CHAPTER © | FETAL PERIOD: NINTH WEEK TO BIRTH 99 EXPECTED DATE OF DELIVERY ‘The expected date of delivery of a fetus is 266 days or 38 weeks after fertilization, that is, 280 days or 40 weeks after the LNMP (see Table 6-2). Approximately 12% of fetuses are born 1 to 2 weeks after the expected time of birth. POSTMATURITY SYNDROME Prolongation of pregnancy for 3 or several weeks beyond the expected date of delvery occurs in 5% to 6% of women. Some infants in such pregnancies develop the postmaturity syndrome, which may be associated with fetal dysmaturity: absence of subcutaneous fat, wrinkling of the skin, or meconium (greenish-colored feces) stain- ing of the skin, and, often, excessive weight. Fetuses with this syndrome have an increased risk of mortalty. Labor is usually induced when the fetus is postmature FACTORS INFLUENCING FETAL GROWTH By accepting the shelter of the uterus, the fetus also takes the risk of maternal disease or malnutrition and of biochemical, immunological and hormonal adjustment “George W. Corner; renowned American embryologist, 1888 to 1981 Fetuses require substrates (nutrients) for growth and pro- duction of energy. Gases and nutrients pass freely to the fetus from the mother through the placental membrane (see Chapter 7, Fig. 7-7). Glucose is a primary source of ‘energy for fetal metabolism and growth; amino acids are also required. These substances pass from the mother’s blood to the fetus through the placental membrane. Insulin required for the metabolism of glucose is secreted by the fetal pancreas; no significant quantities of maternal insulin reach the fetus because the placental membrane is relatively impermeable to this hormone. Insulin, insulin- like growth factors, human growth hormone, and some small polypeptides (such as somatomedin C) are believed to stimulate fetal growth. Many factors may affect prenatal growth; they may be maternal, fetal, or environmental factors. Some factors ‘operating throughout pregnancy, such as maternal vascu- lar disease, intrauterine infection, cigarette smoking, and consumption of alcohol, tend to produce infants with IUGR or small-for-gestational-age (SGA) infants, whereas factors operating during the last trimester, such as mater- nal malnutrition, usually produce underweight infants with normal length and head size. The terms “IUGR” and “SGA” are related, but they are not synonymous. TUGR refers to’a process that causes a reduction in the expected pattern of fetal growth as well as fetal growth potential. Constitutionally small-for-gestational- age infants have a birth weight that is lower than a pre- determined cutoff value for a particular gestational age (<2 standard deviations below the mean or less than the third percentile). Severe maternal malnutrition resulting from a poor-quality diet is known to cause restricted fetal growth (see Fig. 6-11), Low birth weight has been shown to be a risk factor for many adult conditions, including hypertension, dia- betes, and cardiovascular discase. High birth weight due to maternal gestational diabetes is associated with later obesity and diabetes in the offspring. Cigarette Smoking Smoking is a well-established cause of IUGR. The growth rate for fetuses of mothers who smoke cigarettes is less than normal during the last 6 to 8 weeks of pregnancy (see Fig. 6-11). On average, the birth weight of infants whose mothers smoke heavily during pregnaney is 200 g less than normal, and the rate of perinatal morbidity is increased when adequate medical care is unavailable. The effect of maternal smoking, is greater on fetuses whose mothers also receive inadequate nutrition. Cigarette smoking has also been implicated as a major cause of cleft lip and palate. le Pregnancy Individuals of multiple births usually weigh considerably less than infants resulting from a single pregnancy (see Fig. 6-11). It is evident that the total metabolic require- ments of two or more fetuses exceed the nutritional supply available from the placenta during the third trimester Alcohol and Illicit Drugs Infants born to mothers that drink alcohol often exhibit IUGR as part of the fetal alcohol syndrome (see Chapter 20, Fig, 20-17), Similaely, the use of marijuana and other illicit drugs (e.g, cocaine) can cause IUGR and other obstetric complications. Impaired Uteroplacental and Fetoplacental Blood Flow ‘The maternal placental circulation may be reduced by conditions that decrease uterine blood flow (e.g., small chorionic vessels, severe maternal hypotension, and renal disease). Chronie reduction of uterine blood flow an cause fetal starvation resulting in IUGR. Placental dysfunction (e.g., infarction; see Chapter 7) can also cause UGR. ‘The net effect of these placental abnormalities is a reduction of the total area for exchange of nutrients between the fetal and maternal bloodstreams. It is very difficult to separate the effect of these placental changes from the effect of reduced maternal blood flow to the placenta. In some instances of chronic maternal disease, the maternal vascular changes in the uterus are primary and placental defects are secondary.400 THE DEVELOPING HUMAN Genetic Factors and Growth Retardation It is well established that genetic factors can cause IUGR. Repeated cases of this condition in one family indicate that recessive genes may be the cause of the abnormal growth. Structural and numeric chromosomal aberra- tions have also been shown to be associated with eases of retarded fetal growth. IUGR is pronounced in infants th Down syndrome and is very characteristic of fetuses, with trisomy 18 syndrome (see Chapter 20). PROCEDURES FOR ASSESSING FETAL STATUS. Perinatology is the branch of medicine that is concerned with the well-being of the fetus and neonate, generally covering the period from approximately 26 weeks after fertilization to 4 weeks after birth. This subspecialty of medicine combines aspects of obstetrics and pediatrics. Ultrasonography Ultrasonography is the primary imaging modality in the evaluation of fetuses because of its wide availability, low cost, quality of images, and lack of known adverse effects. ‘The chorionic sac and its contents may be visualized by ultrasonography during the embryonic and fetal periods. Placental and fetal size, multiple births, abnormalities of placental shape, and abnormal presentations can also be determined Ultrasound scans give accurate measurements of the biparietal diameter of the fetal cranium (skull}, from which close estimates of fetal age and length can be made. Figures 6-10 and 6-12 illustrate how details of the fetus can be observed in these scans. Ultrasound examinations are also helpful for diagnosing abnormal pregnancies at a very carly stage, Rapid advances in ultrasonography have made this technique a major tool for prenatal |GURE 6-12 A, Three-dimensior recognizable. B, Photograph of the sare neonate, 3 hours aft diagnosis of fetal abnormalities. Biopsy of fetal tissues, such as the skin, liver, kidney, and muscle, can be per- formed with ultrasound guidance. Diagnostic Amniocentesis This is a common invasive prenatal diagnostic procedure, usually performed between 15 and 18 weeks’ gestation. Amniotic fluid is sampled by inserting a 22-gauge needle through the mother’s anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion (Fig. 6-134). Because there is relatively little amniotic fluid before the 14th week, amniocentesis is difficult to perform before this time. ‘The amniotic fluid volume is approximately 200 ml, and 15 to 20 ml ean be safely withdrawn, Amniocentesis is relatively devoid of risk, especially when the procedure is performed by an experienced physician using real-time ultrasonography guidance for outlining the position of the fetus and placenta DIAGNOSTIC VALUE OF AMNIOCENTESIS ‘Amniocentesis is a common technique for detecting genetic disorders (e.g., Down syndrome). The common indications for amniocentesis are ‘Advanced maternal age (238 years) Previous birth of a child with trsomy 21 (Gee Chapter 20, Fig, 20-68) Chromorome abnormality in ether parent ‘Women who are carriers of X-linked recessive isorders (e.g., hemophilia) History of neural tube defects in the family (e.g. spina bifida cystiea; see Chapter 17, Fig. 17-15) Carriers of inborn errors of metabolism ultrasound (sonogram) of a 28-week fetus showing the face. The surface features are clearly bint,CHAPTER 6 | FETAL PERIOD: NINTH WEEK TO BIRTH 100.01 (Courtesy Dr. EA. Lyons, Professor of Radiology and Obstetrics and Gynecology and of Anatomy, Health Sciences Centre and University of Manitoba, Winnipeg, Manitoba, Canada)CHAPTER © Placonia A Chorionic vilus Uterine wall Uttasound ‘wansaucer FETAL PERIOD: NINTH WEEK TO