Antepartum period

“Pregnancy is an immunological balancing act in which the mother’s immune system has to remain tolerant of potential major histocompatibility (MHC) antigens and yet maintain normal immune competence for defense against microorganisms.”¹⁶⁷ The immune changes that occur systemically in the innate and adaptive systems and those that occur at the site of the fetal-maternal interface are described in this section.

Alterations in cell-mediated immunity.

Cell-mediated immunity is somewhat suppressed during pregnancy. Lymphocyte and macrophage synthesis, activation, and function are altered slightly in pregnancy secondary to influences from estrogens, corticosteroids, progesterone, α-fetoprotein (AFP), hCG, human placental lactogen (hPL), prostaglandins, and serum proteins.⁴⁷ Corticosteroids suppress activation of T-cell lymphokines, phagocytic activity, and lymphokine responsiveness of the macrophages.⁴⁷ Prostaglandins (especially PGE₁ and PGE₂), hPL, and AFP also appear to have an immunosuppressive role during pregnancy. AFP may induce production of regulatory T lymphocytes (CD4⁺/CD25⁺).⁴⁸

Most investigators report that the total number of lymphocytes does not change significantly during pregnancy.^48,168 Some investigators have reported a decrease in the T-helper–to–T-suppressor (CD4⁺/CD8⁺) ratio. However, most reports indicate that the number of TCD4⁺ (T-helper cells) decrease progressively to term, while the number of T-suppressor cells (TCD8⁺) tend to remain relatively unchanged.⁴⁸

Because TCD4⁺ cells normally augment the cytotoxic responses involved in graft rejection, a decreased number of these cells may help protect the fetus from rejection by the mother. T-suppressor cell function may increase in late pregnancy and suppress B-cell function.¹⁰⁷ Decreased T-lymphocyte function and efficiency may increase the risk of viral and mycotic infections.

Alterations in antibody-mediated (humoral) immunity.

Although a decreased response of B lymphocytes to antigen stimulation in late pregnancy and after birth has been reported by some authors and changes in levels of specific immunoglobulins have been documented, the antibody-mediated immune response is not significantly altered during gestation.

While a few studies have reported an increase in the number of B cells during pregnancy, most studies do not support this finding.⁴⁸ Some investigators have found that levels of maternal IgG fall as gestation progresses, with decreases ranging from 30% to 40% after 28 weeks.⁴⁸ However, others have found relatively little change. A decrease in IgG has been attributed to hemodilution of pregnancy, enhanced loss of IgG in the urine, and transfer of maternal IgG to the fetus in the last trimester. This relative decrease in IgG, along with alterations in the WBC population, may increase the risk of bacterial colonization with certain pathogens (e.g., streptococci).

Immunoglobulin A (IgA) decreases or remains stable during gestation, immunoglobulin M (IgM) remains stable or may decrease slightly, immunoglobulin E (IgE) undergoes minimal or no change in levels, and immunoglobulin D (IgD) increases until term. The slight decrease in serum IgA may reflect increased levels of IgA found in saliva and other mucosal fluids.⁴⁸ The specific role of IgD in pregnancy is unknown.

Trophoblast and major histocompatibility antigens.

The syncytiotrophoblast does not express either class I or class II MHC antigens, which are the main T cell targets in transplantation rejection.¹²⁴ The cytotrophoblast has a unique nonclassical MHC-I surface antigen, HLA-G, which does not stimulate the classic cytotoxic T-cell response.⁸⁵ HLA-G has a Fas/Fas ligand pathway for killing activated T cells and may help prevent maternal rejection of the fetus by inducing apoptosis of activated maternal T cells.^32,85 HLA-G inhibits NK cell cytotoxicity and dendritic cell (an antigen presenting cell) maturation.^50,176 HLA-G synthesis may be stimulated by IL-10 from the placenta. Extravillous trophoblast expresses HLA-G, HLA-C, and HLA-E (nonclassical MHC-I molecules that help these cells to evade maternal NK toxicity).^111,136,176 HLA-G acts on cells of both the innate and adaptive immune systems and has a major role in reprogramming maternal immune responses at the maternal-fetal interface.¹³⁶ Soluble HLA-G (sHLA-G) molecules are found in maternal plasma and increase from the first trimester on, peaking in the third trimester.¹³⁶ Decreased expression of HLA-G on the extravillous trophoblast, seen in women with recurrent abortion and preeclampsia, alters conversion of the spiral arteries (see Chapter 3).^136,176 Decreased sHLA-G is found with placental abruption, miscarriage, and preeclampsia.¹³⁵

Trophoblastic cells (specifically the villous cytotrophoblast and extravillous trophoblast) express TLRs and may be able to initiate an innate immune response in the presence of microorganisms at the site of implantation.^2,106 In addition, trophoblastic cells contain IDO, which enzymatically degrades tryptophan, a protein essential for T-cell proliferation, and TNF ligands that induce apoptosis. Together these molecules can kill activated immune cells.¹⁵⁸

Natural killer cells.

Two subsets of uterine NK cells are seen: endometrial NK cells, seen during the menstrual cycle, and decidual NK cells, which are seen during pregnancy.^124,182 Decidual NK cells are critical for pregnancy maintenance.⁷² The first direct contact between maternal and fetal tissue occurs 6 to 7 days after conception at the time of implantation. Subsequently, the extravillous trophoblast cells invade the maternal endometrial lining and erode the endothelial tissues that line the maternal spiral arteries (see Chapter 3). NK cells in the pregnant decidua are phenotypically distinct from the NK cells in systemic circulation. Peripheral NK cells express CD56^dim, CD16⁺, and CD160⁺, a combination of characteristics that allow them to be highly cytotoxic. Conversely, decidual NK cells express CD56^bright, CD16⁻, and CD160⁻, which allows them to produce cytokines such as IL-8 and IL-10 that are beneficial for trophoblastic invasion.^{69,72,95,111,131} These NK cells also secrete vascular epithelial growth factor (GF) and placental GF, which are angiogenic factors that promote trophoblast invasion and vascular remodling.^111,124 NK cells accumulate at the site of implantation and in the decidua. They recognize HLA-G, HLA-C, and HLA-E on the invading trophoblast and influence production of cytokines and cytolytic factors that facilitate decidualization and control of trophoblast invasion, angiogenesis, and growth.^{86,95,107,119,176} Galectin-1 (Gal-1) is a carbohydrate binding protein with immunoregulatory functions that is found in high levels in uterine NK cells; Gal-1 is also found on trophoblast cells and may help reduce their cytotoxicity.^72,130 Up-regulation of Gal-1 induces differentiation of dendritic cells into a phenotype that dampens Th1 responses and suppresses autoimmune inflammation.¹¹⁵ Trophoblast HLA-G can block receptors on the NK cell that initiate cell lysis. Thus the NK cell is altered to augment those functions that protect the conceptus while the general cytotoxic roles are down-regulated. Figure 13-6 illustrates how HLA-G on the trophoblast may inhibit maternal NK cells and block NK cytotoxicity toward fetal cells. Maternal stress, smoking, infection, and other factors can alter the NK phenotype and increase the risk of pregnancy complications.⁷²

Decidual macrophages.

Macrophages cluster at the maternal-fetal interface and near the spiral arteries during trophoblast invasion (see Figure 13-5).³ These macrophages produce IL-10, IDO, PGE₂, and other anti inflammatory molecules that trigger alloreactivity by the T cells to further protect the fetus.^113,158 Placental growth hormone (see Chapter 19) may also alter the maternal immune system.¹⁵⁸ Annexin II, a glycoprotein that binds to phospholipids, is produced by the placenta and may inhibit lymphocyte proliferation and IgG and IgM secretion at the placental site. Macrophages stimulated by Th1 cytokines or bacterial products develop a M1 phenotype and produce nitric oxide and free radicals to defend against microorganisms. Macrophages stimulated by Th2 cytokines develop a, M2 phenotype and have immunosuppressive properties. M2 is the common phenotype of decidual macrophages involved in costimulatory signaling.¹¹³

T cells and the TH1/TH2 switch.

