Maternal Physiologic and Immunologic Adaptation to Pregnancy

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Chapter 6 Maternal Physiologic and Immunologic Adaptation to Pregnancy

Maternal physiologic adjustments to pregnancy are designed to support the requirements of fetal homeostasis and growth without unduly jeopardizing maternal well-being. This is accomplished by remodeling maternal systems to deliver energy and growth substrates to the fetus and to remove inappropriate heat and waste products. There appears to be a privileged immunologic sanctuary for the fetus and placenta during pregnancy.

image Cardiovascular System

CARDIAC OUTPUT

The hemodynamic changes associated with pregnancy are summarized in Table 6-2. Retention of sodium and water during pregnancy accounts for a total body water increase of 6 to 8 L, two thirds of which is located in the extravascular space. The total sodium accumulation averages 500 to 900 mEq by the time of delivery. The total blood volume increases by about 40% above nonpregnant levels, with wide individual variations. The plasma volume rises as early as the 6th week of pregnancy and reaches a plateau by about 32 to 34 weeks’ gestation, after which little further change occurs. The increase averages 50% in singleton pregnancies and approaches 70% with a twin gestation. The red blood cell mass begins to increase at the start of the second trimester and continues to rise throughout pregnancy. By the time of delivery, it is 20% to 35% above nonpregnant levels. The disproportionate increase in plasma volume compared with the red cell volume results in hemodilution with a decreased hematocrit reading, sometimes referred to as physiologic anemia of pregnancy. If iron stores are adequate, the hematocrit tends to rise from the second to the third trimester.

TABLE 6-2 CARDIOVASCULAR CHANGES IN PREGNANCY

Parameter Amount of Change Timing
Arterial blood pressures    
Systolic ↓ 4-6 mm Hg All bottom at 20-24 wk, then rise gradually to prepregnancy values at term
Diastolic ↓ 8-15 mm Hg
Mean ↓ 6-10 mm Hg  
Heart rate ↑ 12-18 beats/min 1st, 2nd, 3rd trimesters
Stroke volume ↑ 10%-30% 1st and 2nd trimesters, then stable until term
Cardiac output ↑ 33%-45% Peaks in early 2nd trimester, then stable until term

Data from Main DM, Main EK: Obstetrics and Gynecology: A Pocket Reference. Chicago, Year Book, 1984, p 18.

Cardiac output rises by the 10th week of gestation; it reaches about 40% above nonpregnant levels by 20 to 24 weeks, after which there is little change. The rise in cardiac output, which peaks while blood volume is still rising, reflects increases mainly in stroke volume and, to a lesser extent, in heart rate. With twin and triplet pregnancies, the changes in cardiac output are greater than those seen with singleton pregnancies.

The cardiovascular responses to exercise are altered during pregnancy. For any given level of exercise, oxygen consumption is higher in pregnant than in nonpregnant women. Similarly, the cardiac output for any level of exercise is also increased during pregnancy compared with that seen in a nonpregnant state, and the maximum cardiac output is reached at lower levels of exercise. It is not clear that any of the changes in hemodynamic responses to exercise are detrimental to mother and fetus, but it suggests that maternal cardiac reserves are lowered during pregnancy and that shunting of blood away from the uterus might occur during or after exercise.

MECHANICAL CIRCULATORY EFFECTS OF THE GRAVID UTERUS

As pregnancy progresses, the enlarging uterus displaces and compresses various abdominal structures, including the iliac veins and inferior vena cava (and probably also the aorta), with marked effects. The supine position accentuates this venous compression, producing a fall in venous return and hence cardiac output. In most gravid women, a compensatory rise in peripheral resistance minimizes the fall in blood pressure. In up to 10% of gravid women, however, a significant fall occurs in blood pressure accompanied by symptoms of nausea, dizziness, and even syncope. This supine hypotensive syndrome is relieved by changing position to the side. The expected baroreflexive tachycardia, which normally occurs in response to other maneuvers that reduce cardiac output and blood pressure, does not accompany caval compression. In fact, bradycardia is often associated with the syndrome.