BIRTH 104 Bladder Speculum Chotione vals cathet FIGURE 6-13 A Illustration of amniocentesis. A needle is inserted through the lower abdominal and uterine walls into the amniotic cavity. A syringe is atached and amniotie Suid is withdrawn for diagnostic purposes. B, Drawing illustrating chorion villus sampling. Two sampling approaches are ilustrated: through the maternal anterior abdominal wall with a needle and through the vagina ‘and cervical canal using a malleable catheter. A speculum is an instrument for exposing the vagina. Alpha-Fetoprotein Assay Alpha-fetoprotein (AFP) is a glycoprotein that is synthe- sized in the fetal liver, umbilical vesicle, and gut, AFP is found in high concentrations in fetal serum, with levels peaking at 14 weeks after the LNMP. Only small amounts of AFP normally enter the amniotic fluid. ALPHA-FETOPROTEIN AND aaNet) ‘The concentration of AFP is high in the amniotic fluid surrounding fetuses with severe defects of tre central nervous system and ventral abdominal wall. The amniotic fluid AFP concentration is measured by immunoassay; when the measurement is known and ultrasonographic scanning is performed, approximately 99% of fetuses. with these severe defects can be diagnosed prenatally. When a fetus has an open neural tube defect, the concentration of AFP is also likely to be higher than normal in the maternal serum. The maternal serum AFP, concentration is lower than normal when the fetus has Down syndrome (trisomy 21), Edward syndrome {visomy 18), or other chromosome defects Spectrophotometric Studies Examination of amniotic fluid by spectrophotometric studies may be used for assessing the degree of erythro- lastosis fetalis, also called hemolytic disease of the neonate. This disease results from destruction of fetal red blood cells by maternal antibodies (see Chapter 7, blue box titled “Hemolytic Disease of the Neonate”), The concentration of bilirubin (and other related pigments) is correlated with the degree of hemolytic disease. Chorionic Villus Sampling Biopsies of trophoblastic tissue (5 to 20 mg) may be ‘obtained by inserting a needle, guided by ultrasonogra- phy, through the mother’s abdominal and uterine walls (transabdominal insertion) into the uterine cavity (see Fig. 6-13B). Chorionic villas sampling (CVS) can also be performed transcervically by passing a polyethylene catheter through the cervix under guidance by real-time ultrasonography. For assessing the condition of a fetus at tisk, the fetal karyotype (chromosome characteristics) can’ be obtained; in this way, using CVS, a diagnosis can be made weeks earlier than would be possible with DIAGNOSTIC VALUE OF CHORIONIC STRAT TUN Tc} Biopsies of chorionic vill are used for detecting chromo- somal abnarmalties, inborn errors of metabolsm, and Xlinked disorders. CVS can be performed at between 10 and 12 weeks of gestation. The rate of feta loss is approx imately 0.5% to 1%, a rate that is slightly higher than the rate with amniocentesis, Reports regarding an increased risk of Imo defects after CVS are conflicting, The advan- tage of CVS over amniocentesis is that ¢ can be carried ‘out sooner, so that the results of chromosomal analysis are available several weeks earlier.102 THE DEVELOPING HUMAN Cell Cultures and Chromosomal Analysis The prevalence of chromosomal disorders is. approxi mately 1 in 120 neonates. Fetal sex and chromosomal aberrations can be determined by studying the chromo- somes in cultured fetal cells obtained during amniocente- sis, If conception oceurs by means of assisted reproductive technologies, it is possible to obtain fetal cells by per forming a biopsy of the maturing blastocyst (Fig. 6-144 and B}. These cultures arc commonly done when an autosomal abnormality, such as oceurs in Down syn. drome, is suspected. Knowledge of fetal sex can be useful in diagnosing the presence of severe sex-linked hereditary diseases, such as hemophilia (an inherited disorder of blood coagulation) and muscular dystrophy (a hereditary progressive degenerative disorder affecting skeletal muscles). Moreover, microdeletions and microduplica tions, as well as subtelomeric rearrangements, can now a be detected with fluorescence in situ hybridization tech: nology (see Fig. 6-14C and D). Inborn errors of metabo- lism in fetuses can_also be detected by studying cell cultures. Enzyme deficiencies