Overall, there are more TCD8⁺ cells than CD4⁺ cells in the maternal decidua, which causes immunosuppressive activity to predominate.¹⁰⁷ Changes in the balance of the different T-helper subsets (Th1 versus Th2) result in strengthening of Th2 (antibody-mediated) responses and cytokines (IL-3, IL-4, IL-5, IL-6, and IL-10) and a reduction in Th1 (cell-mediated and graft rejection) responses and cytokines (IL-2, TNF-α, and IFN-γ). This distribution of cytokines at the maternal-fetal tissue interface (see Figure 13-6) is important in implantation, pregnancy maintenance, and maternal tolerance of the fetus. The Th2-specific cytokines IL-4, IL-5, and IL-10 inhibit inflammation and some macrophage functions, and down-regulate IFN-γ production, whereas the Th1 cytokines are the primary effectors of phagocytosis.^{39,111,126,158} T-regulatory (Treg) cells (see Box 13-2 on page 446) normally account for 5% to 10% of peripheral CD4⁺ T cells. These increase two- to threefold during pregnancy beginning prior to implantation, peaking in the second trimester, and decreasing by term (this decrease correlates with the decrease in progesterone).^111,127 Decreased Treg cells are seen with spontaneous abortion.^111,127 The maternal T cells interact with trophoblast cells to support remodeling of the uterine vasculature by removing apoptotic cells, producing matrix proteases, mediating immunotolerance of the fetus, and protecting the fetus from pathogens.¹¹³

Nevertheless, the mother initially creates a weak immune response to the fetus/placenta, as evidenced by production of antibody to paternal MHC antigens, production of specific T cells, and weak cellular sensitivity to paternal and fetal antigens.⁷⁵ This response usually results in an activation (facilitation) reaction rather than rejection response that is mediated by Th2 helper cells with release of Th2 cytokines, which down-regulate Th1 cytokines such as IL-2, IFN-γ, and TNF-α. As a result, maternal immune responses are down-regulated locally at the maternal-placental interface, but are not significantly affected at the systemic level.³⁹ Failure of Th2 responses to increase or of Th1 responses to decrease is associated with an increased risk of recurrent abortion.^25,101

Role of progesterone.

Progesterone promotes production of IL-4 and IL-6, the Th1-to-Th2 switch, and IL-4.^31,50,126 Progesterone also stimulates activated lymphocytes and decidual cells to synthesize progesterone-induced blocking factor (PIBF).^39,155 PIBF stimulates B-cell production of asymmetric antibodies, which are antibodies that have a mannose-rich oligosaccharide group present on one of the Fab regions. Asymmetric antibodies cannot initiate complement or phagocytosis but they can combine with antigen. The result of this combination is an antigen-antibody complex that is univalent and functions as a “blocking antibody” that prevents further antigen-antibody interaction. PIBF also inhibits the cytotoxicity of NK cells.^39,59 Intrauterine inflammation and infection lead to decreased progesterone function and increased proinflammatory cytokines.³¹ Progesterone may up-regulate TLR-4 and suppress TLR-2 to protect against preterm delivery.³¹

Immunologic properties of human milk

The newborn is immunologically immature and therefore vulnerable to infection. Human milk contains many immunologic components, including leukocytes, immunoglobulins, and other proteins (see Table 5-4). Immunologic benefits for the breastfeeding child include lowered risk of developing asthma, cow’s milk allergy, food allergy, gastrointestinal (GI) and respiratory infections, necrotizing enterocolitis, diabetes mellitus, and some immune disorders such as Crohn’s disease, celiac disease, and multiple sclerosis.^45,87,116

The leukocytes in human milk are primarily monocytic macrophages (85% to 90%) and lymphocytes (10% to 15%), with some neutrophils and epithelial cells.^45,116 Monocytic macrophages in human milk synthesize complement, lysozyme, and lactoferrin; transport immunoglobulin; and protect against necrotizing enterocolitis. These cells also have phagocytic activity against Staphylococcus aureus, E. coli, and C. albicans and may help regulate T-cell function.^116,175

Similar concentrations of B and T lymphocytes are found in breast milk. B lymphocytes in human milk produce IgA, IgG, and IgM. T cells produce interferon, macrophage migration-inhibiting factor (MIF), and other cytokines. Because the neonate’s own T cells are functionally immature, human milk may provide significant protection against gram-negative organisms. Human milk often contains antibodies against the O and K antigens of several E. coli serotypes, including K1, which has been associated with neonatal meningitis.

IgM levels are highest in colostrum, decrease after 5 days, and then remain constant for at least 180 days.⁷⁰ Levels of IgG in human milk are also consistent for at least the first 180 days. The immunoglobulin found in highest concentrations (90%) in colostrum and human milk is secretory IgA (sIgA). Levels of sIgA are highest in colostrum, fall gradually until 12 weeks, and then remain stable for the next 2 years of lactation.⁹⁰ The secretory component attached to the IgA monomer protects the IgA molecule from proteolytic digestion in the GI tract. sIgA does not enter the circulation from the gut but provides localized barrier protection by attaching to the mucosal epithelium and preventing attachment and invasion by specific infectious agents.¹¹⁶ sIgA also neutralizes certain viruses and bacterial enterotoxins and inhibits intestinal absorption of proteins and other macromolecules found in foods.¹¹⁶ The latter function may provide protection against the development of allergies. sIgA actions are enhanced by complement.

Human milk contains C3 and C4 and produces complement by the alternative pathway, which can be activated by factors such as bacterial products and circulating proteins. Most of the immunoglobulins in human milk are produced by sensitized antibody cells in the breast that have been transported to that site from gut-associated (i.e., maternal intestinal) lymphatic tissue and bronchotracheal-associated lymphatic tissue. Thus sIgA that is specific for a wide variety of respiratory and enteric bacterial and viral organisms can be found in human milk.⁷⁰ Depending on the mother’s immunologic experience, the immunoglobulins in human milk may provide the infant with protection against pathogens such as diphtheria, pertussis, Shigella, Salmonella, poliovirus, and echoviruses.

Human milk contains other nonspecific protective factors that act synergistically with each other and sIgA to provide immunity to the newborn.^{70,83,169,180} Lactoferrin, α-lactalbumin, and sIgA form the major whey proteins in human milk and constitute 60% to 80% of total human milk protein. Lactoferrin is an iron-binding protein that restricts the availability of iron needed for growth by certain fungi and bacteria such as S. aureus and E. coli. Folic acid and vitamin B₁₂-binding protein restrict available folate and vitamin B₁₂ for bacterial and fungal growth.

Lysozyme is a bactericidal enzyme that lyses the cell walls of many bacteria and enhances Lactobacillus growth. Levels of lysozyme in human milk are several hundred times higher than in cow’s milk. Lactoperoxidase inhibits bacterial growth and bifidus factor, a nitrogen-containing polysaccharide, promotes growth of anaerobic lactobacilli that compete with invasive gram-negative organisms. This factor also limits growth of Shigella and Salmonella. Lysozyme also acts with other substances to destroy E. coli and some strains of Salmonella. Factors in human milk that promote lactobacilli growth include lactose, low pH, and buffers.

