Central nervous system dysfunction, including micro- micro-cephaly; mental retardation; and behavioral disorders,

such as attention deﬁcit disorder

The exact risk incurred by maternal alcohol use is difﬁcult to establish, because the complex pattern of symptoms asso-ciated with FAS can make diagnosis difﬁcult. Consumption of 8 or more drinks daily throughout pregnancy confers a 30% to 50% risk of having a child with FAS. However, even low levels of alcohol consumption (two or fewer drinks per week) have been associated with increased aggressive behavior in children.

Tobacco Use

The risks of smoking during pregnancy have been well-established and include risks to the fetus such as intrauterine growth restriction, low birth weight, and fetal mortality. It is important for the obstetrician to take advantage of the pre-natal visits to educate patients about the risks of smoking for both themselves and their newborns and to coordinate appropriate resources to help patients quit. Counseling pro-grams are available to help patients quit smoking. Nicotine replacement products may be considered, although their safety in pregnancy has not been documented.

Substance Abuse

The use of illicit substances by women of childbearing age has led to an increased number of neonates having had in utero exposure and subsequent risk of adverse effects from a variety of drugs. Fetal drug exposure often is unrecog-nized because of the lack of overt symptoms or structural anomaly following birth.

Illicit drugs may reach the fetus via placental transfer or may reach the newborn through breast milk. The spe-cific effect on the fetus and newborn varies with the respec-tive substances. An opiate-exposed fetus may experience withdrawal symptoms in utero if the woman stops or when the woman goes through withdrawal, either voluntarily or under supervision, or after birth when the delivery by way of the placenta ceases.

Universal screening, using biologic specimens, of women and newborns for substance abuse is not recom-mended. However, all pregnant women should be asked at their ﬁrst prenatal visit about past and present use of alcohol, nicotine, and other drugs, including recreational use of prescription and over-the-counter medications. Use of speciﬁc screening questionnaires may improve detection rates. A woman who acknowledges use of these substances should be counseled about the perinatal implications of their use during pregnancy, and offered referral to an appropriate drug-treatment program if chemical dependence is sus-pected. Careful follow-up during the postpartum period is also recommended.

COMMON SYMPTOMS Headaches

Headaches are common in early pregnancy and may be severe. The etiology of such headaches is not known.

Treatment with acetaminophen in usual doses is recom-mended and is generally adequate. A persistent headache unrelieved by acetaminophen should be further evaluated.

Edema

The presence of signiﬁcant edema in the lower extremi-ties (dependent edema) and/or hands is very common in pregnancy and, by itself, is not abnormal. Fluid retention can be associated with hypertension, however, so that blood pressure as well as weight gain and edema must be evaluated in a clinical context before the ﬁndings are pre-sumed to be innocuous.

Nausea and Vomiting

The majority of pregnant women experience some degree of upper gastrointestinal symptoms in the ﬁrst trimester of pregnancy. Classically, these symptoms are worse in the morning (the so-called morning sickness). However, Estimated Fetal Exposure From Some

Common Radiologic Procedures 6.7

T A B L E

Procedure Fetal Exposure

CT scan of abdomen and lumbar spine 3.5 rad Barium enema or small bowel series 2–4 rad

Intravenous pyelography ≥1 rad

CT scan of head or chest <1 rad

CT pelvimetry 250 rad

Hip film (single view) 200 rad

Abdominal film (single view) 100 cGy

Mammography 7–20 rad

Chest x-ray (2 views) 0.02–0.07 rad

Dental x-ray <0.01 rad

Magnetic resonance imaging 0

(Modified from American College of Obstetricians and Gynecologists. Precis: Obstetrics. 3rd ed. Washington, DC:

American College of Obstetricians and Gynecologists; 2005:14.)

patients may experience symptoms at other times or even throughout the day. Most mild cases of nausea and vom-iting can be resolved with lifestyle and dietary changes, including consuming more protein, vitamin B6, or vita-min B6with doxylamine. Usually, nausea and vomiting improve significantly by the end of the first trimester.

