describe malformations; in 100 A.D., Galen described the morphology of the foetus; in the Koran there are references to malformations in 600 A.D.
      The Renaissance implies the orientation of the arts towards the laws of anatomy and models of the ancient. The scientists of the time and the great artists establish relationships of collaboration: Marc Antonio della Torre and Leonardo da Vinci, Johann Stephan von Calcar and Andreas Vesalius, Michelangelo, Raffael, Paracelsus. In the 15th century, Leonardo da Vinci made embryonic measurement and drew a foetus in the uterus. In the university libraries of Oxford and Berlin were discovered drawings of malformations ever since the 16th century: a parasitic craniopagus twin and a pygopagus - Oxford 1552; twins with dorsum and ventrum conjunctions, dicephalus tribrachius, dicephalus dibrachius - Berlin 1554.
      In 1512 a drawing of Durer was discovered, representing malformed infants. In Berlin was discovered the skeleton of a dicephalus thoracopagus. Professor Gert Horst Schumacher published, in his "Monster und Damoned" - Berlin University, an example of gigantism: "Long Anton" . In the same volume are described frequent anomalies in obstetrics, since 1889: median-cranial junction; thoracopagus; craniopagus frontalis; pygopagus; dicephalus dibrachius dipus; thoracopagus.
      Celebrities with malformations: in 1811, in Siam (Thailand) were born Chang and Eng, conjoined twins (xiphosternopagus). Married at 32, Chang would have 6 children, and his brother, Eng - 5 children; they would even go to court, eventually, for certain misunderstandings; they died in 1874 (at 63 years old), as a result of Chang's contracting bronchopneumonia.       The prevalence of malformations is represented by the statistic study of new-borns, either living or stillborn, that present a certain anomaly:
      - major: 1.5 - 2.5 % of the total number of births (according to other authors, 3 - 7%);
      - minor: 6 - 15%;
      - 1/5 - 4/5 of the pregnancies are miscarried as a result of chromosomal aberration;
      o 10% - in the first 5 weeks;
      o 75% - at the end of the embryogenesis;
      o 15% - up to the 9th month.
      - 80% of abnormal pregnancies are miscarried in the embryonic stage;
      - 18% of the normal pregnancies are lost by miscarriage;
      - miscarriage reduces greatly the number of malformed foetuses;
      - apparently, the real incidence seems to be higher.
      The distribution of congenital anomalies in connection to the etiologic factors involved (Beckman, Brent 1986):
      1. Chromosomal defects or defects which imply a single gene: 20-25%;
      2. Congenital infections (CMV, rubella, toxoplasmosis, syphilis): 3-5%;
      3. Health problems of the mother (alcoholism, diabetes, epilepsy, and so on): 4%;
      4. Drugs and medicaments with teratogenic effects:
       <1%. Wilson (1959) formulated the following principles:
      1. A teratogen is represented by any agent which, acting on the embryo or foetus, induces permanent anomalies to its form.
      2. The susceptibility of an embryo to teratogens depends on the stage of development which it reached at the time of the aggression. Susceptibility is at its fullest during embryogenesis.
      3. Every pathogenic agent presents a particular action on cellular metabolism. The same pathogenic agent may induce different effects depending on the stage of development. Different agents may induce similar effects if they act at the same stage of development.
      4. Phenotype tends to influence the degree of the teratogens' damage.
      5. An agent which may determine malformations increases the incidence of evolution stops in pregnancies.
      6. A teratogen may be neutral to the mother's organism (rubella).
      7. Gestation includes 3 periods: ovulary (fecundation-implantation); embryonic (week 2-8); foetal (after the 8th week of pregnancy). The embryonic period is of susceptibility maximum to the action of teratogens - the period of organogenesis.
      The Potentially teratogenic agents are:
      1. Medicaments: thalidomide, antagonists of folic acid, isomers of vitamin A, certain sexual steroids (diethilstilbestrol).
      2. Infectious agents: CMV, rubella, syphilis, toxoplasma gondii.
      3. Some problems of the mother: alcoholism, chronic diseases of the conjunctive tissue, diabetes, hypothyroidism, virilizante ovarian tumours.
      4. Ionised radiations (> 15-20 rads).
      5. Some chemical substances: methilmercury, herbicides.
      FDA (Food and Drugs Administration) - classified medicaments and drugs into 5 categories:
      1. Cat. A - no risks: vitamins and iron (Fe) preparations;
      2. Cat. B - no significant risks: B-lactamines, macrolides, metronidazole, fungal antagonists, nitrofurans, terbutaline, heparin, insulin, meclizine, prostaglandin antagonists.
      3. Cat. C - there is no sufficient data to prove the existence of side effects: antiasthmatics, beta blockers, digitalin derivatives, furosemide, quinidine, methildopa, verapamil, acyclovir, chlorpromazine.
      4. Cat. D - the risks of administration during pregnancy are smaller than the benefices: cytostatics, anticonvulsives, barbiturice, antiinflammatory drugs, amitriptyline, diazepam, lithium, phenotyazines, progesterones.
      5. Cat. X - embryonic and foetal proven risks which surpass any benefices: isoretinoin, certain antagonists of the folic acid, steroid hormones (diethylstilbestrol, conjugated estrogens and progestins), clomifene, thalidomide.
      Congenital malformations represent an important chapter in prenatal pathology, as the obstetrician plays an active role both in the precocious prenatal diagnosis of a possible malformation, and in determining the risk of recurrence in the affected families. Congenital malformations, major or minor, may be incompatible with life (intrauterine or postnatal), may be tolerated, totally or partially correctable, present from birth or discovered later. Major malformations are those with surgical, aesthetic or functional implications and with increased vital risk. Minor malformations are those without any surgical, aesthetic or functional implications. The proportion of malformations increases with age by the diagnosis of latent forms. The majority of malformations are isolates on different apparata and systems and have a multifactorial aetiology. The rest are associated (plurimalformations) and have a genetic aetiology.
      The teratogenic specificity depends on the metabolising and neutralising ability of the teratogens, the gestational age being critical during the first two months. In multifactorial transmission, the following facts are not known precisely: the manner of transmission to descendants, the nature of the environmental factors or the number of genes involved. The frequency and recurrence of malformations with multifactorial transmission is much rarer than in the case of diseases differently transmitted.
      The role of the genetic advice is to inform the genitors on the cause of the malformation, on the later evolution of the new-born and on the risk of death, as well as on the surgical correction possibilities. It is very important to inform the genitors on the prenatal diagnosis and on the risk of recurrence. The acknowledgment and assessment of the maternal and foetal risk factors involved in perinatal death are also important to the GP, to the purpose of hospitalisation and choice of a favourable alternative regarding the evolution and prognosis for both mother and infant.

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