EMBRYOLOGY OF THE TWINS AND TERATOLOGY dr RB

EMBRYOLOGY OF THE TWINS AND TERATOLOGY dr. RB. Soeherman H M. Kes

THE TWINS I. Dizygotic Twins II. Monozygotic. Twins III. Conjoined Monozygotic. Twins

I. Dizygotic Twins -Fraternal twins = heterolog -They may or may not have different sex -The individual members have no more resemblance than brothers or sisters of ages different -They result from simultaneous shedding of two oocytes and the fertilization by two different spermatozoa

-Both zygotes implant individually in the uterus and each develops its own placenta, its own amnion, and its own chorionic sac -Sometimes, however, the two placentas are located so close together that fusion occurs -Similarly the walls of the chorionic sacs may also come into close apposition and fuse

II. Monozygotic Twins - Uniovuler = identical twins = homolog twins -They result from the splitting of the zygote at various stages of development - The earliest separation occur at two cell stage both blastocysts implant separately and each embryo has its own placenta and chorionic sac

- In most case the splitting of the zygote occurs at the early blastocyst stage - In rare cases, the separation occurs at the stage of the bilaminar germ disc just before the appearance of the primitive streak - Some times large anastomoses cause circulatory disturbances, resulting in one large and one small partner

- Blood groups, fingerprint, sex and external appearance such as eye and hair color are the same - Have a common placenta and common chorionic cavity, but separate amniotic cavity

Conjoined monozigotic twin -If the embryonic disc does not devide completely or adjacent embryonic discs fuse, various types of conjoinned MZ twins may form. Parasitic twins: small bowel with right lower limb in parasitic twin. Parasitic fetus: lower limb and pelvis attached to the thorax of infant Dicephalic(two head) conjoined twin

-The partners of monozygotic twins are connected to each other only by a common skin bridge or by a common liver bridge (Siamese twins)

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TERATOLOGY CONGENITAL MALFORMATION

• Teratology: the study of birth defects, their causes and investigations pertaining to both structural and behavioral abnormalities • The incidence: 0. 75 to 1. 98 % in studies of official records and birth certificates • When compared with data from hospital and clinic birth records, variation of 1. 43 to 3. 3 % are probably more accurate.

THE CAUSE OF CONGENITAL MALFORMATIONS • I. Enviromental factors • II. Chromosomal and genetic factors I. Enviromental factors A. Infectious Agents 1. Rubella or German Measles German measles affecting pregnant women in the early stages of gestation could lead to congenital malformations in the offspring

• Rubella virus can cause malformations of the: - eye (cataract and microphthalmia) - internal ear (congenital deafness due destruction of the organ of Corti) - heart (PDA: persistence of the ductus arteriosus as well as atrial and ventricular septal defects: VSD) - and occasionally of the teeth (enamel layer) • The virus may also be responsible for some cases of brain abnormalities and mental retardation

¬ Virus also causes IUGR (intrauterine growth retardation), myocardial damage, and vascular abnormalities ¬ The type of malformation is determined by the stage of embryonic development at which infection occurs: * Cataracts result from infection during the 6 th week of pregnancy * Deafness from infection during the 9 th week of pregnancy

* Dental deformities between the 6 th and 9 th weeks * Abnormalities of the central nervous system follow infection in the 2 nd trimester * Cardiac defects follow infection in the 5 th to 10 th weeks

2. Cytomegalovirus - The congenital cytomegalic inclusion disease is the result of a human cytomegalovirus infection acquired in utero from an asymptomatically infected mother - The principal findings of the infection are: microcephaly, cerebral calcifications, blindness and chorioretinitis, and hepatosplenomegaly

- Initially the disease was recognized only at autopsy and was based on the presence of enlarged cells, with large nuclei containing giant inclusion bodies - The inclusion bodies in cells lining of renal tubules, and may be present in the urine - When the embryo is affected at an early stage of development the damage is so severe that it is unable to survive

3. Herpes Simplex Virus -The infection is transmitted close to the time of delivery, and the abnormalities are: microcephaly, microphthalmos, retinal dysplasia, hepatosplenomegaly and mental retardation -The child acquires the infection from the mother at birth as a venereal disease and the symptoms of the disease then develop during the first 3 weeks of age

4. Other Viral Infections and Hyperthermia - Malformations following maternal infections with measles, mumps, hepatitis, poliomyelitis, chickenpox, ECHO, Coxsackie, and influenza virus have been described - The other infectious agents is that most are pyrogenic and increased body temperature (hyperthermia) has been implicated as a teratogen

5. Toxoplasmosis -The affected child may have cerebral calcification, hydrocephalus, or mental retardation -The disease is usually unrecognized in pregnant women

6. Syphilis -In the offspring syphilis may lead to congenital deafness and mental retardation -Organs such as the lung and liver are characterized by diffuse fibrosis

B. Radiation - Treating pregnant women with large doses of roentgen rays or radium cause malformations: microcephaly, skull defects, spina bifida, blindness, cleft palate and defects of the extremities - The nature of the malformation depends on the dose of radiation and the stage of development at which the radiation is given

-The offspring of Japanese women pregnant at the time of the atomic bomb explosions over Hiroshima and Nagasaki revealed that among the survivors: - 28 % aborted, - 25 % gave birth to children who died in their 1 st year of life, and - 25 % of the surviving children had abnormalities of the central nervous system

C. Chemical Agents 1. Thalidomide - An antinauseant and sleeping pill - The defects produced by thalidomide are absence or gross deformities of the long bones: amelia and meromelia (total or partial absence of the extremities), intestinal atresia and cardiac abnormalities