Other immune components of human milk include. MIF; antiviral and antistaphylococcal factors; interferon (which prevents viral replication); lipase (which increases levels of free fatty acids and monoglycerides that may act against certain viruses); and oligosaccharides (which are complex carbohydrates that prevent attachment of bacteria and other antigens to gut epithelial receptors). Human milk acetic and lactic acid are two by-products of breast milk digestion in the gut. These acids decrease stool pH and inhibit growth of Shigella and E. coli. In addition, human milk can induce the production of immune factors such as sIgA by the infant. Maternal T cells in breast milk stimulate development of immune cells in the newborn thymus; thus the thymus gland of a breastfed infant is larger than the thymus in an infant receiving formula.^45,116

In preterm infants, human milk may have a critical role in providing protection against infection and the development of allergies. The preterm infant’s gastrointestinal tract lacks many intrinsic local host defense factors including sIgA, lysozyme, and gastric acid. In addition, the intestinal mucosal barrier function is more immature (see Gut Host Defense Mechanisms).¹⁷⁵ As a result, the preterm infant is at higher risk for bacterial penetration through the intestines and development of sepsis and necrotizing enterocolitis compared to term infants. The lack of sIgA and immaturity of the intestinal mucosa increase the likelihood of foreign macromolecules entering the circulation, which may increase the risk of allergies in genetically susceptible infants.¹⁷⁵ Human milk may enhance maturation of the intestinal mucosal barrier, thereby reducing the risk of both infections and allergies. Increased levels of sIgA, lactoferrin, and lysozyme have been found in milk from mothers of preterm infants.¹⁷⁵ Thus mothers of preterm infants may have an important immune adaptation that provides additional protection from infection for their infants.

Spontaneous abortion

There are multiple etiologies for spontaneous abortion. Immunologic factors include activation of an immune response secondary to microbial infection (e.g., chlamydia, listeriosis, parvovirus B19, or toxoplasmosis), an exaggerated maternal immune response to trophoblastic invasion (e.g., predominance of Th1 reactivity), a cytokine-induced failure of the ovary to produce sufficient progesterone, and the presence of autoimmune antibodies such as antiphospholipid antibodies that interfere with placentation.^138,142,176 Decreased expression of HLA-G on the extravillous trophoblast is seen in some women with recurrent abortion and is associated with altered conversion of the spiral arteries.^136,176 Decreased sHLA-G is also seen with spontaneous abortion.¹³⁵ Spontaneous abortion is also associated with decreased Treg cells in the decidua and increased peripheral T-cell activation.^30,111,127 Voisin suggests that some spontaneous abortions before 3 months in primiparous women may be secondary to a defect in active maternal tolerance of the fetus, whereas rejection after the third month or in women who have had a prior pregnancy may be due to excess rejection-type responses with increased levels of Th1 inflammatory cytokines such as IFN-γ, TNF-α, and TNF-β.¹⁶⁸

Women who experience recurrent pregnancy loss, that is, three or more consecutive spontaneous abortions, exhibit decidual NK cell activity that is similar to the activity of NK cells in peripheral circulation, and a concomitant shift toward exaggerated Th1 immune responses instead of the usual pregnancy-exaggerated Th2 responses.³⁸ It is unclear whether the altered NK cells are the result of the Th1 predominance or whether the Th1 response is the result of a different population of decidual NK cells that cause spontaneous abortion instead of trophoblast expansion.

Recent evidence suggests that inadequate progesterone production occurs when the hypothalamic-pituitary-gonadal axis is inhibited by systemic immune activation that triggers a noninflammatory pathway for pregnancy failure.⁴³ This cytokine-induced failure of the ovary to produce progesterone results in resorption of the embryo. Both NK cells and TNF-α are effectors that can block this process by inhibiting the suppressor of cytokine signaling (SOCS) proteins, which are involved in the inhibition of progesterone production by the ovary.^43,142

Risk of maternal infection

Even with alterations in host defense mechanisms, most women are not significantly immunocompromised during pregnancy nor do they experience a significant increase in the severity of bacterial infections during pregnancy.¹⁰⁷ However, suppression of maternal Th1 cell-mediated immunity may increase maternal susceptibility to, but not necessarily severity of, certain infections, especially viruses and certain opportunistic pathogens, including C. albicans, Pneumocystis jiroveci (formerly Pneumocystis carinii), T. gondii, L. monocytogenes, Streptococcus pneumoniae, Neisseria gonorrhoeae, Mycobacterium tuberculosis, polio, rubella, influenza, varicella, CMV, and herpes simplex virus (HSV).^40,47,107 Genetic polymorphisms in the genes that encode modulators of innate mucosal immunity, such as IL-6, IL-8, and TNF-α, may increase the risk of altered vaginal microflora.⁵² Alterations in neutrophil chemotaxis and function also contribute to the persistence of infections during pregnancy.^48,129 Changes in the frequency of infections during pregnancy are also due to other reasons. For example, the increased incidence of urinary tract infections and pyelonephritis during pregnancy is primarily due to anatomic alterations in the urinary tract that result in urinary stasis (see Chapter 11).

Viral infections, however, are seen more frequently during pregnancy, especially during the second and third trimesters, and tend to be more severe. For example, in pregnant women, primary varicella is more likely to result in pneumonia and increased morbidity and the risk of complications with influenza is increased (see Chapter 10).⁴⁰

Although methodological limitations are prevalent, most studies of HIV infection find that pregnancy does not appear to significantly increase the risk of death, disease progression, or CD4⁺ counts below 200, although there are suggestive trends for these events to occur in some studies.⁸ Antiviral therapies during pregnancy have significantly reduced perinatal transmission and improved outcomes for HIV-infected women and their infants.^8,40,104 Infected women experience a greater reduction in TCD4⁺ cells during pregnancy and a longer time to return to normal after pregnancy than noninfected women, but the effects are equivocal.^8,80

Fungal infections are also seen more frequently during pregnancy with an increase in symptomatic vulvovaginitis during the third trimester. The increased incidence of fungal infections is related to increased adherence of Candida to vaginal mucous membranes, increased glycogen in the vagina, enhanced proliferation of Candida under the influence of estrogen, and alterations in cell-mediated immunity.⁴⁰ The incidence of infection with protozoa (e.g., malaria, amebiasis) and helminthic (intestinal parasites) organisms is increased in countries where these organisms are prevalent. During pregnancy, malaria is more frequent and more severe, with an increased risk of sequelae. The malaria parasite has an affinity for placental tissue, leading to stillbirth and preterm birth. In addition, malaria is a major cause of low birth weight in endemic areas.⁴⁷ Latent malaria can be reactivated by iron overload during pregnancy.

Inflammation, infection, and preterm labor

Inflammation (decidual, chorioamnionic, or systemic) is a significant etiologic factor in preterm labor (see Chapter 4 and Figure 4-7). “Preterm labor is a syndrome initiated by multiple mechanisms including intrauterine infection, uteroplacental ischemia or hemorrhage, uterine overdistention, cervical disease, stress, endocrine disorders, and other immunologically mediated processes.”^{31,p. 209} Many of these processes lead to inflammation at the maternal-fetal interface. Onset of labor involves inflammatory mediators, which these events can trigger.

Both acute and chronic maternal infections are associated with preterm labor. Intrauterine infection leads to activation of the innate immune system. Recognition of microorganisms by TLRs results in release of inflammatory chemokines and cytokines. Proinflammatory cytokines (IL-1β, TNF-α, IL-8, Il-6) in combination with microbial endotoxins increase prostaglandin production and release of matrix metalloproteases and other substances that can lead to cervical ripening, fetal membrane rupture, and increased myometrial contractility.³¹

Urinary tract infections have also been associated with preterm labor (see Chapter 11). Maternal fever can lead to maternal dehydration, resulting in increased uterine activity, which, along with elaboration of prostaglandins, may result in initiation of labor. In women with acute infections, high temperature alone may lead to the release of catecholamines and corticotropin-releasing hormone and increase uterine irritability. Preterm labor is discussed further in Chapter 4.