The venous compression by the gravid uterus elevates pressure in veins that drain the legs and pelvic organs, thereby exacerbating varicose veins in the legs and vulva and causing hemorrhoids. The rise in venous pressure is the major cause of the lower extremity edema that characterizes pregnancy. The hypoalbuminemia associated with pregnancy also shifts the balance of the other major factor in the Starling equation (colloid osmotic pressure) in favor of fluid transfer from the intravascular to the extracellular space. Because of venous compression, the rate of blood flow in the lower veins is also markedly reduced, causing a predisposition to thrombosis. The various effects of caval compression are somewhat mitigated by the development of a paravertebral collateral circulation that permits blood from the lower body to bypass the occluded inferior vena cava.

During late pregnancy, the uterus can also partially compress the aorta and its branches. This is thought to account for the observation in some patients of lower pressure in the femoral artery compared with that in the brachial artery. This aortic compression can be accentuated during uterine contractions and may be a cause of fetal distress when a patient is in the supine position. This phenomenon has been referred to as the Posiero effect. Clinically, it can be suspected when the femoral pulse is not palpable.

REGIONAL BLOOD FLOW

Blood flow to most regions of the body increases and reaches a plateau relatively early in pregnancy. Notable exceptions occur in the uterus, kidney, breasts, and skin, in each of which blood flow increases with gestational age. Two of the major increases (those to the kidney and to the skin) serve purposes of elimination: the kidney of waste material and the skin of heat. Both processes require plasma rather than whole blood, which gives point to the disproportionate increase of plasma over red blood cells in the blood expansion.

Early in pregnancy, renal blood flow increases to levels about 30% above nonpregnant levels and remains unchanged as pregnancy advances. This change accounts for the increased creatinine clearance and lower serum creatine level. Engorgement of the breasts begins early in gestation, with mammary blood flow increasing 2 to 3 times in later pregnancy. The skin blood flow increases slightly during the third trimester, reaching 12% of cardiac output.

There is little information on the distribution of blood flow to other organ systems during pregnancy. The uterine blood flow increases from about 100 mL/min in the nonpregnant state (2% of cardiac output) to about 1200 mL/min (17% of cardiac output) at term. Uterine blood flow and thus gas and nutrient transfer to the fetus are vulnerable. When maternal cardiac output falls, blood flow to the brain, kidneys, and heart is supported by a redistribution of cardiac output, which shunts blood away from the uteroplacental circulation. Similarly, changes in perfusion pressure can lead to decreases in uterine blood flow. Because the uterine vessels are maximally dilated during pregnancy, little autoregulation can occur to improve uterine blood flow.

image Respiratory System

The major respiratory changes in pregnancy involve three factors: the mechanical effects of the enlarging uterus, the increased total body oxygen consumption, and the respiratory stimulant effects of progesterone.

RESPIRATORY MECHANICS IN PREGNANCY

The changes in lung volume and capacities associated with pregnancy are detailed in Table 6-3. Assessment of mechanical changes during pregnancy reveals that the diaphragm at rest rises to a level of 4 cm above its usual resting position. The chest enlarges in transverse diameter by about 2.1 cm. Simultaneously, the subcostal angle increases from an average of 68.5 degrees to 103.5 degrees during the latter part of gestation. The increase in uterine size cannot completely explain the changes in chest configuration because these mechanical changes occur early in gestation.

TABLE 6-3 LUNG VOLUMES AND CAPACITIES IN PREGNANCY

Test Definition Change in Pregnancy
Respiratory rate Breaths/minute No significant change
Tidal volume The volume of air inspired and expired at each breath Progressive rise throughout pregnancy of 0.1-0.2 L
Expiratory reserve volume The maximum volume of air that can be additionally expired after a normal expiration Lowered by about 15% (0.55 L in late pregnancy compared with 0.65 L postpartum)
Residual volume The volume of air remaining in the lungs after a maximum expiration Falls considerably (0.77 L in late pregnancy compared with 0.96 L postpartum)
Vital capacity The maximum volume of air that can be forcibly inspired after a maximum expiration Unchanged, except for possibly a small terminal diminution
Inspiratory capacity The maximum volume of air that can be inspired from resting expiratory level Increased by about 5%
Functional residual capacity The volume of air in lungs at resting expiratory level Lowered by about 18%
Minute ventilation The volume of air inspired or expired in 1 min Increased by about 40% as a result of the increased tidal volume and unchanged respiratory rate

Data from Main DM, Main EK: Obstetrics and Gynecology: A Pocket Reference. Chicago, Year Book, 1984, p 14.