Effective and safe treatments for more serious cases include antihistamine H1-receptor blockers and phenothiazines. The most severe form of pregnancy-associated nausea and vom-iting is hyperemesis gravidum, which occurs in less than 2% of pregnancies. This condition may require hospitaliza-tion, with ﬂuid and electrolyte therapy and medications.

Heartburn

Heartburn (gastric reﬂux) is common, especially post-prandially, and is often associated with eating large meals or spicy or fatty foods. Patient education about smaller and more frequent meals and blander foods, combined with not eating immediately before retiring, is helpful.

Antacids may be helpful, used judiciously in pregnancy.

Constipation

Constipation is physiologic in pregnancy, associated with increased transit time, increased water absorption, and often decreased bulk. Dietary modifications, including increased fluid intake and increased bulk with such foods as fruits and vegetables, are usually helpful. Other useful interventions may include use of surface-active bowel softeners such as docusate, supplemental dietary fibers such as psyllium hydrophilic mucilloid, and lubricants.

Fatigue

In early pregnancy, patients often complain of extreme fatigue that is unrelieved by rest. There is no specific treatment, other than adjustment of the woman’s sched-ule to the extent possible to accommodate this temporary lack of energy. Patients can be reassured that the symp-toms disappear in the second trimester.

Leg Cramps

Leg cramps, usually affecting the calves, are common during pregnancy. A variety of treatments, including oral calcium supplement, potassium supplement, or tonic water have been proposed over the years, none of which are uni-versally successful. Massage and rest are often advised.

Back Pain

Lower back pain is common, especially in late pregnancy.

The altered center of gravity caused by the growing

fetus places unusual stress on the lower spine and asso-ciated muscles and ligaments. Treatment focuses on heat, massage, and limited use of analgesia. A specially fitted maternal girdle may also help, as will not wearing shoes with high heels.

Round Ligament Pain

Sharp groin pain, especially as pregnancy advances, is common, often quite uncomfortable, and disturbing to patients. This pain is often more pronounced on the right side because of the usual dextrorotation of the gravid uterus. The woman should be reassured that the pain represents stretching and spasm of the round ligaments.

Modiﬁcation of activity, especially more gradual move-ment, is often helpful; analgesics are rarely indicated.

Varicose Veins and Hemorrhoids

Varicose veins are not caused by pregnancy, but often ﬁrst appear during the course of gestation. Besides the disturb-ing appearance to many patients, varicose veins can cause an aching sensation, especially when patients stand for long periods of time. A support hose can help diminish the discomfort, although it has no effect on the appearance of the varicose veins. Popular brands of support hose do not provide the relief that prescription elastic hose can.

Hemorrhoids are varicosities of the hemorrhoidal veins.

Treatment consists of sitz baths and local preparations.

Varicose veins and hemorrhoids regress postpartum, although neither condition may abate completely. Surgical correction of varicose veins or hemorrhoids should not be undertaken for approximately the ﬁrst 6 months post-partum to allow for the natural involution to occur.

Vaginal Discharge

The hormonal milieu of pregnancy often causes an increase in normal vaginal secretions. These normal secretions must be distinguished from infections such as vaginitis, which has symptoms of itching and malodor, and bacterial vaginosis, which has been linked to preterm labor. Spontaneous rupture of membranes, which is characterized by leakage of thin, clear ﬂuid, is another possible cause that must be considered.

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7 Assessment of Genetic Disorders in Obstetrics and Gynecology

By acquiring a basic knowledge of reproductive genetics, the learner will be able to better understand patterns of inheritance, learn the principles of prenatal testing and its application to the diagnosis of fetal anomalies.

77 DNA molecule is “read” from one end (called the 5-prime [5′] end) to other end (called the 3-prime [3′] end). A mes-senger RNA (mRNA) molecule is formed that is exported from the cell nucleus into the cytoplasm. This mRNA contains a translation of the genetic code into “codons.”