Although high levels of IgG and sIgA in maternal cervical mucus may provide protection against infection from vaginal pathogens, vaginal and cervical organisms have been linked with the initiation of preterm labor and premature rupture of membranes.^63,139 Both these events are probably mediated via inflammatory cytokines that stimulate prostaglandin E₂α production.¹³⁹

Chorioamnionitis and cerebral palsy

Chorioamnionitis or inflammation of the placental membranes increases the risk that the fetus will develop cerebral palsy.^53,178 Although the exact mechanism has not been completely determined, several processes may contribute to the underlying pathophysiology. Elevated levels of fetal cytokines produced in response to maternal infection may directly injure the fetal brain or cause damage indirectly by increasing the permeability of the blood-brain barrier and facilitating passage of cytokines and microbial products into the brain. The presence of microbial products may induce an inflammatory process in the brain that damages the fetal brain and induces periventricular leukomalacia. Inflammation of the placental membranes may contribute to cerebral palsy by interfering with gas exchange and inducing a hypoxic-ischemic injury in the fetus (see Figure 6-4). Maternal fever may raise the core temperature of the fetus, which could be harmful to the fetal brain. Finally, maternal infection could cause direct infection of the fetal brain. Although the fetus is more susceptible to adverse effects of maternal infection early in gestation, the placenta is a poorer barrier against some pathogens late in gestation. Consequently, while adverse fetal effects of maternal infection are more likely at early gestational ages, the incidence of fetal infection is more likely late in pregnancy.¹⁷⁸ The attributable risk of cerebral palsy secondary to chorioamnionitis is estimated as approximately 12% in term infants and approximately 28% in preterm infants.¹⁷⁸

Immunization and the pregnant woman

Alterations in the immune system during pregnancy do not seem to significantly alter the woman’s responses to immunization.^42,47,49 Potential risks associated with immunization during pregnancy include fetal viremia, teratogenesis, interference with development of the infant’s response to immunizations during childhood, and maternal side effects that might compromise uteroplacental function.¹⁴³

Ideally, immunization of women of childbearing age should occur at least 3 months before conception (or immediately after delivery) to reduce the risk of infection and adverse fetal effects.^13,42 Immunity can be achieved by either passive or active means. At times, passive immunizations may be recommended during pregnancy after accidental or potential exposure to an organism associated with significant maternal or fetal risks.¹³ Passive immunity involves transfer of antibodies from an actively immunized to a nonimmunized person and confers short-term protection until the antibodies are catabolized by the nonimmunized person’s system. The physiologic transfer of antibodies from mother to fetus and injection of γ-globulin are both examples of passive immunity.

Active immunity involves exposure to some form of the antigen (attenuated or live organisms rendered noninfectious, inactivated or killed organisms, inactivated exotoxins or toxoids) that stimulates the production of antibodies and memory cells against that antigen by the nonimmunized person. Active immunization induces long-lasting or permanent immune responses.^42,143

Immunization of pregnant women with live attenuated viruses or bacteria is not recommended because there is a small risk of transfer of the antigen to the fetus.^42,154 Immunization with measles (rubeola), mumps, and rubella vaccines is specifically contraindicated because of potential adverse fetal consequences. However, if a woman is accidentally vaccinated for rubella early in pregnancy, the risk of adverse fetal effects appears to be low, and therapeutic abortion is not recommended.⁴² Inactive (i.e., dead) viruses (e.g., pneumococcal, influenza, diphtheria, tetanus, hepatitis B) are considered safe for use in pregnancy.^13,14,42,154 Since the risk of influenza-related morbidity is increased during pregnancy, influenza vaccinations are recommended for all pregnant women during flu season, regardless of trimester.^15,42 Administration of immunization for rubella during the first few days after birth is often recommended. The woman who receives rubella vaccine should be counseled to use methods to prevent conception for at least 4 weeks.^13,143

Blood and blood products given within 14 days of active immunization may interfere with the effectiveness of the vaccine, because blood may contain antibodies against the antigens in the vaccine and therefore interfere with the woman’s own immune response.¹⁷² Although there is a small theoretic risk of transfer of antigens through breast milk or nasopharyngeal secretions from a recently immunized woman to her infant, this is a rare event without significant reported morbidity.¹⁷² Current recommendations regarding specific immunizations during pregnancy can be found in several reviews.^{13,49,143,154}

Malignancy and pregnancy

Theoretically, alterations in the maternal immune system could increase the risk of malignancy because cell-mediated immunity, which is suppressed in the pregnant woman, normally protects against virally induced tumors. Some investigators have suggested that there is an increase in rate of progression and decreased survival times in women with breast and cervical cancer during pregnancy, but this has generally not been supported.³³ However, a delay in diagnosis (due to breast changes during pregnancy with increased engorgement and nodularity) may result in a more advanced stage at time of diagnosis.³³ Gestational breast cancer (diagnosis during pregnancy, lactation, or the first year postpartum) tends to involve “larger tumors, more frequent nodal involvement, metastasis and vascular invasion.”^{33, p. 893} The effect of pregnancy on malignant melanoma is also variable.³³ Melanoma may intensify during pregnancy and, then recede or disappear after delivery.¹⁷¹ The basis for this change has been attributed to increased levels of melanocyte-stimulating hormone during pregnancy (see Chapter 14) and hormonal stimulation of estrogen receptors found on melanoma cells.

Immunologic aspects of preeclampsia

Preeclampsia is a complex, multifaceted disorder involving alterations in many major body systems (see Chapter 9 and Table 9-5). There is increasing evidence that vascular endothelial cell injury is an early event in the pathogenesis of preeclampsia.^132,133,148 The exact cause of this damage is unclear but an immunologic role has been suggested.^{9,132,133,148} Factors that support an immunologic basis for preeclampsia include an increased incidence of the disorder in primigravidas or, in the case of multiparas, a pregnancy with a new partner or different sperm donor; an increase in pregnancies with a large placental mass (e.g., multiple pregnancies) or hydatidiform mole; a decreased incidence in repeat pregnancies (even if the previous pregnancy ended in a miscarriage) with the same father and consanguineous marriages; a decrease with longer cohabitation with the father before pregnancy (and thus exposure to paternal antigens in semen); and the presence of pathologic changes in the uterine vessels near the placental site that are similar to those with allograft rejection.^132,133,148

Specific alterations in the immune system have been observed in women with preeclampsia. Many of these changes are exaggerations of the inflammatory changes normally found during pregnancy. However, women with preeclampsia have a further reduction of NK cell activity with increased peripheral and reduced decidual NK cells (which alters placental development and spiral artery remodeling), altered macrophage activation, more TCD8⁺ cytotoxic cells, decreased TCD4⁺-to-TCD8⁺ ratio, more immune (antibody-antigen) complexes, increased levels of fibronectin, decreased IDO activity, and alterations in complement.^{9,25,132,133,148} In women with preeclampsia the usual Th1/Th2 pattern during pregnancy is altered so that Th1 predominates with increased levels of inflammatory cytokines, including TNF-α, IL-2, IL-6, and IL-8, but reductions in IL-10.^{9,31,133,138,148} In addition, increased expression of TLRs by the interstitial trophoblast or alterations in TLR signal transduction may contribute to local abnormal cytokine levels that lead to the development of preeclampsia.^9,77,107,135 Decreased placental HLA-G expression and sHLA-G are also reported.^{100,133,136,148,176} These changes alters conversion of the spiral arteries and increase the risk of vascular endothelial injury, which appears to be the underlying mechanism that results in preeclampsia.