As pregnancy progresses, the enlarging uterus elevates the resting position of the diaphragm. This results in less negative intrathoracic pressure and a decreased resting lung volume; that is, a decrease in functional residual capacity (FRC). The enlarging uterus produces no impairment in diaphragmatic or thoracic muscle motion. Hence, the vital capacity (VC) remains unchanged. These characteristics—reduced FRC with unimpaired VC—are analogous to those seen in a pneumoperitoneum and contrast with those seen in severe obesity or abdominal binding, where the elevation of the diaphragm is accompanied by decreased excursion of the respiratory muscles. Reductions in both the expiratory reserve volume and the residual volume contribute to the reduced FRC.

OXYGEN CONSUMPTION AND VENTILATION

Total body oxygen consumption increases about 15% to 20% in pregnancy. About half of this increase is accounted for by the uterus and its contents. The remainder is accounted for mainly by increased maternal renal and cardiac work. Smaller increments are due to greater breast tissue mass and to increased work of the respiratory muscles.

In general, a rise in oxygen consumption is accompanied by cardiorespiratory responses that facilitate oxygen delivery (i.e., by increases in cardiac output and alveolar ventilation). To the extent that elevations in cardiac output and alveolar ventilation keep pace with the rise in oxygen consumption, the arteriovenous oxygen difference and the arterial partial pressure of carbon dioxide (PCO2), respectively, remain unchanged. In pregnancy, the elevations in both cardiac output and alveolar ventilation are greater than those required to meet the increased oxygen consumption. Hence, despite the rise in total body oxygen consumption, the arteriovenous oxygen difference and arterial PCO2 both fall. The fall in PCO2 (to 27-32 mm Hg), by definition, indicates hyperventilation.

The rise in minute ventilation reflects an approximate 40% increase in tidal volume at term; the respiratory rate does not change during pregnancy. During exercise, pregnant subjects show a 38% increase in minute ventilation and a 15% increase in oxygen consumption above comparable levels for postpartum subjects.

When injected into normal nonpregnant subjects, progesterone increases ventilation. The central chemoreceptors become more sensitive to CO2 (i.e., the curve describing the ventilatory response to increasing CO2 has a steeper slope). Such increased respiratory sensitivity to CO2 is characteristic of pregnancy and probably accounts for the hyperventilation of pregnancy.

In summary, both at rest and with exercise, minute ventilation and, to a lesser extent, oxygen consumption are increased during pregnancy over the nonpregnant control values. The respiratory stimulating effect of progesterone is probably responsible for the disproportionate increase in minute ventilation over oxygen consumption.

image Renal Physiology

image Homeostasis of Maternal Energy Substrates

The metabolic regulation of energy substrates, including glucose, amino acids, fatty acids, and ketone bodies, is complex and interrelated.

image Placental Transfer of Nutrients

The transfer of substances across the placenta occurs by several mechanisms, including simple diffusion, facilitated diffusion, and active transport. Low molecular size and lipid solubility promote simple diffusion. Substances with molecular weights greater than 1000 Daltons, such as polypeptides and proteins, cross the placenta slowly, if at all.

Amino acids are actively transported across the placenta, making fetal levels higher than maternal levels. Glucose is transported by facilitated diffusion, leading to rapid equilibrium with only a small maternal-fetal gradient. Glucose is the main energy substrate of the fetus although amino acids and lactate may contribute up to 25% of fetal oxygen consumption. The degree and mechanism of placental transfer of these and other substances are summarized in Table 6-4.

