DEVELOPMENT AND MALDEVELOPMENTGAMETOGENESIS pptx

55 GAMETOGENESIS The production of ova and sperm occurs via the process of meiosis (whereas somatic cells undergo division via mitosis). Oogene- sis produces ova, and spermatogenesis produces sperm. One sper- matogonium results in four sperm, and one oogonium results in one ovum and two polar bodies. Meiosis is a reduction division nor- mally allowing each gamete to contain 23 chromosomes (haploid). Thus, when fertilization occurs and the two haploid gametes unite, the resulting zygote contains 46 chromosomes (diploid) under normal circumstances. Two meiotic divisions occur, and each contains several stages. FIRST MEIOTIC DIVISION A. Prophase I has five stages. 1. Leptotene, wherein the chromatin condenses into individual elongated threadlike structures. 2. Zygotene, the migration of single threadlike chromosomes toward the nuclear equatorial plate where homologous chromosomes pair to form bivalents that exchange segments at several points (synapses). 3. Pachytene, where chromosomes contract and thicken, then split longitudinally into two chromatids attached at the centromere. 4. Diplotene is marked by crossing-over of the nonidentical chromatid constituents of homologous chromosomes at bridges or chiasms. The male sex chromatids (X and Y chromatids), however, do not cross over. 5. Diakinesis, the last stage, which occurs when the bivalents contract, chiasms move toward the ends of the 3 DEVELOPMENT AND MALDEVELOPMENT CHAPTER Copyright 2001 The McGraw-Hill Companies. Click Here for Terms of Use. BENSON & PERNOLL’S 56 HANDBOOK OF OBSTETRICS AND GYNECOLOGY chromosome, homologs pull apart, and the nuclear membrane disappears. B. During metaphase I, the very short and thick bivalents are aligned along the equatorial plate of the cell spindle forms. C. In anaphase I, the centromeres divide so that the homologous chromatids (rather than the identical sister chromatids) are drawn to opposite poles of the spindle. D. Telophase I is marked by spindle breakage, division of cellu- lar cytoplasm, and formation of a nuclear membrane. The cell cytoplasm is equally divided in the male but is unequally distributed in the female. In the latter, most of the cytoplasm goes to the secondary oocyte so that basically only nuclear material becomes the first polar body, which subsequently disintegrates. SECOND MEIOTIC DIVISION A. Metaphase II reveals new spindle forms, and the chromosomes align along the equatorial plate. B. In anaphase II, the chromatids pull apart to opposite poles of the spindle, with complete division of the centromere. C. Telophase II entails the division of the spindle and cell cytoplasm (again equally in the male and unequally in the female), forming one ovum and the second polar body. Secondary oocyte development arrests at metaphase II until pen- etration by a sperm. Then meiosis is completed, and the polar body is discarded. FETAL MALDEVELOPMENT TERMINOLOGY A chromosome is the paired basic structure containing the genes in a linear arrangement. Humans have 23 pairs of chromosomes (46 total), of which 22 pairs are autosomes and 1 pair (either XX or XY) determine the individual’s sex. A locus is a gene’s specific site on a chromosome. A gene is a sequence of chromosomal nucleotides that forms the production code for specific proteins, that is, unit of genetic information. Alleles are different genes that occupy the same position on homologous chromosomes and potentially affect a similar function. Heterozygous refers to dissimilar members of a gene pair, and homozygous refers to similar members of a gene pair. A dominant characteristic is recognized when the phenotypic effect of the gene is the same in the heterozygous state as in the homozygous state. In contrast, a recessive characteristic is one that is only produced in the homozygous state. The genotype is the genetic makeup of the individual and is expressed with the number, then the sex chromosomes, then any specific defects (e.g., 45,XO; 46,XX; 47,XY,21ϩ). The pheno- type is the physical appearance of the individual with his or her various observed characteristics. The abbreviation p is used for the short arm of chromosomes and q for the long arm (as determined from the chromosome’s centromere). Homologous means the same relative position and is often applied to chromosomes and genes. A mutagen is an agent (e.g., physical, chemical) that induces genetic mutation. Mutations involve macromolecular or micromolec- ular change in germ cell DNA and are a permanent transmissible alteration. A teratogen is an agent (or factor) that causes defects in the developing organism. Teratogenic changes may be caused by mutations or by a number of other processes. In utero development is divided into three phases. The ovular phase comprises the first 4 weeks after fertilization. This period is characterized by rapid mitotic divisions, resulting in a blastula. At 5–7 days after fertilization, the products of conception, now characterized by development of the blastocyst and separation into mi- croscopically