The pregnant woman with an autoimmune disease

The effect of pregnancy on autoimmune disorders is varied; individual women experience improvement, exacerbation, or no change depending on the disorder. These differences may be related to the immune mechanism involved in the specific disorder; that is, whether the disorder involves alteration in Th1 responses (which decrease during pregnancy) or Th2 responses (which increase). Autoimmune disorders are thought to impair T-suppressor cell activity, resulting in hyperactive B-lymphocyte response and production of autoantibodies that form immune (antibody-antigen) complexes with their target antigens.¹²² Autoantibodies damage tissue either by directly reacting with antigens on the surface of cells or by combining with antigens to form immune complexes.^121,122 The immune complexes activate the complement cascade, which in turn stimulates phagocytosis, inflammatory responses, and tissue damage.

Because the usual changes in the immune system during pregnancy are the exact opposite of these events, women with autoimmune disorders may experience an improvement in their symptoms.^121,122 For example, 75% of women with rheumatoid arthritis experience improvement during pregnancy (which is associated with increased Th1 mediators, which are decreased in pregnancy), followed by a relapse within the first 3 months postpartum.^92,111,184 Other changes during pregnancy that might lead to this amelioration include changes in plasma levels of maternal humoral factors, depression of cell-mediated immunity, and suppression of inflammatory reactions.^{92,97,111,122,184}

Pregnancy is unlikely to alter the natural history of SLE unless the woman has nephritis or is experiencing a flare at the time of conception.⁹⁷ However, SLE can adversely impact the course of pregnancy.³⁰ Women with mild disease that is under control for 6 to 12 months before and during pregnancy usually experience no exacerbation of SLE during pregnancy, and some may improve. Exacerbation, when it occurs, has been reported to be more frequent in early pregnancy and during the first 6 to 8 weeks after birth.¹⁸⁴ Postpartum exacerbation may represent a rebound phenomenon as suppression of cell-mediated activity is terminated.¹²²

SLE involves production of autoantibodies of the IgG class and increases in Th2 mediators, which are increased in pregnancy normally.¹²² Women with SLE who have anticardiolipin antibodies or lupus anticoagulant antibodies have an increased risk of thrombosis, spontaneous abortion, thrombocytopenia, preeclampsia, fetal growth restriction, and preterm birth.^{92,97,159,170} Lupus anticoagulant factor is an immunoglobulin that binds to prothrombin-activating complexes and predisposes the woman to recurrent thrombosis in the spiral arteries and placental infarction. Some women with SLE who have anti-Ro/SS-A or anti-LA/SS-B will have a fetus with neonatal lupus erythematosus.^92,103 These infants have congenital heart block, cutaneous lupus rashes, cytopenia, and possibly other systemic manifestations. This syndrome is usually transient and resolves after birth, although complete heart block may not be transient.⁹² Fetal heart block occurs because the anti-Ro/SS-A or anti-LA/SS-B antibodies lodge in the fetal cardiac conducting system and interfere with conduction pathways.²⁴

Fetal and neonatal complications associated with transplacental passage of maternal antibodies

Potentially damaging IgM class antibodies, such as the ABO antigens, and allergy-producing IgE antibodies generally do not cross the placenta. Smaller, potentially damaging maternal IgG antibodies may cross the placenta as a result of Rh incompatibility (see next section) or one of several maternal chronic diseases, leading to transient disorders in some neonates.⁶⁴ Neonatal effects from the passage of these IgG antibodies range from mild to severe. In general, if the disorder is not fatal during the perinatal period, manifestations are transient and regress as maternal antibody is catabolized.

Maternal Graves’ disease may involve transplacental passage of a thyroid-stimulating immunoglobulin resulting in transient neonatal hyperthyroidism (in approximately 1% of offspring) that can persist for up to 2 to 6 months.^84,128 Myasthenia gravis is associated with passage of maternal IgG against acetylcholine receptors, resulting in transient myasthenia gravis in 10% to 20% of offspring. Symptoms can last from a few hours to up to 3 months.¹⁵² Because symptoms usually develop after 12 hours of age, infants who appear healthy at birth may later develop respiratory failure.¹⁸ The delay in symptom onset may be due to transfer of anticholinesterase drugs from the mother or elevated AFP.¹⁵² Maternal antiplatelet antibodies induce fetal thrombocytopenia in up to 50% of the offspring of women with immune thrombocytopenia. The greatest neonatal risk is for severe hemorrhage in the perinatal period. In most infants, platelet levels reach lowest levels at 4 to 6 days after birth and return to normal by 1 to 2 months.¹⁸ Risk to infants from antibody passage in women with SLE is described in the previous section.

Rho(D) isoimmunization and ABO incompatibility

Rho(D) isoimmunization can be used as a model to examine the application of immunologic principles and to illustrate how the interaction of maternal and fetal host defense mechanisms can result in pathophysiologic processes during the perinatal period. Isoimmune hemolytic disease, hemolytic disease of the newborn (HDN), and erythroblastosis fetalis are all terms for a disorder caused by transplacental passage of maternal IgG antibody that reacts with antigens on the fetal red blood cell (RBC) and leads to cell lysis. The fetal-neonatal effects include an increased risk of neonatal hyperbilirubinemia and, in severely affected infants, can include severe anemia, congestive heart failure, and death. Because maternal antibody remains in the infant’s circulation, the hemolytic process continues after birth.

The Rh system involves a group of at least 45 different RBC surface antigens controlled by genes encoding Rh proteins (DCE). The Rh locus is on the short arm of chromosome 1.¹⁰² A related protein, Rh glycoprotein, is essential for expression of the Rh antigen. Antigens of the D group are the ones usually involved in incompatibility between mother and fetus. Rho(D) isoimmunization occurs when an Rho(D)-negative mother carrying an Rho(D)-positive fetus produces antibody against the D antigen on the fetal RBC. Isoimmunization can also occur with other RBC antigens such as Kell, Duffy, Kidd, MNS, and the ABO system.

Rho(D) isoimmunization is of particular clinical importance because the D antigen is a potent antigen, is present in large amounts on the fetal RBC, appears as early as 6 weeks’ gestational age, and stimulates formation of IgG-type antibody and memory cells in the mother.⁶² The amount of antigen necessary to trigger an immune response in the mother varies for each person, as does the intensity of the response by the mother’s immune system. The incidence of Rho(D) isoimmunization is relatively low, ranging from 10% to 14% if Rho(D) immune globulin (RhIG) is not given after birth to less than 2% if RhIG is given.^23,61 The R₂ phenotype (cDE) expresses the most D antigen and increases the risk of maternal sensitization.¹⁶² Rho(D)-negative women are unlikely to have antibodies against the D antigen unless they have been immunized during a previous pregnancy or from a mismatched blood transfusion. As a result, isoimmunization is rare in first pregnancies. Normally during pregnancy the small amounts of fetal blood (less than 0.05 mL) that cross the placenta and enter the maternal circulation are too small to trigger production of antibodies by the mother’s immune system. In a few women, however, as little as 0.01 mL of fetal blood has been reported to cause maternal immunization (sensitization).²³ Detectable fetal blood cells can be found in approximately 3% of pregnant women in the first trimester, 12% in the second trimester, and 45% in the third trimester.^62,162 Approximately 1% to 2% of Rho(D)-negative women develop anti-D antibodies during their first pregnancy.²³ This number can be reduced by prophylactic administration of RhIG during pregnancy.