TABLE 6-4 MATERNAL-FETAL TRANSFER DURING PREGNANCY

Function Substance Placental Transfer
Glucose homeostasis Glucose Excellent—”facilitated diffusion”
  Amino acids Excellent—active transport
  Free fatty acids (FFA) Very limited—essential FFA only
  Ketones Excellent—diffusion
  Insulin No transfer
  Glucagon No transfer
Thyroid function Thyroxine (T4) Very poor—diffusion
  Triiodothyronine (T3) Poor—diffusion
  Thyrotropin-releasing hormone (TRH) Good
  Thyroid-stimulating immunoglobulin (TSI) Good
  Thyroid-stimulating hormone (TSH) Negligible transfer
  Propylthiouracil Excellent
Adrenal hormones Cortisol Excellent transfer and active placental conversion of cortisol to cortisone beginning at mid-pregnancy
  ACTH No transfer
Parathyroid function Calcium Active transfer against gradient
  Magnesium Active transfer against gradient
  Phosphorus Active transfer against gradient
  Parathyroid hormone Not transferred
Immunoglobulins IgA Minimal passive transfer
  IgG Good—both passive and active transport from 7 wk gestation
  IgM No transfer

At mid-gestation, placental 11-β hydroxysteroid dehydrogenase converts cortisol to cortisone.

Data from Main DM, Main EK: Obstetrics and Gynecology: A Pocket Reference. Chicago, Year Book, 1984, p 37.

image Other Endocrine Changes

image Placental Transfer of Oxygen and Carbon Dioxide

FETAL OXYGENATION

The placenta receives 60% of the combined ventricular output, whereas the postnatal lung receives a greater proportion of the cardiac output. Unlike the lung, which consumes little of the oxygen it transfers, a significant percentage of the oxygen derived from maternal blood at term is consumed by placental tissue. The degree of functional shunting of placental blood past exchange sites is about 10-fold greater than in the lung. A major cause of this functional shunting is probably a mismatch between maternal and fetal blood flow at the exchange sites, analogous to the ventilation-perfusion inequalities that occur in the lung.

The uteroplacental circulation subserves fetal gas exchange. Oxygen, carbon dioxide, and inert gases cross the placenta by simple diffusion. The rate of transfer is proportional to the difference in gas tension across the placenta and the surface area of the placenta; and the transfer rate is inversely proportional to diffusion distance between maternal and fetal blood. The placenta normally does not pose a significant barrier to respiratory gas exchange, unless it becomes separated (abruption placenta) or edematous (severe hydrops fetalis).

Figure 6-1 depicts the anatomic distribution of uterine and umbilical blood flow and O2 transfer across the placenta. A maternal shunt, which describes the fraction of blood shunted to the myoendometrium and is estimated to constitute 20% of uterine blood flow, is depicted. Similarly, a fetal shunt, which supplies blood to the placenta and fetal membranes and accounts for 19% of umbilical blood flow, is shown. The maternal-to-fetal PO2 and PCO2 gradients are calculated from measurements of gas tensions in the uterine and umbilical arteries and veins. The umbilical vein of the fetus, like the pulmonary vein of the adult, carries the circulation’s most highly oxygenated blood. The umbilical venous PO2 of about 28 mm Hg is relatively low by adult standards. This relatively low fetal tension is essential for survival in utero because a high PO2 initiates physiologic adjustments (e.g., closure of the ductus arteriosus and vasodilation of the pulmonary vessels) that normally occur in the neonate but would be harmful in utero.

image

FIGURE 6-1 Placental transfer of oxygen and carbon dioxide. BE, base excess; Hb, hemoglobin.

(Adapted from Bonica JJ: Obstetric Analgesia and Anesthesia, 2nd ed. Amsterdam, World Federation of Societies of Anesthesiologists, 1980, p 29.)

Although not involved in respiratory gas exchange, fetal breathing movements are critically involved in lung development and in the development of respiratory regulation. Fetal breathing differs from that in the adult in that it is episodic, sensitive to fetal glucose concentrations, and inhibited by hypoxia. Because of its sensitivity to acute O2 deprivation, fetal breathing is used clinically as indicator of the adequacy of fetal oxygenation.

FETAL AND MATERNAL HEMOGLOBIN DISSOCIATION CURVES

Most of the oxygen in blood is carried by hemoglobin in red blood cells. The maximum amount of oxygen carried per gram of hemoglobin, that is, the amount carried at 100% saturation, is fixed at 1.37 mL. The hemoglobin flow rates depend on blood flow rates and hemoglobin concentration. The uterine blood flow at term has been estimated at 700 to 1200 mL/min, with about 75% to 88% of this entering the intervillous space. The umbilical blood flow has been estimated at 350 to 500 mL/min, with more than 50% going to the placenta (see Figure 6-1).