2. Aminopterin - This compound belongs to the antimeteabolites and an antagonist of folic acid - It has been used during early pregnancy to induce therapeutic abortion in women suffering from tuberculosis - The defects are anencephaly, meningocele hydrocephalus, and cleft lip and palate

3. Anticonvulsants - Diphenylhydantoin (phenytoin) and trimethadion, which are used by epileptic women - Teratogenic potential - The major malformations such as: - heart abnormalities, - facial clefts, and - microcephaly

- Specifically, diphenylhydantoin produces broad spectrum of abnormalities, includimg - craniofacial defects, - nail and digital hypoplasia, - growth abnormalities and mental deficiency - These defects constitute a distinct pattern of dysmorphogenesis known as the “fetal hydantoin syndrome”

4. Trimethadione - Used in treatment of petit mal seizures - Teratogenic - These drugs produced a characteristic pattern of abnormalities including: - malformed ears, - cleft palate, - cardiac defects, - urogenital and skeletal anomalies which are collectively referred to as the “trimethadione syndrome”

5. Antipsychotic and antianxiety agents Antipsychotic agents: - phenothiazine and lithium: teratogens - High risk if these agents are used during pregnancy Antianxiety agents: - diazepam (Valium), chlordiazepoxide and Meprobamate, - increase in cleft lip with or without cleft palate in offspring from mothers taking the drug during pregnancy

A number of other compounds which might be damaging to the embryo or fetus: - Propylthiouracil and potassium iodide (goiter and mental retardation), - Streptomycin (deafness), - Sulfonamides (kernicterus), - Imipramine, antidepressant (limb deformities) - Tetracyclines (bone and tooth anomalies),

- Amphetamines (oral clefts and cardiovascular abnormalities), - Walfarin, anticoagulant (chondrodysplasia and microcephaly) and - Quinine (deafness) - Aspirin (salicylates), the most commonly ingested drug during pregnancy, is potentially harmful to the developing offspring when used in large doses

6. The increasing problems in todays society is the effect of social drugs such as - LSD (Lysergic acid diethylamide), - PCP( Phencyclidine, angel dust ), - Marijuana, alcohol and cocaine. In the case of LSD, limb abnormalities and malformations of the central nervous system have been reported - The heavy smoking during pregnancy causes small babies

The defects of maternal alcohol ingestion: - Craniofacial abnormalities (short palpebral fissures and hypoplasia of the maxilla ), - Limb deformities (altered joint mobility and position), and - Cardiovascular defects (ventricular and septal abnormalities) Together with mental retardation and growth deficiency, make up the “fetal alcoholic syndrome”

7. Isotretinoin (13 -cis-retinoic acid) acid - an analogue of vitamin A - the drug is prescribed for the treatment of cystic acne and other chronic dermatoses - but it is highly teratogenic - been shown to cause a pattern of malformations as the “isotretinoin or vitamin A embryopathy”

D. Hormones 1. Androgenic agents - The synthetic progestins which are frequently used during pregnancy to avert abortion - Ethisteron and norethisterone have considerable androgenic activity, and many cases of masculinization of the genitalia in female embryos - The abnormalities consisted of an enlarged clitoris associated with varying degrees of fussion of the labioscrotal folds

2. Diethylstilbestrol - A synthetic estrogen, was commonly used to prevent abortion - Increased incidence of carcinoma of the vagina and cervix following exposure to the drug in utero - A high percentage of these exposed women suffer from reproductive dysfunction which appears to be due in part to congenital malformations of the uterus, uterine tubes, and upper vagina

-Male embryos exposed in utero can also be affected, as evidenced by an increase in malormation of the testes, and abnormal sperm analysis -In contrast to females, males do not demonstrated an increased risk of developing carcinomas of the genital system

3. Cortisone In experiment: Cortisone injected into mice and rabbit at certain stages of pregnancy causes a high percentage of cleft palates in the offspring 4. Maternal diabetes - Disturbances in carbohydrate metabolism during pregnancy in diabetic mothers cause a high incidence of stillbirths, neonatal deaths, abnormally large infants, and congenital malformations

- A variety of malformations have been observed, including: - cardiac, skeletal and central nervous system anomalies - skeletal defects also occur and consist of partial or complete agenesis of sacral vertebrae in conjunction with hindlimb hypoplasia

- If women with previous histories of congenital defects and indications of disturbed carbohydrate metabolism were treated with insulin or thyroid, or both, subsequent pregnancies resulted in fewer miscarriages, stillbirth, and infants with congenital malformations

E. Nutritional deficiencies - Endemic cretinism, which is related to maternal iodine deficiency have been found in humans F. Hypoxia - Children born at relatively high altitudes are usually lighter in weight and smaller than those born near or at sea level - Women with cyanotic cardiovascular disease often give birth to small infants, but usually without gross congenital malformations

G. Enviromental Chemicals: organic mercury In Japan: - The fish contained an abnormally high level of organic mercury, which was spewed into Minamata Bay, and other coastal water of Japan by large industries A number of mothers with diets consisting mainly of fish had given birth to children with multiple neurological symptoms resembling cerebral palsy

In the United States: - when seed corn sprayed with a mercurycontaining fungicide was fed to hogs, and the meat was subsequently eaten by a pregnant women several thousand babies were affected

Actions of Teratogens 1. The stage of embryonic development determines the susceptibility to teratogenic factors. 2. The effect of a teratogenic factor depends on the genotype. 3. A teratogenic agent acts in a specific way on a particular cell metabolism.

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