discernible body pole and preplacental zones, implant into the endometrium. Gastrulation begins, and the organ anlagen are relatively positioned. From the 5th through the 8th weeks of pregnancy, the conceptus is termed the embryo. This is the period of organ differentiation. From the 9th week until delivery, the conceptus is termed a fetus. Only a few new structures develop after the 8th week. Thus, the fetal period is principally concerned with differentiation, growth, and maturation (Table 3-1). Developmental age (fetal age) is the age of the offspring calculated from the date of conception. This may be important to embryologists but is rarely used by obstetricians or pediatricians, who are especially concerned with gestational age, that is, the calculated age of the fetus from the first day of the LMP (as- suming a 28-day cycle). Gestational age is expressed in completed weeks. CONGENITAL DEFECTS Congenital anomalies (birth defects, malformations) are significant, usually deleterious, deviations from normal standards of structure CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 57 BENSON & PERNOLL’S 58 HANDBOOK OF OBSTETRICS AND GYNECOLOGY TABLE 3-1 TIME OF INSULT AND POTENTIAL MALFORMATION Developmental Age (Weeks) Malformation 3 Ectromelia Ectopia cordis Omphalocele Sympodia 4 Ectromelia Hemivertebra Omphalocele Tracheoesophageal fistula 5 Carpal or pedal ablation Cataract (nuclear) Facial clefts Hemivertebra Microphthalmia Tracheoesophageal fistula 6 Agnathia Carpal or pedal ablation Cataract (lenticular) Cleft lip Congenital heart disease Aortic anomalies Gross septal defects Microphthalmia 7 Brachycephaly Cleft palate Congenital heart disease Ventricular septal defects Pulmonary stenosis Digital ablation Epicanthus Micrognathia 8 Brachycephaly Congenital heart disease Digital stunting Epicanthus Nasal bone ablation Persistent ostium primum and function. In the United States, the incidence of congenital anomalies recognizable at birth is 3%–7%. With careful longitudinal follow-up, however, the incidence may reach 10%. The impact of congenital defects on human life is immense. Abnormalities are the single major cause of infant mortality (Ͼ20% of all infant deaths). Added to the impact of these deaths is the lost potential and ex- pense to society involving damaged survivors. Practitioners are most often questioned about congenital defects arising from the following situations: the gravida exposed to a potentially fetotoxic agent, the family that has had an anomalous infant, parents with a previous abnormal offspring or pregnancy loss, or a couple with a known defect who want to reproduce. Although it is not the purpose of this text to provide all the information in detail or the skills necessary to function as a counselor in these circumstances, it is our purpose to describe certain broad principles that may be of value in caring for these patients. CREATION OF A DEFECT Criteria for the recognition of a defect-creating agent include the following. ● An abruptly increased incidence of a particular defect or association of defects (syndrome). ● A known environmental alteration coincident with the increase in a particular defect. ● Evident exposure to the environmental alteration at a stage of pregnancy (usually early) that yields characteristic defect(s). ● Absence of other factors that might create the same abnor- mality. NATURE OF THE INSULT Causes of some defects are known (% of total): chromosomal aberrations or recognized genetic transmission (23%–25%), drugs and environmental agents (4%–5%), infections (2%–3%), and maternal metabolic aberration (1%–2%). However, the cause remains un- known for 60%–70% of all anomalies. KNOWN GENETIC TRANSMISSIONS (MENDELIAN INHERITANCE DISORDERS) Known genetic transmissions (ϳ20%) are the largest single ascer- tainable contributors to mutagenic and teratogenic defects. CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 59 BENSON & PERNOLL’S 60 HANDBOOK OF OBSTETRICS AND GYNECOLOGY Roughly half of these conditions can be described by their mendelian inheritance patterns (i.e., autosomal dominant, autosomal recessive, or sex-linked). The chance of an offspring inheriting a characteristic can be determined by the rules of each inheritance pattern. Autosomal Dominant With autosomal dominant inheritance, a mutation in one gene of an allelic pair results in a different phenotypic expression or characteristic. The phenotypic expression of this characteristic (pene- trance) can vary with environmental or other genetic influences (e.g., with recombination). Examples of autosomal dominant conditions include achondroplasia, color blindness (yellow–blue), Ehlers-Danlos syndrome, Huntington’s chorea, Marfan’s syndrome, mitral valve prolapse, neurofibromatosis, adult polycystic renal disease, and Von Willebrand’s disease. The rules of autosomal dominant inheritance follow. ● The characteristic appears with equal frequency in both sexes. ● At least one parent must have the characteristic (unless it is a new mutation). ● Homozygous-normal mating results in all