The hemoglobin concentration of the blood determines its oxygen-carrying capacity, which is expressed in milliliters of oxygen per 100 mL of blood. In the fetus at or near term, the hemoglobin concentration is about 18 g/dL, and oxygen-carrying capacity is 20 to 22 mL/dL. Maternal oxygen-carrying capacity of blood, which is generally proportional to hemoglobin concentration, is lower than that of the fetus.

The affinity of hemoglobin for oxygen, which is reflected as the percent saturation at a given oxygen tension, depends on chemical conditions. As is illustrated in Figure 6-2, when compared with that in nonpregnant adults, the binding of oxygen by hemoglobin is much greater in the fetus under standard conditions of PCO2, pH, and temperature. In contrast, maternal affinity is lower under these conditions, with 50% of hemoglobin saturated with O2 at a PO2 of 26.5 mm Hg (P50) for mother compared with 20 mm Hg for the fetus.

In vivo, the greater fetal temperature and lower pH shift the O2-dissociation curve to the right, while the lower maternal temperature and higher pH shift the maternal curve to the left. As a result, the O2-dissociation curves for the fetal and maternal blood are not too dissimilar at the site of placental transfer. Maternal venous blood probably has an O2 saturation of about 73% and a PO2 of about 36 mm Hg, and the corresponding values for blood in the umbilical vein are about 63% and 28 mm Hg. As the only source of O2 for the fetus, blood in the umbilical vein has a higher O2 saturation and PO2 than blood in the fetal circulation (Figure 6-3). In the presence of a low fetal arterial PO2, fetal oxygenation is maintained by a high rate of blood flow to fetal tissues, which is supported by a very high cardiac output. This feature, along with the lower P50 of fetal blood, results in normal O2 delivery to fetal organs.

image

FIGURE 6-3 The fetal circulation. Numbers represent approximate values of percent saturation of blood with oxygen in utero.

(Adapted from Parer JJ: Fetal circulation. In Sciarra JJ [ed]: Obstetrics and Gynecology, Vol 3: Maternal and Fetal Medicine. Hagerstown, MD, Harper & Row, 1984, p 2.)

The decrease in the affinity of hemoglobin for oxygen produced by a fall in pH is referred to as the Bohr effect. Because of the unique situation in the placenta, a double Bohr effect facilitates oxygen transfer from mother to fetus. When CO2 and fixed acids are transferred from fetus to mother, the associated rise in fetal pH increases the fetal red blood cell’s affinity for oxygen uptake. The concomitant reduction in maternal blood pH decreases oxygen affinity and promotes its unloading of oxygen from maternal red cells.

image Fetal Circulation

Several anatomic and physiologic factors must be noted in considering the fetal circulation (Table 6-6; see Figure 6-3).

TABLE 6-6 COMPONENTS OF THE FETAL CIRCULATION

Fetal Structure From/To Adult Remnant
Umbilical vein Umbilicus/ductus venosus Ligamentum teres hepatis
Ductus venosus Umbilical vein/inferior vena cava (bypasses liver) Ligamentum venosum
Foramen ovale Right atrium/left atrium Closed atrial wall
Ductus arteriosus Pulmonary artery/descending aorta Ligamentum arteriosum
Umbilical artery Common iliac artery/umbilicus Superior vesical arteries; lateral vesicoumbilical ligaments

Data from Main DM, Main EK: Obstetrics and Gynecology: A Pocket Reference. Chicago, Year Book, 1984, p 34.

The normal adult circulation is a series circuit with blood flowing through the right heart, the lungs, the left heart, the systemic circulation, and finally the right heart. In the fetus, the circulation is a parallel system with the cardiac outputs from the right and left ventricles directed primarily to different vascular beds. For example, the right ventricle, which contributes about 65% of the combined output, pumps blood primarily through the pulmonary artery, ductus arteriosus, and descending aorta. Only a small fraction of right ventricular output flows through the pulmonary circulation. The left ventricle supplies blood mainly to the tissues supplied by the aortic arch, such as the brain. The fetal circulation is a parallel circuit characterized by channels (ductus venosus, foramen ovale, and ductus arteriosus) and preferential streaming, which function to maximize the delivery of more highly oxygenated blood to the upper body and brain, less highly oxygenated blood to the lower body, and very low blood flow to the nonfunctional lungs.