At birth, larger quantities of fetal blood (0.5 mL or more) may enter the maternal circulation. This amount of fetal blood (if the fetus is Rho[D] positive) is sufficient to stimulate formation of both anti-D antibody and memory cells in many women (Figure 13-7, A). Formation of memory cells results in permanent immunization. During subsequent pregnancies, even a very small amount of blood from an Rho(D)-positive fetus entering the mother’s system may be enough to trigger memory cells to produce antibodies against the D antigen on the fetal RBC. The antibodies that are produced in this secondary response are predominantly of the IgG₁ and IgG₃ subclasses and are thus actively transported across the placenta (see Transplacental Passage of Maternal Antibodies) to the fetal circulation where they hemolyze fetal RBCs (see Figure 13-7, B). With development of RhIG (a human γ-globulin concentrate of anti-D), initial active immunization of most Rh-negative women can be prevented. RhIG is given prophylactically at 28 weeks to prevent immunization during pregnancy; in the first 72 hours after birth if the newborn is Rh-positive; or after any potentially immunizing events such as an abortion, ectopic pregnancy, amniocentesis, or significant antepartal bleeding. A dose of RhIG at 28 weeks provides protection for approximately 12 weeks (i.e., until term).^62,102 The incidence of immunization during pregnancy is 1.6% to 2%, decreasing to 0.1% to 0.18% with administration of both antenatal and postpartum RhIG.^62,102,162 RhIG does not cause hemolysis in the fetus even though the majority of the antibodies are transported across the placenta.^61,93,162

RhIG destroys fetal RBCs in the mother’s system before the foreign D antigen on these cells can be recognized by her immune system and trigger formation of antibodies and, more importantly, memory cells (see Figure 13-7, C). However, the exact mechanism by which RhIG acts to prevent alloimmunization is unclear.¹⁰² Three potential mechanisms have been suggested for the action of RhIG: (1) clearance of antigen from the mother’s system; (2) antigen-blocking by attaching to antigenic sites on the fetal cells, thereby preventing interaction with maternal lymphocytes; or (3) central inhibition of antibody production.^23,26,62,162 The last theory suggests that RhIG forms immune complexes with the Rho(D) antigen. Immune complexes suppress the stimulating effect of helper T lymphocytes, which in turn suppresses antibody formation by B lymphocytes.^62,162

The standard dose (300 mcg) provides protection for up to 15 mL of fetal RBCs.⁶² Because development of an adequate antibody response to a specific antigen can take days or weeks in persons not previously sensitized, RhIG can probably be given up to at least 2 weeks after birth (possibly longer) if omitted earlier for some reason.⁶² After antenatal administration of RhIG, some women may develop a low (1:4 or less) anti-D serum antibody titer. This positive titer reflects a passive immunity from the RhIG. The infant of a mother who received RhIG prophylaxis within 12 weeks may have a weakly positive direct Coombs test due to placental transfer of RhIG antibodies. Neither of these responses indicates maternal immunization, and postpartum RhIG administration is indicated.^23,62

ABO incompatibility

The potential for isoimmunization also exists with ABO incompatibility, although severe hemolytic disease in the fetus and newborn is rare even though ABO incompatibility is three times as common as Rho(D) incompatibility. Previous exposure and immunization are not necessary with ABO incompatibility because the mother already has naturally occurring antibodies against fetal RBC antigens. The most common situation in which ABO incompatibility occurs is with a type O mother and a type A (Figure 13-8, A) or, less frequently, type B infant. The A antigen seems to be more antigenic than the B antigen. The type O mother has naturally occurring anti-A and anti-B antibodies in her serum that can react against the A or B antigens on the fetal RBCs. ABO incompatibility could also occur with a type AB infant but never with a type O infant (type O RBCs have neither A nor B antigens for maternal anti-A or anti-B antibodies to identify and react against).

Why is ABO incompatibility a relatively mild disorder compared with Rho(D) isoimmunization? The primary reason is that the antibodies of the ABO system are primarily IgM, which does not cross the placenta. However, rarely these antibodies may be of the IgG type. IgG antibodies of the ABO system are more common in persons with type O blood; hence ABO isoimmunization occurs most frequently between mothers who are type O and their type A or type B infants. Because A and B antigens also appear on somatic cells and are secreted into body fluids in most people, there is a large quantity of antigen to compete with the fetal RBCs for any maternal antibody. In addition, the fetus may have its own anti-A or anti-B antibodies that can neutralize maternal antibody. There are fewer A and B antigens than D antigens on the fetal RBCs, and these antigens are relatively weak, resulting in only a weakly positive Coombs test. ABO isoimmunization and probably Rho(D) isoimmunization do not occur in the opposite direction (i.e., from baby to mother) because fetal antibodies tend to be in a macroglobulin form that cannot cross the placenta.

The simultaneous occurrence of Rho(D) and ABO isoimmunization has a protective effect that reduces the likelihood of maternal Rho(D) sensitization. This is illustrated in Figure 13-8, B, with an Rho(D)-negative, type O (naturally occurring anti-A and anti-B serum antibodies) woman who is carrying a fetus who is Rho(D)-positive and type A (with A and B RBC antigens). The naturally occurring maternal anti-A antibody destroys fetal cells entering maternal circulation (during pregnancy or at delivery) before they can trigger the mother’s immune system to produce anti-D antibodies and memory cells. If anti-D antibodies and memory cells are not formed, the woman remains unimmunized.^23,162

Transitional events

With the transition to extrauterine life, newborns move from the usually sterile, protected environment of the uterus into an environment filled with organisms, some of which are potentially pathogenic, and other antigens that challenge their still immature host defense mechanisms. During the initial days after birth, the newborn must contend with several challenges to the immune system, including (1) development of normal microorganism flora on mucosal surfaces (skin, respiratory system, and GI tract); (2) responding to bacterial colonization by potential pathogens; (3) processing exposure to dietary proteins that are potential allergens; (4) responding to exposures to other ingested or inhaled environmental agents with antigenic potential; and (5) beginning the transition from Th2-dominated fetal responses.

Alterations in innate immunity

The inflammatory response and phagocytosis (see Figures 13-1, 13-2, and Box 13-1 on page 446) in the newborn are different when compared with adult function because functional limitations of the infant’s polymorphonuclear monocytes (PMNs) affect leukocyte metabolic activities, mobilization, chemotaxis, adhesion, opsonization, phagocytic activity, and intracellular killing. The neonate’s PMNs are more rigid (due to an altered cytoskeleton), less deformable (due to generation of less actin), and have a poorer response to chemotactic stimulators and impaired receptor mobilization.^76,144 These limitations alter movement kinetics and orientation of the PMNs. The neonate’s PMNs are less able to leave the blood vessel to reach the site of pathogen invasion because of the decreased deformability. The newborn’s PMNs have less ability to adhere to the vascular epithelium, leading to poorer aggregation of PMNs along the vessel wall near the site of injury.^22,66,76 L-selectin expression, which is critical for initial neutrophil adhesion to vascular endothelium and migration, is low in neonates and decreases in the first 24 to 72 hours; levels are even lower in preterm infants.^{22,76,144,180} Neonatal neutrophils have a three- to fourfold decrease in bactericidal permeability-increasing protein, which may increase the risk of gram-negative sepsis.²²

Neonatal PMNs do not respond as readily as those of older individuals to chemotactic factors.^28,70 Chemotaxis (see the definition in Table 13-2) in neonates is about half as efficient as chemotaxis in adults, resulting in slower, more random movement of neutrophils and monocytes to the site of antigenic invasion.^28,76,180 This is secondary to the structural and functional limitations of neonatal PMNs and due to lower levels of chemotaxis-stimulating substances in the neonate’s blood. These limitations are exacerbated in septic infants.¹⁸⁰ The increased IL-6 production reduces PMN migration; however, IL-8 priming during labor improves PMN chemotaxis.^180,183 Other factors that alter chemotaxis include impaired PMN calcium metabolism, altered actin polymerization and adhesion defects.⁷⁶ In the fetus, the chemotaxis response is consistent from 24 weeks to term, decreases after birth, and then increases to reach adult levels in term infants by about 2 weeks of age.^28,22,140 In preterm infants, chemotaxis does not begin to respond efficiently until 2 to 3 weeks after birth and develops slowly.²⁸ The reason for this is unclear. Achievement of chemotaxis function at adult levels is delayed in more immature preterm infants, with less than two thirds of them achieving adult values by 42 weeks.¹⁴⁰ Therefore these infants remained at higher risk for infection even after reaching their due dates.