offspring having the characteristic. ● Heterozygous-normal matings result in 50% of the offspring having the characteristic. ● If it is a rare trait, most individuals demonstrating the characteristic will be heterozygous. Autosomal Recessive With autosomal recessive inheritance, one affected gene of an allelic pair is insufficient to evoke a phenotypic expression of the characteristic (i.e., different from the normal). With homozygos- ity, however, the characteristic appears. Environment and genetic influences may affect the expressivity of the defect in the carrier state. Examples of autosomal recessive conditions include al- binism, chondrodystrophy, myotonia, color blindness (total), cystic fibrosis, dysautonomia, galactosemia, Gaucher’s disease, homocystinuria, phenylketonuria, sickle cell anemia, Tay-Sachs disease, Wilson’s disease, and mucopolysaccharidosis I-H, I-S, III IV, VI, and VII. The rules of autosomal recessive inheritance follow. ● The characteristic occurs with equal frequency in both sexes. ● For the characteristic to be present, both parents must be carriers. ● If both parents are homozygous, all offspring will have the characteristic. ● If both parents are heterozygous, offspring will have the characteristic in the following distribution: 25% not affected, 50% carrier (heterozygous), 25% with the characteristic (homozygous). ● Frequent occurrence of rare recessive characteristics is often related to consanguineity. X-Linked Recessive When a gene on the X chromosomes is affected, but it is unable to evoke the characteristic if heterozygous, it is said to be X-linked recessive. However, the characteristic is expressed in males because of their single X chromosome. Examples of X-linked recessive conditions include androgen insensitivity syndromes (both complete and incomplete), color blindness (red–green), G-6-PD deficiency, gonadal dysgenesis, hemophilia A and B, Lesch-Nyhan syndrome, and mucopolysaccharidosis II. The rules of X-linked recessive inheritance include the following. ● The characteristic occurs primarily in males. ● If both parents are unaffected but produce a male with the characteristic, the mother is a carrier. ● If the father is affected and there is an affected male offspring, the mother must be at least heterozygous for the characteristic. ● A female with the abnormal characteristic may acquire it by the following: Inheritance of the recessive gene from both her mother and father (father affected, mother heterozygous), Inheritance of the recessive gene from one of her parents and expression occurs as a result of the Lyon hypothesis (functional selection of one X chromosome for this and subsequent progeny). X-Linked Dominant If a gene on the X chromosome is affected and able to produce the characteristic in the heterozygous state, it is said to be X-linked dominant. Examples of X-linked dominant conditions include cer- vicooculoacoustic syndrome, hyperammonemia, and orofaciodigi- tal syndrome I. The rules of X-linked dominant inheritance follow. ● The characteristic affects males and females with equal frequency. ● Affected male–normal female mating results in 50% affected offspring. ● Affected homozygous female–normal male mating results in all offspring being affected. CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 61 BENSON & PERNOLL’S 62 HANDBOOK OF OBSTETRICS AND GYNECOLOGY ● Heterozygous female–normal male mating results in 50% affected offspring. ● Heterozygous females may not demonstrate the dominant characteristic (see Lyon hypothesis). MULTIFACTORIAL INHERITANCE Multifactorial or polygenic inheritance is the inheritance of a characteristic as a result of the interaction of numerous genes and the environment. Such inheritance cannot be classified according to mendelian principles. It is, however, extremely important in normal inheritance (e.g., human physical features) as well as many common malformations (e.g., anencephaly, cleft palate, meningomye- locele, and pyloric stenosis). That the defects are inheritable is discerned from incidence. That is, the defects noted occur with a frequency of 0.5–2/1000 in Caucasians but occur in 2%–5% of sib- lings of affected infants with normal parents. That the abnormalities are not entirely environmental is discerned from concordance (a higher frequency of such abnormalities in monozygotic than dizy- gotic twins, e.g., the defects are 4–8 times more common in monozygotic twins.) CHROMOSOME ABNORMALITIES IN NUMBER AND MORPHOLOGY Chromosomal aberrations are alterations in both number and morphology. They account for 3%–5% of all human anomalies mani- fest at birth. The numerical disorders probably most commonly occur during meiosis as a result of failure of the doubled chromosomal complement to be equally divided between the two daughter cells (nondisjunction). When subsequently recombined with a normal gamete, this results in one zygote having an extra chromosome (trisomy) and another with a missing chromosome (monosomy). Autosomal monosomy is almost always lethal. If the monosomy occurs in the sex