The umbilical vein, carrying oxygenated (80% saturated) blood from the placenta to the fetal body, enters the portal system. A portion of this umbilical-portal blood passes through the hepatic microcirculation, where oxygen is extracted, and thence through the hepatic veins into the inferior vena cava. Most of the blood bypasses the liver through the ductus venosus, which directly enters the inferior vena cava, which also receives the unsaturated (25% saturated) venous return from the lower body. Blood reaching the heart through the inferior vena cava has an oxygen saturation of about 70%, which represents the most highly oxygenated blood in the heart. About one third of blood returning to the heart from the inferior vena cava preferentially streams across the right atrium, mixing with blood from the superior vena cava to the foramen ovale into the left atrium, where it mixes with the relatively meager pulmonary venous return. Blood flows from the left atrium into the left ventricle, and then to the ascending aorta.

The proximal aorta, carrying the most highly saturated blood leaving the heart (65%), gives off branches to supply the brain and upper body. Most of the blood returning through the inferior vena cava enters the right atrium, where it mixes with the unsaturated blood returning through the superior vena cava (25% saturated). Right ventricular outflow (O2 saturation of 55%) enters the aorta through the ductus arteriosus, and the descending aorta supplies the lower body with blood having less O2 saturation (about 60%) than that flowing to the brain and the upper body.

The role of the ductus arteriosus must be emphasized. Right ventricular output enters the pulmonary trunk, from which its major portion, owing to the high vascular resistance of the pulmonary circulation, bypasses the lungs by flowing through the ductus arteriosus to the descending aorta. Although the descending aorta supplies branches to the lower fetal body, the major portion of descending aortic flow goes to the umbilical arteries, which carry deoxygenated blood to the placenta.

image Immunology of Pregnancy

Nearly 60 years ago, Peter Medawar recognized the apparent paradox of the immunologic evasion of the semiallogenic fetus to maternal response. He proposed three hypotheses to explain this paradox: (1) anatomic separation of mother and fetus; (2) antigenic immaturity of the fetus; or (3) immunologic “inertness” (tolerance) of the mother. In the intervening years, it has become apparent that both the mother and her fetus are immunologically aware of one another and yet tolerance exists for the most part. Furthermore, while the maternal immune response during pregnancy is qualitatively different, pregnancy does not result in an overall maternal immunosuppression.

It is clear that the growth and development of a semiallogeneic conceptus within an immunologically competent mother depends on the manner in which pregnancy alters the immune regulatory mechanisms. Historically, attention in addressing the “Medawar paradox” has focused exclusively on the mother, but it is now known that mammalian fetuses are capable of mounting immune responses in utero. The interplay between the fetal and maternal immune systems is complex and is a current active area on investigation.

INNATE AND ADAPTIVE IMMUNITY

Mammalian (including human) immune systems have two fundamental responses: an early “innate” and a later more specific and robust adaptive response.

The innate immune system response is the first line of defense and includes surface barriers (mucosal immunity), saliva, tears, nasal secretions, perspiration, blood and tissue monocyte-macrophages, natural killer (NK) cells, endothelial cells, polymorphonuclear neutrophils, the complement system, dendritic cells, and the normal microbial flora. The adaptive immune system is composed of cell-mediated (T lymphocytes) and humoral (B lymphocytes-antibodies) responses. Activation of T and consequently B lymphocytes is critical for the development of lifelong memory immune responses.

Innate immune cells have evolutionary acquired mechanisms that recognize the foreign nature of the inciting antigen and mount a transient protection within hours. There is no need for major histocompatibility complex (MHC) molecules. The epithelial cell interaction with the antigens induces the release of cytokines and chemokines, which attract the macrophages, dendritic cells, and NK cells. Macrophages and neutrophils then engulf and lyse the pathogens and produce cytokines. NK cells play the key role in destroying the virally infected cells. Damaged epithelial cells lead to the activation of complements. Complements can directly kill the microbes by punching holes in their membrane and indirectly by opsonizing them, which facilitates their phagocytosis. Complements also promote the inflammatory cell recruitment. The cytokines released from the immune cells activate the vascular endothelial cells, increasing permeability, allowing immune effector cells to penetrate into the tissues.