Newborns, particularly preterm infants, have decreased serum opsonic activity, resulting from low levels of immunoglobulins and complement components. In addition, neonates have difficulty recognizing and destroying encapsulated bacteria unless the pathogen is first opsonized by attaching complement fragments and immunoglobulins (see Table 13-2).¹⁴⁴

Most studies report that phagocytic activity in the healthy term newborn is similar to phagocytic activity in adults, although newborn phagocytic cells are less responsive to stimulation by chemotaxic factors.^66,70 Thus phagocytosis is diminished to some extent by the decreased availability of neutrophils (the primary circulating phagocyte) at the invasion site due to altered chemotaxis. Macrophage (the primary tissue phagocyte) activity in response to cytokines (see Tables 13-2 and 13-3) from T cells is also decreased. Phagocytic activity and intracellular bactericidal activity of PMNs are probably not significantly different from the same function in adults in most healthy infants and are similar to adult levels by about 2 weeks.^18,28,70 However, some authors have reported that even healthy preterm infants born at less than 33 weeks’ gestation have a poorer phagocytosis response for the first few months of life, possibly due to poor opsonization.²²

Activated neutrophils normally undergo apoptosis within 24 to 48 hours. Neonatal neutrophils have a delay in apoptosis, prolonging their survival, possibly related to decreased expression of caspase-3, a component of several apoptosis pathways. The increased survival may be an advantage in fighting infection, but the elongated activation may increase the risk of chronic inflammation and disorders such as chronic lung disease.⁷⁶

Phagocytosis has been found to be normal in most stressed neonates, although decreased phagocytosis toward some gram-negative bacteria has been reported. Infants who experience health complications either in utero or after birth (e.g., hypoxic-ischemic events, respiratory distress, meconium aspiration, sepsis, or hyperbilirubinemia) demonstrate significantly decreased bactericidal activity in response to both gram-positive and gram-negative organisms. Bactericidal activity may be reduced even further in VLBW infants who weigh less than 600 g.¹⁸ The cause is unclear but may relate to developmental immaturity with intrinsic alterations or defects in leukocyte metabolic activity, or it may result from peroxidative damage to the cell.⁶⁶ There are several changes in cellular metabolism associated with phagocytosis including the respiratory “burst” with a rapid increase in oxygen consumption, the hexose monophosphate (HMP) shunt that is involved with glycolysis activity, and the production of toxic oxygen metabolites necessary for bactericidal activity. These activities are reduced in term infants with sepsis and in preterm infants of less than 34 weeks’ gestation.^22,28,180 In preterm infants these metabolic processes remain low for the first 1 to 2 months of life.^22,28

The number of neutrophils varies during the first few days after birth, with an increase after birth that peaks at 12 to 24 hours, declines to 72 hours, then remains stable during the neonatal period.^70,76 This increase is blunted and lower levels are seen in preterm infants.⁷⁶ The increase after birth is probably due to movement of marginated neutrophils into the main circulation.^76,144 PMN levels below 3000 m³ in the first 3 days or below 1500 m³ after the first 3 days are unusual in term infants; neutrophil levels may normally be as low as 1100 m³ in preterm infants.⁷⁰ Although low PMN levels are normally associated with neonatal infection, they are also seen in infants born prematurely or after hypoxic-ischemic events, and in infants with intraventricular hemorrhage or Rh hemolytic disease.⁷⁰

Bone marrow reserves, which are neutrophil storage pools (NSPs), are lower in the neonate, especially preterm infants. This is due to a reduction in granulocyte macrophage–colony-stimulating factor (GM-CSF).^28,76,82 Approximately one third of preterm infants have a functional neutropenia.¹²² In neonates, especially preterm infants, the marrow is probably functioning at or near capacity for neutrophil proliferation. Therefore these infants are less able to increase production much further with infection and the NSP becomes exhausted more rapidly.^89,122,180 This may account for the neutropenia and shift to the left (release of immature forms of neutrophils) often seen with sepsis, especially in VLBW infants.²⁸

Toll-like receptors (TLRs) and antigen presenting cells (APC) (see Box 13-1 on page 446) are different in neonates than adults. Neonatal TLR-mediated cytokine response is characterized by decreased Th1 proinflammatory cytokines (TNF-α, IL-12, IL-1B, IFN-γ) due in part to progesterone, PGE2, and plasma adenosine levels.^91,125,180 Plasma adenosine is increased with hypoxia and stress and inhibits TNF-α production by the monocytes and production of Th1 cytokines.¹⁸⁰ Labor up-regulates TLR-4 on monocytes and PMNs.^147,180 SP-A, SP-D, and alveolar macrophages act as pattern recognition and signaling molecules via interaction with TLRs, CD-14⁺, and other components of the innate system.¹⁷³ TLRs may play a role in the pathogenesis of necrotizing enterocolitis, in particular, abnormal TLR-4 signaling in the intestines.^7,179 TLR-4 is a receptor for lipopolysaccharides (a component of the outer membrane of gram-negative bacteria). The altered signaling by TLR-4 limits innate responses to these organisms.⁷

APC function is decreased in the neonate resulting in increased reliance of the innate system for pathogen removal.¹⁸⁰ Cord blood dendritic cells have an immature phenotype and low chemokine levels, decreased endocytoxic activity, decreased antigen presenting and costimulatory capacity, and produce low levels of IL-12.⁹¹ Neonatal dendritic cells require greater stimulation for activation and are poorer stimulants of T-cell proliferation with impaired IL-12 production.¹⁸⁰ Neonatal APCs express low levels of costimulatory molecules such as CD40, CD80, and CD86.⁷⁰ This characteristic, along with low IL-12 production by APCs and IFN-γ by neonatal T-helper cells reduces the infant’s ability to induce Th1 responses and may lead to immune tolerance rather than response.^91,180

The number of monocytes in infants is highest in the first 24 hours after birth and then decreases over the next month.¹⁴⁵ Neonatal monocyte chemotaxis and phagocytosis are altered during sepsis with a decreased delivery of these macrophages to infection sites.^{70,82,89,125,180} Neonatal monocytes and dendritic cells have impaired expression of MHC II and costimulatory molecules, reducing antigen presentation to CH4⁺ T cells.¹⁸⁰ Synthesis of interferon (IFN)-γ, interleukin (IL)-8, IL-10, extracellular matrix proteins, fibronectin, and leukotrienes by neonatal monocytic macrophages is reduced.⁸² Monocyte antibody-dependent cellular cytotoxicity is about 50% of adult values.⁸² Monocyte adhesion is similar to that of adults.⁵⁷ Monocytic bactericidal activity and processing of antigens are generally considered to be adequate.