chromosomes, however, Turner’s syndrome (45,XO) results. Most of these individuals are spontaneously aborted, but some survive. Autosomal trisomy may occur with all chromosomes, but most commonly results in trisomy 16, trisomy 21 (Down syndrome), trisomy 18, and trisomy 13. Again, most are aborted, but a few survive through advanced pregnancy. Sex chromosomal trisomy results in hyperploidy. Another etiology for chromosomal alteration of number and morphology is a parent who has an abnormal chromosomal constituency (e.g., balanced translocation carriers). Morphologic chromosomal defects may also relate to chromosomal breakage (e.g., Fanconi’s anemia). Nondisjunction occurring in the postzygotic interval leads to mosaicism (cell lines with different combinations of the same basic chromosomal constituency). Mosaicism, not infrequent, must be dif- ferentiated from chimerism (cell lines from two different chromosomal constituencies), which rarely, if ever, occurs in humans. Other defect etiologies (drugs and environmental agents, infections, and maternal metabolic imbalance) are discussed under “Specific Teratic Agents.” TIMING OF THE INSULT The stage of development when the insult occurs largely determines the potential adverse effect or malformation. For example, the free- floating zygote is probably less influenced by deleterious agents than it might be later. An insult that affects the zygote during this interval is most likely to result in abortion. Injury during the 2nd–7th weeks is marked by fetal wastage, structural malformations with time-related specific defects, carcinogenesis, or severe intrauterine growth retardation (Table 3-1). During weeks 9–40, should a defect occur the fetus may develop central nervous system anomalies, behavioral disorder, functional abnormalities, reproductive system defects, and intrauterine growth retardation. INTENSITY OF THE INSULT Most fetotoxic agents can be reduced to a level that is not harmful, and most relatively innocuous agents can be increased in dose to a lethal level. Thus, it is crucial to ascertain the dosage and the time over which the exposure occurred. Other considerations of dosage must include the nature of the agent and the available information (generally literature) concerning the agent’s mutagenic or teratogenic potential. HOST RESISTANCE MECHANISMS Whether or not exposure to a fetotoxic agent creates a defect in a particular situation is influenced by numerous factors: the interaction of the agent with the maternal organism (e.g., absorption, pen- etration, and elimination), transport to the fetus, interaction with the fetus (e.g., activation, inactivation, and excretion), and repara- tive phenomena (e.g., local host factors influencing outcome and genetic mechanisms potentially influencing outcome). CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 63 BENSON & PERNOLL’S 64 HANDBOOK OF OBSTETRICS AND GYNECOLOGY SPECIFIC TERATIC AGENTS PERINATAL INFECTIONS Pregnancy results in decreased maternal resistance to infection. Thus, the potential exists for both reactivation of latent infections and more severe sepsis should infection occur. The developing embryo and fetus are at greatest risk from infective agents during the first trimester, presumably as a result of limited capability for im- munologic response. Table 3-2 summarizes some specific infective agents and their potential perinatal or fetotoxicity. Additionally, the effect of various infective agents on the mother (e.g., fever, respiratory distress) can adversely affect the fetus either directly or in- directly (e.g., initiation of premature labor). DRUGS Despite recent attempts at reduction, the use of multiple prescription and nonprescription drugs during pregnancy continues. Ex- cluding vitamins and iron, the majority of women will take at least one prescription and several nonprescription drugs at some point in pregnancy. Too frequently, this occurs at a critical time, for example, before the diagnosis of pregnancy. The FDA has established categories of potential for drugs causing birth defects to guide drug usage during pregnancy (Table 3-3). Drug teratogenicity has such species specificity that it is diffi- cult to extrapolate data from one species to another. Thus, it may be impossible to fully test human teratogenicity in laboratory animals. Indeed, few of the large number of drugs reported to be teratogenic in laboratory animals have been proven to be human teratogens. Nonetheless, there are so many fetotoxic drugs that it is beyond the purpose of this text to detail them. Every physician and nurse, however, must become familiar with each drug they ad- minister using more complete sources. Table 3-4 includes examples of fetotoxic drugs in several categories. IONIZING RADIATION Ionizing radiation has long been known to have both mutagenic and teratogenic effects. The National Committee on Radiation Protec- tion has stated the amount of ionizing radiation believed to be relatively safe for the embryo is 10 rads. At Ͼ15 rads fetal exposure, there is suggestive evidence of an increased incidence of childhood leukemia by age 10. In contrast to older units, modern radiologic equipment has both vastly safer shielding and much lower expo- sures for imaging (e.g., a chest x-ray should not exceed 0.03 rad). [...]