Transcription is regulated by promoter and enhancer sequences. Promotor sequences guide the direction of translation, from 5′ to 3′, and are located on the 5′ end.

Enhancer sequences have the same function, but are found further down the 5′ end of the DNA molecule.

After transcription is complete, mRNA is used as a template to construct the amino acids that are the build-ing blocks of proteins. In this process, called translation, each codon is matched to its corresponding amino acid.

The amino acid strand grows until a “stop” codon is encountered. At this point, the now completed protein undergoes further processing and is then either used inside the cell or is exported outside the cell for use in other cells, tissues, and organs. Errors in the DNA replication process can occur in a variety of ways and lead to a mutation, a change in the normal gene sequence. Most DNA replica-tion errors are rapidly repaired by enzymes that proofread and repair mistakes.

Replication errors are of four basic kinds: (1) missense mutations, in which one amino acid is substituted for another; (2) nonsense mutations, in which premature stop codons are inserted in a sequence; (3) deletions;

and (4) insertions. An example of a replication error causing a recognized disease is Huntington disease, in which an abnormal number of CAG repeats occurs in the Huntington gene. DNA can also be damaged by environ-mental factors, such as ultraviolet light, ionizing radiation, or chemicals.

Chromosomes

The genetic information in the human genome is packaged as chromatin, within which DNA binds with several ecent discoveries in the ﬁeld of genetics have led to

the increased use of genetic principles and tech-niques in all areas of medicine, including obstetrics and gynecology. In obstetrics, prenatal screening is rou-tinely performed to detect genetic disorders such as Down syndrome and cystic ﬁbrosis. In gynecology, clinicians can offer appropriate genetic testing for women deemed at high risk for genes that increase the risk of breast, bowel, and ovarian cancers. In the future, genetic evaluation may lead to earlier and more accurate diagnosis of conditions such as diabetes. Gene-based therapies may also be used to treat diseases with greater speciﬁcity and fewer side effects than conventional treatments.

BASIC CONCEPTS IN GENETICS

Knowledge of the basic principles of genetics and an under-standing of their application are essential in current med-ical practice. These principles form the basis for screening, diagnosis, and management of genetic disorders.

Genes: Definition and Function

Genes, the basic units of heredity, are segments of deoxyri-bonucleic acid (DNA) that reside on chromosomes located in cell nuclei. DNA is a double-stranded helical molecule. Each strand is a polymer of nucleotides made up of three components: (1) a “base,” which is either a purine (adenine [A] or guanine [G]) or a pyrimidine (cytosine [C]

or thymine [T]); (2) a 5-carbon sugar; and (3) a phospho-diester bond. The strands of the DNA helix run in an antiparallel fashion, adenine binding to thymine and cyto-sine binding to guanine. These base pairs, in their nearly limitless combinations, constitute the genetic code.

The information in the DNA must be processed before it can be used by cells. Transcription is the process by which DNA is converted to a messenger molecule called ribonucleic acid (RNA). During transcription, the

R

chromosomal proteins to make chromosomes. A karyo-type reveals the morphology and number of chromo-somes. Somatic cells are all the cells in the human body that are not gametes (eggs or sperm). Germ cells, or gametes, contain a single set of chromosomes (n= 23) and are described as haploid in number. Somatic cells contain two sets of chromosomes, for a total of 46 chromosomes.

These cells are diploid, signifying that they have a 2n chro-mosome complement (2n = 46). These chromosome pairs consist of 22 pairs of autosomes, which are similar in males and females. Each somatic cell also contains a pair of sex chromosomes. Females have two X sex chromosomes;

males have an X and a Y chromosome.

CHROMOSOMEREPLICATION ANDCELLDIVISION

Chromosomes undergo two types of replication, meiosis and mitosis, which are signiﬁcantly different and produce cell types with crucially different capabilities. Mitosis is the replication of chromosomes in somatic cells. It is fol-lowed by cytokinesis, or cell division, that results in two daughter cells containing the same genetic information as the parent cell. Meiosis only occurs in germ cells. It is also followed by cytokinesis; but, in this case, cytokinesis results in four daughter cells with a haploid count.

