November 16, 1995 Hundreds of thousands of times a year a single-celled zygote, smaller than a grain of sand, transforms into an amazingly complex network of cells, a newborn infant. Through cellular differentiation and growth, this process is completed with precision time and time again, but very rarely a mistake in the "blueprint" of growth and development does occur. Following is a description of how the pathways of this intricate web are followed and the mistakes which happen when they are not. The impressive process of differentiation changes a single-cell into a complicated system of cells as distinct as bold and bone. Although embryonic development takes approximately nine months, the greatest amount of cellular differentiation takes place during the first eight weeks of pregnancy. This period is called embryogenesis. During the first week after fertilization, which takes place in the Fallopian tube, the embryo starts to cleave once every twenty-four hours (Fig. 1). Until the eight or sixteen cell stage, the individual cells, or blastomeres, are thought to have the potential to form any part of the fetus (Leese, Conaghan, Martin, and Hardy, April 1993). As the blastomeres continue to divide, a solid ball of cells develops to form the morula (Fig. 1). The accumulation of fluid inside the morula, transforms it into a hollow sphere called a blastula, which implants itself into the inner lining of the uterus, the endometrium (Fig. 1). The inner mass of the blastula will produce the embryo, while the outer layer of cells will form the trophoblast, which eventually will provide nourishment to the ovum (Pritchard, MacDonald, and Gant, 1985). Figure 1:Implantation process and development during embryogenesis (Pritchard, MacDonald and Gant, 1985) During the second week of development, gastrulation, the process by which the germ layers are formed, begins to occur. The inner cell mass, now called the embryonic disc, differentiates into a thick plate of ectoderm and an underlying layer of endoderm. This cellular multiplication in the embryonic disc marks the beginning of a thickening in the midline that is called the primitive streak. Cells spread out laterally from the primitive streak between the ectoderm and the endoderm to form the mesoderm. These three germ layers, which are the origins of many structures as shown in Table 1, begin to develop. Table 1: Normal Germ Layer Origin of Structures in Some or all Vertebrates (Harrison, 1969) Normal Germ Layer Origin of Structures in Some or All Vertebrates Ectoderm Mesoderm Endoderm Skin epidermis Hair Feathers Scales Beaks Nails Claws Sebaceous, sweat, and mammary glands Oral and anal lining tooth enamel Nasal epithelium Lens of the eye Inner earBrainSpinal cordRetina and other eye partsNerve cells and gangliaPigment cellsCanal of external earmedulla of the adrenal glandPituitary gland Dermis of the skinConnective tissueMusclesSkeletal componentsOuter coverings of the eyeCardiovascular system Heart Blood cells Blood vesselsKidneys and excretory ductsGonads and reproductive ductsCortex of the adrenal glandSpleenLining of coelomic cavitiesMesenteries LiverGall bladderPancreasThyroid glandThymus glandParathyroid glandsPalatine tonsilsMiddle earEustachian tubeUrinary bladderPrimordial germ cellsLining of all organs of digestive tract and respiratory tract During the third week of development, the cephalic (head) and caudal (tail) end of the embryo become distinguishable. Most of the substance of the early embryo will enter into the formation of the head. Blood vessels begin to develop in the mesoderm and a primitive heart may also be observed (Harrison, 1969). Cells rapidly spread away from the primitive streak to eventually form the neural groove, which will form a tube to the gut. When the neural folds develop on either side of the groove, the underlying mesoderm forms segmentally arranged blocks of mesoderm called somite. These give rise to the dermis of the skin, most skeletal muscles, and precursors of vertebral bodies. the otocyst, which later becomes the inner ear, and the lens placodes, which later form the lenses of the adult eyes, are derived from the ectoderm. The strand of cardiovascular functioning is apparent during the fourth week. The heart shows early signs of different chambers and begins to pump blood through the embryo which simultaneously has well developed its kidneys, thyroid gland, stomach, pancreas, lungs, esophagus, gall bladder, larynx, nd trachea (Carlson, 1981). Several new structures are observed, organs continue developing, and some previously formed structures reorganize during the fifth week of embryogenesis. The cranial and spinal nerves begin to form and the cerebral hemispheres and the cerebellum are visible. The spleen, parathyroid glands, thymus gland, retina, and gonads, all new structures, also begin to form. The gastrointestimer tract undergoes considerable development as the middle part of the primitive intestine becomes a loop larger than the abdominal cavity. Next, it must then project into the umbilical cord until there is room for the entire bowel. Finally, the heart develops walls or atrial and ventricular septa and atriventricle cushion. These cushions thicken the junction of the atrium and ventricle. the atrial and ventricular septa meanwhile divide their respective chambers into right and left halves (Harrison, 1969). The sixth week is characterized by the completion of most organ formation. The embryo