can be determined by incu: bating cells recovered from amniotic fluid and then detecting the specific enzyme deficiency in the cells, Noninvasive Prenatal Diagnosis Down syndrome {trisomy 21) is the most commonly known chromosomal disorder. Children born with this, condition have varying degrees of intellectual disabilities. Noninvasive screening for trisomy 21 is based on the isolation of fetal cells in maternal blood and the detection of cell-free DNA and RNA. Such DNA-based diagnostic tests need additional refinement to improve their reliabil ity for the detection of fetal trisomy of chromosomes 13, 18, and 21 D FIGURE 6-14 A Microscopic images of human blastocyst with trophectoderm cells (which will form extraembryonic tisves) staring to hatch, B, The trophectader cells biopsied with assist cl laser exiting, C and D, Fluorescence in sity hybridization images in aneuploidy blastocysts C, Three dots that have stained green in A incicate the presence of three chromosomes 21 in the sample (46,X%, 421). D, One cot that has stained red in B indicates the presence of onk (From Lang L, Wang CT, Sun X, et al: Identification of cbr DNA miezoarray, PLoS ONE 8:4, 2013 nasomal errors in human preimplan 1¢ chromosome 13 in the sample (05,XX, -13)CHAPTER © Fetal Transfusion Fetuses with hemolytic disease of the neonate can be treated by intrauterine blood transfusions. The blood is injected through a needle inserted into the fetal peritoneal cavity, With recent advances in, percutaneous umbilical cord blood sampling, blood and packed red blood cells can be transfused directly into the umbilical vein for the treatment of fetal anemia due to isoimmunization. The need for fetal blood transfusions is reduced nowadays ‘owing to the treatment of Rh-negative mothers of Rh-positive fetuses with anti-Rh immunoglobulin, which in many cases prevents development of this disease. Fetal transfusion of platelets directly into the umbilical cord vein is carried out for the treatment of alloimmune thrombocytopenia. Also, fetal infusion of drugs in a similar manner for the treatment of a few medical condi- tions in the fetus has been reported. Fetoscopy Using fiberoptic instruments, external parts of the fetal body may be directly observed. The fetoscope is usually introduced through the mother's abdominal and uterine walls into the amniotic cavity. Fetoscopy is usually carried out at 17 to 20 weeks of gestation, but with new approaches, such as transabdominal thin-gauge embryo fetoseopy, it is possible to detect certain defects in the ‘embryo ot fetus during the first trimester. Because of the higher risk to the fetus compared with other prenatal diagnostic procedures, fetoscopy now has few indications for routine prenatal diagnosis or treatment of the fetus. Fetoscopy combined with laser coagulation is used to treat fetal conditions such as twin-twin transfusion syn- drome. Fetoscopy has also been used for the release of amniotic bands {see Chapter 7, Fig. 7-21), Percutaneous Umbilical Cord Blood Sampling Fetal blood samples may be obtained directly from the umbilical vein by percutaneous umbilical cord blood sampling, or cordocentesis, for the diagnosis of many fetal abnormal conditions, including aneuploidy, fetal ‘growth restriction, fetal infection, and fetal anemia. Per- cutaneous umbilical cord blood sampling is usually per- formed after 18 weeks of gestation under continuous direct ultrasound guidance, which is used to locate the ‘umbilical cord and its vessels, The procedure also permits treating the fevus directly, including transfusion of packed red blood cells for the management of fetal anemia result: ing from isoimmunization. Magnetic Resonance Imaging When planning fetal tweatment, magnetic resonance imaging (MRI) may be used to provide more information about a defect that has been detected in ultrasonic images. Important advantages of MRI ate that st does not use ionizing radiation and it has high soft tissue contrast and resolution (Fig, 6-15) FETAL PERIOD: NINTH WEEK TO BIRTH 108, FIGURE 6-15 Saginal magnet resonance image of the pelvis ofa pregnant woman. The fetus isin the breech presenta- lion. Note the brain, eyes, and Iver Fetal Monitoring Continuous fetal heart rate monitoring in high-risk preg- nancies is routine and provides information about the ‘oxygenation of the fetus. There