The critical link between the innate immune response and the adaptive immune response is antigen presentation. Foreign proteins that are phagocytosed are processed intracellularly, and then expressed on the cell surface complexed with MHC II. Additionally, the presenting cells provide critical secondary signals (through cell surface molecules) that are permissive for appropriate T-cell activation. Among the most efficient antigen-presenting cells are dendritic cells.

Dendritic cells play a key role in alerting the adaptive immune responses. Immature dendritic cells engulf the pathogens, carry them to the lymph nodes, and present them to CD4+ T lymphocytes. Activated T cells develop surface receptors for specific foreign antigens and undergo clonal proliferation. Cytotoxic (activated) T cells can directly kill target cells expressing viral antigens together with MHC I. In contrast to antigens presented in the context of MHC II, a portion of all cellular proteins are expressed on the cell surface of all normal cells in the context of MHC I. By this mechanism, the immune system can determine whether a cell is producing self proteins or if the cell has been altered (e.g., by virus) to produce foreign proteins.

Once CD4+ T cells are activated, they can direct an immune response by secreting proteins (cytokines) that activate surrounding cells. By secreting interferon-γ and interleukin-2 (IL-2), a CD4+ T cell induces a cellular immune response through CD8+ “killer” T cells. By secreting IL-4 and IL-5, CD4+ T cells promote B cells to proliferate and differentiate for immunoglobulin (antibody) production. B cells exposed to antigen for the first time produce immunoglobulin M (IgM). As the affinity of the immunoglobulin (antibody) increases, the B cell undergoes a genetic rearrangement and may produce a variety of different antibodies. The most specific are usually of the IgG subtype. IgG crosses the placenta and will accumulate into the fetus.

DEVELOPMENT OF FETAL IMMUNITY

The innate immune effector cells first arise from hematopoietic progenitors noted in the blood islands of the yolk sac. By 8 embryonic weeks, the fetal liver becomes the source of these cells, and by 20 weeks, the fetal bone marrow takes over.

Macrophage-like cells arise from the yolk sac around 4 weeks; by 16 weeks, a fetus has the same number of circulating macrophages as adults, but they are less functional. The fetus has fewer tissue macrophages. Immature granulocytes can be found in the fetal spleen and liver by 8 weeks. NK cells are detected in the liver by 8 to 13 weeks and complements 2 and 4 by 8 weeks. C1, 3, 5, 7, 9 are found in the serum by 18 weeks. Maternal complements do not cross placenta into the fetus. The complement system continues to mature after parturition, and adult levels are reached by 1 year of age. Skin, one of the main innate barriers, completes its development 2 to 3 weeks after birth.

The cellular component of the adaptive immunity, T cells, are also derived from hematopoietic progenitors that are first seen in the blood islands of the yolk sac by 8 weeks. To differentiate into activated T cells, they must first migrate to the thymus gland, a relatively large organ in the fetus, the sole function of which appears to be to nurture and develop T cells. After maturation, T cells develop into either CD4 or CD8 types according to the surface receptor expressed. By 16 weeks, the thymus contains T cells in proportion to those found in the adult. In the newborn, the proportion of CD4 helper T cells and CD8 T cells is similar to that in the adult. However interferon-γ production is less efficient in fetal CD4 helper T cells.

Fetal B cells are first detected in the liver by 8 weeks, and around the second trimester, B-cell production is mostly from the bone marrow. Fetal B cells secrete IgG or IgA during the second trimester, but IgM antibodies are not secreted until the third trimester. Cord IgM levels greater than 20 mg/dL suggest an intrauterine infection. Maternal IgG crosses the placenta as early as the late first trimester, but the efficiency of the transport is poor until 30 weeks. Significant passive immunity can be transferred to the fetus in this manner, and for this reason, premature infants are not as well protected by maternal antibodies. IgM, because of its larger molecular size, is unable to cross the placenta. The other immunoglobulins (IgA, IgD, and IgE) are also confined to the maternal compartment, but the fetus can make its own IgA and IgM.