has a more identifiable human face with basic structure of the eyes and ears now developed. Hard and soft palates appear, the salivary glands begin to form, and there is an early differentiation of the cells that later develop into the teeth. Division of the heart is essentially completed and the valves begin to form. The primitive intestinal tract is divided into the anterior and posterior chambers that will later develop into the urinary bladder and the rectum, respectively. At the end of the week, the gonads are histologically recognizable as either testes or ovaries (Pritchard, MacDonald, and Gant, 1985). The embryo looks similar to miniature human when it enters the seventh week of embryogenesis. During this last week, the pituitary gland takes a definitive structure, the eyelids become visible, the last group of muscles begin to form, and bone marrow appears for the first time. the main concerns of this period are the different developments taking place in the male and female. This is first shown as the M llerian ducts degenerate in males, but continues to develop in females, where they will later differentiate to become the Fallopian tubes, the uterus and the inner part of the vagina. The Wolffian ducts degenerate in female embryos, but continue to develop into the ductus deferens in the male. Although the external genitalia continue to grow and develop, they are still unable to be visibly identified as male or female. By the end of this week the placenta begins to take on definite characteristics, and for the first time blood from the maternal circulation enters the placental circulation (Carlson,1981). After this period of embryogenesis the embryo is given the name fetus. The remainder of pregnancy is primarily concerned with growth and cellular differentiation, but during this period of growth, mistakes which can cause birth defects are still highly effective, as they were in the first seven weeks of development. What are some of these defects which begin during the first trimester of pregnancy and how are they caused? Obviously the process of a developing embryo and fetus is very complicated and although most of the babies born each year are free from any abnormalities, up to five percent of all newborn infants have congenital anomalies, birth defects (Cunningham, MacDonald, and Gant, July/August 1989). Seventy percent of birth defects are unknown spontaneous errors of development. Of the thirty percent which are known, twenty-five percent are associated with genetic factors that include major chromosomal defect and point mutations, three percent with venereal diseases such as syphilis and rubella, and two percent with teratogens, medications and drugs (Cunningham, MacDonald, and Gant, Feb./March 1991).
Spontaneous errors in development, whose causes are unknown, can happen in the central nervous system, face, gut, genitourinary system, and heart as shown in Table 2. The time during pregnancy which these may occur is also is also shown in Table 2 and ranges from twenty-three days to twelve weeks, all which fall into the first trimester. How these anomalies are triggered in birth defects is unknown. Neural Tube Defects, which causes are also unknown, are some of the most common defects and result in infant mortality or serious disability. These abnormalities include anencephaly, a malformation characterized by cerebral hemispheres that are absent, and spina bifida, an exposed , ruptured spine (Medicine, March 1993). TABLE 2. Relative timing and development of pathology of certain birth defects (Adapted from Cunningham, MacDonald and Gant, February/ March 1991). Birth defects by area Time limit Central Nervous System Closure of anterior neural tube Closure in a portion of posterior neural tube 26 days28 days Face Closure of lip Fusion of maxillary palatal shelves resolution of branchial cleft 36 days10 weeks8 weeks Gut Lateral septation of foregut into trachea Lateral septation of cloaca into rectum and urogenital sinus Recanalization of duodenum Rotation of intestinal loop Return of midgut from yolk sac to abdomen Obliteration of vitelline duct Closure of pleuroperitoneal canal 30 days6 weeks7 to 8 weeks10 weeks10 weeks10 weeks6 weeks Genitourinary system Migration of infraumbilical mesenchyme Fusion of lower portion of M llerian ducts Fusion of urethral folds (labia minora) 30 days10 weeks12 weeks Heart Directional development of bulbous cordis septum ventricular septum closure 34 days6 weeks Limb Genesis of radial bone Separation of digital rays 38 days6 weeks Complex Prechordal mesoderm development Development of posterior axis 23 days23 days On the other hand the effects and consequences of teratogens are known. "A teratogen is any agent such as a medication or other systemically absorbed chemical or factor like hyperthermia, that produces permanent abnormal embryonic physical development or physiology (Cunningham, MacDonald, and Gant, Feb./March 1991). The embryonic period is most critical with respect to malformations because it encompasses organogenesis. Drugs and chemicals such as alcohol and organic mercury can cause mental retardation, while infection such as varicella, the chicken pox, can cause limb defects, neurologic anomalies, and skin scars (Baker, April 1990). A more complete list of drugs, chemicals and infections, and their effects are listed in Table 3. These type of birth defects are unique because abnormalities due to drugs and chemical exposure are potentially