ate various causes of prenatal fetal distress, such as maternal diseases that reduce oxygen transport to the fetus (e.g, cyanotic heart disease). Fetal distress (e.g., indicated by an abnormal heart rate or rhythm) suggests that the fetus is in jeopardy. A noninvasive method of monitoring uses transducers placed on the mother’s abdomen. SUMMARY OF FETAL PERIOD ‘© The fetal period begins 8 weeks after fertilization (10 weeks after the LNMP) and ends at birth. It is char acterized by rapid body growth and differentiation of tissues and organ systems, An obvious change in the fetal period is the relative slowing of head growth compared with that of the rest of the body ‘© Atthe beginning of the 20th week, lanugo (fine downy hair) and head hair appear and the skin is coated with vernix easeosa (a fatty cheesy substance). ‘The eyelids are closed during most of the fetal period, but they begin to reopen at approximately 26 weeks. At this time, the fetus is usually capable of extrauterine exis- tenee, mainly because of the maturity of its respiratory system, ‘© Up to 30 weeks, the fetus appears reddish and wizened (wrinkled) because of the thinness of its skin and theCHAPTER © TO BIRTH 103.01 or of Obstetric and (Courtesy Dr, Deborah Levine, Direct cologic Ultrasound, Beth lersel Deaconess Medical Center, Boston, MA)404 THE DEVELOPING HUMAN FIGURE 6-16 Fetus at 21 woeks undergoing bilateral Lreterostomies, the establ shment of openings of the ureters nto ‘he bladder (From Harnson MR, Globus MS, Filly RA, editors: The Unbom patient: prenatal ciagnosis and treatment, ed 2, Philadel. phis, 1994, Saunders) relative absence of subcutaneous fat, Fat usually devel- ops rapidly at 26 to 29 weeks, giving the fetus a smooth, healthy appearance (see Fig. 6-9) © The fetus is less vulnerable to the teratogenic effects of drugs, viruses, and radiation, but these agents may interfere with growth and normal funetional develop- ment, especially of the brain and eyes. © The physician can determine whether a fetus has a particular disease or birth defect by using various diag- nostic techniques, such as amniocentesis, CVS, ultra- sonography, and MRI © In selected cases, treatments can be given to the fetus, such as drugs to correct cardiac arrhythmia or thyroid disorders, Surgical correction of some birth defects in utero (Fig. 6-16) is also possible (eg. ureters that do not open into the bladder can be surgically corrected). CLINICALLY ORIENTED PROBLEMS — ee eo CASE 6-1 A woman in the 20th week of a high-risk pregnancy was scheduled for a repeat cesarean section. Her physician wanted to establish an expected date of delivery. #* How would an expected date of delivery be established? # When would labor likely be induced? # How could this be accomplished? CASE 6-2 A 44-year-old pregnant woman was worried that her fetus may have major birth defects #* How could the status of her fetus be determined? #* What chromosomal abnormality would be most likely? # What other chromosomal aberrations might be detected? _— SS CASE 6-3 A 19-year-old woman in the second trimester of pregnancy asked a physician whether her fetus was tulncrable to over-the-counter drugs and street drugs She also wondered about the effect of her heavy drinking and cigarette smoking on ber fetus ® What would the physician likely tell her? _———— aS CASE 6-4 An ultrasound examination of a pregnant woman revealed that her fetus had IUGR © What factors may cause IUGR? Discuss how these factors might influence fetal growth. #* Which factors can the mother eliminate? Would removing these factors result in reversal of IUGR? Se CASE 6-5 A woman in the first trimester of pregnancy who twas lo undergo amniocentesis expressed concerns about a miscarriage and the possibility of injury to ber fers # What are the risks of these complications? # What procedures are used to minimize these risks? # What other technique might be used for obtaining cells for a chromosomal study? ——————EE CASE 6-6 A pregnant woman is told that she is going to have an ABP test to determine whether there are any birth defects, © What is AFP and where can it be found? #* What types of fetal defect can be detected by an AEP assay of maternal serum? # What is the significance of high and low levels of AFP? Discussion of these problems appears in the Appendix at the back of the book.