... bleeding) Clear cell carcinoma of the vagina and cervix, vaginal adenosis, cervical and vaginal ridges, cervical hoods, and uterine Androgens Anticonvulsant therapy Antineoplastic agents Antithyroid agents Amphetamines Benzothiadiazides Chloroquine Chlorpropamide Cocaine Coumarin (Warfarin) Diethylstilbestrol (Continued) BENSON & PERNOLL’S HANDBOOK OF OBSTETRICS AND GYNECOLOGY 70 TABLE 3-4 (Continued) Drug... Chickenpox or shingles, increased abortions and stillbirths, hydrocephalus, microcephaly, seizures, cataracts, microphthalmia, Horner’s syndrome, optic nerve atrophy, nystagmus, chorioretinitis, mental retardation, skeletal hypoplasia, urogenital anomalies Smallpox, increased abortions and stillbirths Microcephaly, hydrocephaly microphthalmia, CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 67 TABLE 3-2 (Continued)... ERYTHEMATOSUS (SLE) Maternal SLE increases the rate of abortion and can result in a perinate with cardiac arrhythmia, most notably complete heart block There are reported cases of congenital disseminated lupus in the newborn of affected mothers Thrombocytopenia may be present in the fetus and newborn of mothers with SLE CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 73 IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)... but benefits may outweigh risk (e.g., lifethreatening illness, no safer effective drug); patient should be warned Fetal abnormalities in animal and human studies; risk not outweighed by benefit Contraindicated in pregnancy B C D X CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 69 TABLE 3-4 FETOTOXIC DRUGS Drug Fetotoxicity Aminoglycosides 8th nerve defects, possible ocular damage Masculinization or pseudohermaphroditism... degenerative changes, eye defects, and congenital anomalies Fetal death, endocardial fibroelastosis, malformations (?) Spinal or bulbar poliomyelitis (Continued) BENSON & PERNOLL’S HANDBOOK OF OBSTETRICS AND GYNECOLOGY 66 TABLE 3-2 (Continued) Maternal Infection Rubeola Rubella Vaccinia Varicella zoster Variola Venezuelan equine encephalitis virus Fetotoxicity Increased abortions and stillbirth Growth retardation,... (especially caudal dysplasia) CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 71 TABLE 3-4 (Continued) Drug Fetotoxicity Phenothiazines Slight increase in malformations Facial anomalies, microcephaly, mental retardation, nail hypoplasia, growth retardation Neonatal jaundice if used in third trimester Stained teeth, do not use in second or third trimester Limb reduction anomalies Developmental delay, speech difficulty,...CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 65 TABLE 3-2 INFECTIONS WITH KNOWN PERINATAL OR FETAL TOXICITY Maternal Infection Coxsackie B virus Cytomegalovirus Hepatitis Herpes simplex virus Human immunodeficiency virus (HIV) Human parvovirus B19 Mumps Poliomyelitis Fetotoxicity Viruses Myocarditis Microcephaly, hydrocephaly, cerebral palsy, brain calcifications, chorioretinitis, deafness, psychomotor and mental... PERNOLL’S HANDBOOK OF OBSTETRICS AND GYNECOLOGY detected, the immediate concern is whether this fetus is in severe distress from asphyxia, requiring immediate delivery, or whether time is available for further evaluation and routine delivery Fetal echocardiography may determine whether or not there are associated cardiac defects or signs of congestive heart failure If congestive heart failure is present and. .. euglycemics The caudal regression syndrome is the most specific and rarely occurs except in diabetics Fetal blood glucose levels are approximately 80% of maternal levels Because insulin does not cross the placenta, the fetal pancreas produces insulin to attempt to regulate fetal blood glucose 72 BENSON & PERNOLL’S HANDBOOK OF OBSTETRICS AND GYNECOLOGY levels in the normal range Thus, the fetus responds... dystocia and delivery complications, especially birth injury The neonate born of a noncontrolled diabetic mother also has increased incidence of prematurity, respiratory distress syndrome, polycythemia, hyperbilirubinemia, hypomagnesemia, and hypocalcemia THYROID DISORDERS Maternal hyperthyroidism can result in fetal goiter formation The newborn can experience fatal thyrotoxicosis if unrecognized and untreated . normal standards of structure CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 57 BENSON & PERNOLL’S 58 HANDBOOK OF OBSTETRICS AND GYNECOLOGY TABLE 3-1 TIME OF INSULT AND POTENTIAL MALFORMATION Developmental Age. ascer- tainable contributors to mutagenic and teratogenic defects. CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 59 BENSON & PERNOLL’S 60 HANDBOOK OF OBSTETRICS AND GYNECOLOGY Roughly half of these. influencing outcome and genetic mechanisms potentially influencing outcome). CHAPTER 3 DEVELOPMENT AND MALDEVELOPMENT 63 BENSON & PERNOLL’S 64 HANDBOOK OF OBSTETRICS AND GYNECOLOGY SPECIFIC