preventable (Cunningham, MacDonald, and Gant, Feb./March 1991). TABLE 3. Effects and comments of documented teratogens (ACOG Technical Bulletin, Feb.1985) Agent Effects Comments Drugs and Chemicals Alcohol Growth retardation, mental retardation, various major and minor malformations Risk due to ingestion of one or two drinks per day (1-2 oz) may cause a small reduction in average birth weight. Androgens Hermaphroditism in female offspring, advanced genital development in males Effects are dose dependent and related to stage of embryonic development. Depending on time of exposure, clitoral enlargement or labioscrotal fusion can be produced. Anticoagulants Hypoplastic nose, bony abnormalities, broad short hands with shortened phalanges, intrauterine growth retardation, deformations of neck, central nervous system defects Risk for a seriously affected child is considered to be 25% when anticoagulants that inhibit vitamin K are used in the first trimester. Antithyroid drugs fetal goiter Goiter in fetus may lead to malpresentation with hyperextended head. Diethylstilbestrol (DES) Vaginal adenosis, abnormalities of cervix and uterus in females, possible infertility in males and females Vaginal adenosis is detected in over 50% of women whose mothers took these drugs before the ninth week of pregnancy. Lead Increased abortion rate and stillbirths Central nervous system development of the fetus may be adversely affected. Lithium Congenital heart disease Heart malfunctions due to first trimester exposure occur in approximately 2%. Organic mercury Mental retardation, spasticity, seizures, blindness Exposed individuals include consumers of contaminated grain and fish. Contamination is usually with methyl mercury Isotrtinoin (Accutane) Increased abortion rate, nervous system defects, cardiovascular effects, craniofacial dysmorphism, cleft palate First trimester exposure may result in approximately 25% anomaly rate Thalidomide Bilateral limb deficiencies-days 27-40, anotia and microtia-days 21-27, other abnormalities Of children whose mothers used thalidomide, 20% show the effect. Trimethadione Cleft lip or cleft palate, cardiac defects, growth retardation, mental retardation Risks for defects or spontaneous abortion is 60-80% with first trimester exposure. Valproic acid Neural tube defects Exposure must be prior to normal closure of neural tube during first trimester to get open defect. Infections Rubella Cataracts, deafness, heart lesions, plus expanded syndrome including effects on all organs Malformation rate is 50% if mother is infected during first trimester. Varicella possible effects on all organs including skin scarring and muscle atrophy Zoster immune globulin is available for newborns exposed during last few days of gestation. Chromosomal abnormalities, the leading cause of birth defects, develop during meiotic division in the gonad, the organ which produces sex cells. A chromosome may drop out of the dividing cell and thus be lost. Fertilization of this type of gamete results in a zygote with a missing chromosome. If the gamete fails to split equally at meiotic division and the cell with the extra chromosome is fertilized, the zygote becomes trisomic (Pritchard, MacDonald, and Gant, 1985). Down Syndrome, the most common chromosomal defect, results from an extra chromosome (trisomy 21). Less common is chromosomal translocation defect. Translocation is the transfer of a segment of one chromosome to a different site on the same chromosome or to a different chromosome (Pritchard, MacDonald, and Gant, 1985). Many other syndromes, their chromosomal complement, and signs of these syndromes which are recognizable at birth are shown in Table 4. TABLE 4. Findings in established chromosomal abnormalities in man (Pritchard, MacDonald, and Gant, 1985) Syndrome Chromosomal Complement Signs Recognizable at Birth Turners 45 / X Lymphangiectatic edema of hands and feet Klinefelters 47 / XXY None Triple X 47 / XXX None YY 47 None Downs trisomy 21 47 Mongoloid facies, Simian line Translocation 46 Same Trisomy 13 - 15 47 Cleft palate, Harelip, Eye defects, Polydactyly Trisomy 16 - 18 47 Finger flexion, Lowest ears, Digital arches Cat cry 46 (Deletion B 5) Cat cry, Moon face During the first trimester of prgnancy, an embryo must correctly make its way through a complex matrix of differentiation and development to become a normal infant. When something does go wrong, the embryo or fetus will unfortunately have some type of defect. The amazing accuracy with which a single cell can become something as complex as a newborn infant is a truley incredible feat! Works Cited Baker, David A. "Danger of Varicella-Zoster Virus Infection." Contemporary OB/GYN April 1990: 52. Carlson, Bruce M. Patten's Foundations of Embryology. McGraw-Hill Inc. 1981. Cunningham, MacDonald, and Gant. Williams Obstetrics, Supplement no. 10. 18th ed, Prentice-Hall, Inc. Februay/March 1991: 2,3. "Folic Acid for the Prevetion of Recurrent Neural Tube Defect." Medicine March 1993. Harrison, Ross G. Organization and Develpment of the Embryo. Yale University Press. 1969. Leese, Conaghan, Martin, and Hardy. "Early Human Embryo Metabolism." Bio Essays vol. 15, No. 4 April 1993: 259. Pritchard, MacDonald, and Gant. Williams Obstetrics. 17th ed, Prentice-Hall, Inc. 1985: 139-142, 800. Pritchard, MacDonald, and Gant. Williams Obstetrics, Supplement no. 13. 17th ed, Prentice-Hall, Inc. July/August 1987: 2. "Teratology." ACOG Technical Bulletin February 1985.