Somatic cells undergo cell division based on the cell cycle. There are four stages of the cell cycle: G1, S, G2, and M. G1, or gap 1, occurs immediately after mitosis and is a period of inactivity with no DNA replication. During G1 all the DNA of each chromosome is present in the 2n form.

The next phase is S, or synthesis, where the chromosomes double to become two identical sister chromatids with a 4n chromosome complement. During G2, or gap 2, the cells prepare for mitosis. G1, S, and G2 are also called inter-phase, which is the period between mitoses.

Mitosis

The goal of mitosis is to form two daughter cells that have a complete set of genetic information. Mitosis is divided into ﬁve stages: prophase, prometaphase, meta-phase, anameta-phase, and telophase. During prophase the chro-matin swells, or condenses, and the two sister chromatids are in close approximation. The nucleolus disappears, and the mitotic spindle develops. Spindle ﬁbers start to form centrosomes, microtubule-organizing centers that migrate to the poles of the cell. In prometaphase the nuclear mem-brane vanishes and the chromosomes begin to disperse.

They will eventually attach to the microtubules that form the mitotic spindle. Metaphase is the stage of maximal condensation. The chromosomes are in a linear formation in the center of the cell, between the two spindle poles. It is during metaphase where cells can most easily be analyzed to obtain a karyotype from an amniocentesis or chorionic villus sampling (CVS). Anaphase is initiated when the two chromatids separate. They form daughter chromosomes that are drawn to opposite poles of the cell by the spindle ﬁbers. Finally, telophase is when the nuclear membrane starts to reform around the independent daughter cells, which then go into interphase (Fig. 7.1).

Meiosis

Meiosis differs from mitosis in that a haploid number of cells are initially produced in two successive divisions. The first division (meiosis I)is termed a reduction division, because of the resulting decrease in chromosome number from diploid to haploid. Meiosis I is also divided into four stages:

prophase I, metaphase I, anaphase I, and telophase I.

Prophase I is further divided into five substages: lep-totene, zygotene, pachytene, diplotene, and diakinesis.

In prophase I the chromosomes condense and become shorter and thicker. It is during the pachytene substage that crossing over takes place, resulting in four distinct gametes. However, it is during anaphase where most of the genetic variation occurs. In anaphase I the chromosomes go to opposite poles of the cell by independent assort-ment, signifying that there are 2²³, or >8 million, possi-ble variations. Anaphase I is also the most error-prone step in meiosis. The process of disjunction, where the chromo-somes go to opposite poles of the cell, can result in non-disjunction, where both chromosomes go instead to the

Chromosome

Double-structured chromosome

Centriole

(A)

Prophase

(B)

Prometaphase

(C)

Metaphase

(D)

Anaphase

(E)

Telophase

(F)

Daughter cells

FIGURE 7.1. Stages of mitosis. (Modified from Sadler TW.

Langman’s Medical Embryology. 10th ed. Baltimore, MD:

Lippincott Williams & Wilkins; 2006:12.)

same pole. Nondisjunction is a common cause of chromosomally abnormal fetuses.

The second meiotic division (meiosis II) is similar to mitosis, except that the process occurs within a cell with a haploid number of chromosomes. Meiosis II is also divided into four stages: prophase II, metaphase II, anaphase II, and telo-phase II. The result of meiosis II is four haploid daughter cells. After anaphase II, the possibilities for genetic varia-tion are further increased by 2²³× 2²³, ensuring genetic vari-ation (Fig. 7.2).

ABNORMALITIES INCHROMOSOMENUMBER

Any alteration in the chromosome number is called heteroploidy.