Physiologically, newborns have higher neutrophil and lymphocyte counts. The neutrophil counts decrease by 1 week of age, whereas lymphocyte counts continue to rise. The proportion of lymphocytes and absolute lymphocyte counts are higher in neonates compared with adults.

IMMUNOBIOLOGY OF THE MATERNAL-FETAL INTERACTION

Pregnancy poses a special immunologic problem. The embryo must implant and cause a portion (placenta) to invade the uterine lining in order to gain access to the maternal circulation for nutrition and gas exchange. The maintenance of the antigenically dissimilar fetus in the uterus of the mother is of primary importance in obstetrics. The total picture of immune regulation at the maternal-fetal interface is yet to be elucidated, but the following is a synopsis of the current level of understanding.

The primary sites of modulation of the maternal response are the uterus, regional lymphatics, and placenta. In the uterus, NK-cell–mediated inflammation is necessary for the appropriate attachment and penetration of the fertilized egg into the uterine wall and for early placental development, whereas increased suppressive T cells, the presence of molecules that inactivate the previously activated maternal lymphocytes (CTLA4), and the absence of B cells provide the needed immune quiescence to allow for successful pregnancy. The placenta and the membranes provide the key barrier in protecting the growing fetus from microbial pathogens and toxins circulating in the mother’s blood. Syncytiotrophoblast, which makes up the cell barrier between the fetal and maternal blood in the placenta, does not express classic self and nonself MHC I and II molecules. Deeper trophoblastic cells do not express MHC II, but some express MHC I and are not stimulatory. This allows protection from invading microbes but at the same time prevents the destruction of the fetus.

HLA-G suppresses the adaptive and innate immune responses in the placenta and promotes the release of antiinflammatory cytokines such as IL-10. The soluble forms of HLA-G are found in the blood of pregnant women. HLA-G is thought to act by suppressing the activity of uterine NK cells, which normally destroy cells that lack the expression of MHC I.

The understanding of mechanisms of immune regulation is largely derived from the study of autoimmune diseases. Many disease-free individuals possess potentially autoreactive T cells. A variety of mechanisms regulate the response of CD4+ T cells so that they don’t react against self antigens. Naïve T helper cells have the potential to become a variety of specialized T cells. There are now four well-recognized possibilities, each with a unique role and ability to cross-regulate. TH1 cells drive cell-mediated immunity by secreting IL-2 and interferon-γ. TH2 cells drive humoral reactions (antibody and B cell) by secreting IL-4. Regulatory T cells are a subtype that suppresses ongoing cellular immune reactions through cell contact. Lastly, there is a newly described proinflammatory population of T cells (TH17) that secrete IL-17. These TH17 cells under normal circumstances are important for the clearance of parasites, bacteria, and fungi, but under pathologic conditions, they appear to play a crucial role in the development of autoimmune disease. One of the hallmarks of T-cell regulation is the ability of these specialized T-cell populations to cross-regulate.

ROLE OF IMMUNOLOGY IN PREGNANCY-ASSOCIATED CONDITIONS

The major pregnancy-associated immunologic disease process is hemolytic disease of the newborn. Rh factor incompatibility, which is the most important of these conditions, is discussed in Chapter 15.

Hemolytic disease secondary to non-Rh sensitization and the destruction of lymphocytes or platelets secondary to sensitization against specific surface antigens have the same pathogenesis. Fetal cellular antigens leak into the maternal circulation, primarily at birth, and initiate an immune response. The reaction to these foreign antigens (primarily Rh) leads to a humoral response. Initially, only a weak IgM response can be measured. In a subsequent pregnancy, the maternal immune system undergoes a memory response, and highly specific IgG molecules are secreted by memory plasma cells. These antibodies cross the placenta and attach to the fetal Rh-bearing RBCs. The consequence is the sequestration and destruction of fetal RBCs in the fetal spleen, leading occasionally to profound fetal anemia and hydrops.

Although the Rhesus antigen (Rh) is the most common cause of fetal alloimmunization-induced fetal anemia, other antigens are also implicated. The Kell antigen has the additional problem that the maternal IgG against Kell also suppresses erythropoiesis in the fetal bone marrow. ABO incompatibility does not lead to a significant maternal immune response to fetal antigens. Thus, the nature of the antigen is important, but the reason certain antigens are potentially pathogenic is poorly understood.