Heteroploidy can occur in two forms: euploidy and ane-uploidy. In euploidy, the haploid number of 23 chromo-somes is altered. An example of euploidy is triploidy, in which the haploid number has been multiplied by 3. The karyotype is 69,XXX or 69,XXY. Triploidy results from double fertilization of a normal haploid egg or from fer-tilization by a diploid sperm. Such abnormalities usually

result in conceptions of partial hydatidiform moles and end spontaneously in the ﬁrst trimester.

In aneuploidy, the diploid number of 46 chromo-somes is altered. The trisomies are aneuploidies in which there are three copies of an autosome instead of two.

Examples include trisomy 21 (Down syndrome) trisomy 18 (Edward syndrome) trisomy 13 (Patau syndrome), and trisomy 16. Most trisomies result from maternal meiotic nondisjunction, a phenomenon that occurs more frequently as a woman ages (Fig. 7.3 and Table 7.1).

Sex chromosome abnormalities occur in 1 of every 1000 births. The most common are 45,X; 47,XXY;

47,XXX; 47,XYY; and mosaicism (the presence of 2 or more cell populations with different karyotypes). Numeric sex chromosome abnormalities can result from either maternal or paternal nondisjunction.

ABNORMALITIES INCHROMOSOMESTRUCTURE

Structural alterations in chromosomes are less common than numerical alterations. Structural abnormalities that

Pairing begins

Anaphase of 1st meiotic division

Cells resulting from 1st meiotic division

Cells resulting from 2nd meiotic division Cell contains 23

double-structured chromosomes

Cell contains 23 single chromosomes

Pairing of chromosomes

Chiasma formation

Pulling apart of double-structured

chromosomes

(A) (B) (C)

(F)

(E)

(G)

(D)

FIGURE 7.2. Stages of meiosis. (Modified from Sadler TW. Langman’s Medical Embryology. 10th ed.

Baltimore, MD: Lippincott Williams & Wilkins; 2006:13.)

Primary oocyte or spermatocyte after DNA duplication 46 double-structured chromosomes

Nondisjunction 1st meiotic division

Nondisjunction 2nd meiotic division Normal

meiotic division

2nd meiotic division

2nd meiotic division 2nd meiotic

division

24 chromosomes

22 chromosomes

22 24 22 24

23 single chromosomes

(A) (B) (C)

Commonly Diagnosed Chromosomal Abnormalities

Chromosome Abnormality Live Birth Incidence Characteristics Trisomy 21

(Down syndrome)

Trisomy 18

(Edwards syndrome) Trisomy 13

(Patau syndrome) Trisomy 16

45,X

47,XXX; 47,XYY;

47,XXY (Klinefelter syndrome)

del(5p)

1:800

1:8000

1:20,000

1:10,000

Each approximately 1:900

1:20,000

Moderate to severe mental retardation; characteristic facies;

cardiac abnormalities; increased incidence of respiratory infections and leukemia; only 2% live beyond 50 years

Severe mental retardation; multiple organic abnormalities; less than 10% survive 1 year

Severe mental retardation; neurologic, ophthalmologic, and organic abnormalities; 5% survive 3 years

Lethal anomaly occurs frequently in first-trimester spontaneous abortions; no infants are known to have trisomy 16

Occurs frequently in first-trimester (Turner syndrome) sponta-neous abortions; associated primarily with unique somatic features; patients are not mentally retarded, although IQs of affected individuals are lower than those of siblings

Minimal somatic abnormalities; individuals with Klinefelter syn-drome are characterized by a tall, eunuchoid habitus and small testes; 47,XXX and 47,XYY individuals do not usually exhibit somatic abnormalities, but 47,XYY individuals may be tall Severe mental retardation, microcephaly, distinctive facial fea-tures, characteristic “cat’s cry” sound (cri du chat syndrome) 7.1

T A B L E

FIGURE 7.3. Comparison of normal and abnormal meiotic divisions. (A) Normal meiotic division.

(B) Nondisjunction in the first meiotic division. (C) Nondisjunction in the second meiotic division.

(Modified from Sadler TW. Langman’s Medical Embryology. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:15.)

Dalam dokumen Obstetrics and Gynecology (Halaman 89-98)