Fibronectin, a glycoprotein found in plasma and tissues, inhibits bacterial adherence to epithelial cells; enhances antibody binding of bacteria such as staphylococci and GBS; and is involved in opsonization and clearance of fibrin, immune complexes, and platelets. Neonatal levels of plasma fibronectin average 50% of adult values, with the lowest levels seen in preterm infants and those with hypoxic-ischemic events or respiratory distress.^18,70,89 C-reactive protein (CRP) synthesis is similar in uninfected neonates and adults. A diminished CRP response has been observed in the first 12 to 24 hours after birth in infants infected with group B streptococcus.⁶⁷

Numbers of natural killer (NK) cells, which provide protection against tumors or virus-infected cells, are similar to or greater than those in adults, but NK activity is reportedly decreased to 15% to 60% of adult activity.^58,70,89 Neonatal NK cells are phenotypically different from those of adults with a lower cytolytic capacity.⁵⁸ Most adult NK cells are CD56^high, whereas most neonatal NK cells are CD56^low, a more immature form.⁵⁷ Neonatal NK cells are less able to bind to target cells and have limited lytic ability.⁸⁹ The altered activity is probably mediated by the decreased levels of interferon and other cytokines that normally augment NK cell function. NK cells in preterm infants have decreased cytotoxic function.⁵⁷

In general, the total number of circulating lymphocytes is similar to adult levels at birth but falls during the first 3 days and plateaus by 10 days of age. The ratio of T lymphocytes to B lymphocytes is lower in cord blood than in adult blood.⁷⁰ Neonatal mast cells secrete more histamine than adult cells, which alters dendritic cell cytokine production. Mast cells may play a role in development of erythema toxicum.¹⁸⁰

APCs (including monocytes, macrophages, and dendritic cells) in the neonate “exhibit deficits in pathogen recognition, activation after stimulation, phagocytic function, bactericidal function and amplification of the immune response that may increase the risk for development and progression of EONS [early-onset neonatal sepsis].”^{180, p. 314} The ability of neonates to localize infection is limited. As a result, septicemia is more likely to develop in neonates from spread of the pathogenic organism to the blood and cerebrospinal fluid. A major factor in this inability to localize infection is impaired chemotaxis. Adequate phagocytosis and killing of many pathogenic organisms such as GBS depend on complement (especially C3) and opsonic activity. Serum concentrations of C3 and thus opsonic activity are proportional to gestational age, further increasing the risk of sepsis in preterm infants.⁷⁰

The inability to localize infection results in clinical manifestations of infection that are different in the newborn compared to the adult, and this can make the diagnosis of sepsis in the neonate difficult. Specifically, signs of sepsis in the neonate are often subtle and nonspecific, involving changes in activity, tone, color, or feeding. In addition, neonates have a poor hypothalamic response to pyrogens; therefore fever is not a reliable indicator of infection in the neonate. Alterations in innate immunity are summarized in Table 13-6.

Alterations in cell-mediated immunity

Absolute numbers of T lymphocytes in the newborn are higher than in adults, but the functional ability of newborn T cells is decreased, as is the diversity of specific T-cell receptors, which results in a delay in the response to specific organisms.^5,89 Cytotoxic activity of neonatal T cells is 30% to 60% less than in adults, and cytokine production is reduced.¹⁰¹ Examples of cytokines and their roles are found in Table 13-3; cytokine production in the newborn is summarized in Table 13-8.

T-suppressor activity tends to dominate in the newborn.¹⁰⁸ Although Th2 (antibody-mediated) helper responses are the dominant response in the neonate, the T-helper cells provide relatively poor support of B cells.¹⁴⁴ For example, neonatal T cells do not induce neonatal B cells to produce some of the immunoglobulins that adult B cells would produce.³⁷ CD4⁺/CH25^high Treg cells are found in high levels in cord blood.^44,125 These cells suppress T-cell proliferation in response to cytokines and Th1 cytokine (especial IFN-γ) production thus limiting adaptive responses. This is an advantage in limiting autoimmunity but also limits responses to infection and vaccines.¹²⁵

At birth most of the T lymphocytes are primary cells (i.e., naive cells) with few secondary memory T cells. Neonatal naive T cells differ from adult naive T cells in that the neonatal cells have a higher turnover rate and limited Th1 responses.⁹⁶ Primary T cells release less cytokine and have a diminished response to antigens.^{37,114,139,144} The most prevalent T-cell phenotype in the neonate is the CD45RA⁺ (naive) cell. These cells account for 90% of the neonate’s T cells, decreasing to 50% (similar to adults) by 10 years of age. CD45RA⁺ cells are “naive” because of the fetus’s lack of exposure to foreign antigens. When exposed to a foreign antigen presented by a B lymphocyte or dendritic cell, the neonatal CD45RA⁺ cells differentiate into CD45RO⁺ (memory) cells.⁹⁹ The neonatal CD45RO⁺ cell is capable of producing significant amounts of cytokines (e.g., IFN-γ, TNF-α, GM-CSF) and acting as a helper cell for B-cell function.^{37,114,139,144} However, because the newborn’s T cells have no previous experience with most antigens until exposed and sensitized after birth, it probably takes 4 to 6 weeks for the newborn to achieve minimal adaptive immune protection.¹⁸

Impairment of cytokine production alters cell-mediated immunity, immunoglobulin production, and innate responses.^94,98 Although some cytokine production by neonatal T cells is altered, IL-1, IL-2, and IL-6 levels are normal or slightly reduced. However, levels of IL-4, IL-8, IL-12, and IFN-γ are reduced.^82,88,98 The decrease in IL-4 and IFN-γ is consistent with the “naive” state of CD45RA⁺ cells.^55,96 IL-8 levels are markedly lower in preterm infants, limiting neutrophil mobilization and chemotaxis.⁵⁵ Development of necrotizing enterocolitis and bronchopulmonary dysplasia in preterm infants has been postulated to be related in part to unregulated cytokine production.⁷⁰ Genomic polymorphisms in gene encoding for production of cytokines may help explain individual differences in neonatal susceptibility to sepsis.

Neonates have down-regulation of Th1 responses with a decreased capacity to produce cytokines thus promoting Th1 (cell-mediated) responses with a blunted response to activation by IFN-γ, possibly due to decreased signal transduction.^{6,17,88,96,99} This may increase susceptibility to oropharyngeal candidiasis.⁹⁸ Neonatal T cells are able to increase cytokine production when stimulated. For example, CD8⁺ cytotoxic T cells can be stimulated and reach near adult levels of function in some cases with cytomegalovirus (CMV) exposure.^65,96 However, neonatal T cells require greater stimulation as well as stimulation from additional factors (e.g., accessory cells and signaling molecules) than adult cells to achieve full activity.^5,70,144 Cell-mediated immunity is further depressed in small-for-gestational-age (SGA) infants. These infants have a smaller proportion of T lymphocytes and altered lymphocyte function than appropriate-for-gestational-age (AGA) infants, perhaps secondary to alterations in thymic activity. The thymus of SGA infants is smaller in weight and volume and demonstrates histologic alterations and decreased activity of thymic inductive factors, which may contribute to immune dysfunction in these neonates.

Alterations in antibody-mediated (humoral) immunity

The fetal and neonatal differences in antibody-mediated immunity are primarily due to the alterations in T-cell activity, immature cytokine function, and the effects of passive immunization from immunoglobulins acquired transplacentally and/or through breastfeeding. Activity of B cells requires signaling from the interaction of surface antigen and T-helper cells to amplify the immune response.⁷⁰ Because T-cell activity and cytokines are needed to enhance B-cell function, there is a reduction in fetal and neonatal production of immunoglobulins.^66,82 T-cell–dependent B responses have a delayed onset, peak at lower levels, are of shorter duration, and show different IgG isotypes than in adults.^70,96 T-cell–independent B responses are also deficient, especially in response to antigens with capsular polysaccharide coats such as group B streptococcus.^96,149 Neonatal B cells have fewer IL-5 receptors, decreased activation by IL-10, and poorer responses to Th2 antigens.^79,149 Many neonatal B cells have CD5+ surface antigens (B1a cells). B1a cells are not dependent on T-cell help for activation as are conventional B cells (B2).^79,114 However, neonatal T cells do not stimulate B cells to switch production of immunoglobulins from IgM to IgG or IgA. As a result, neonates produce primarily IgM and little IgG and IgA, even when exposed to bacteria with polysaccharide capsules.^79,144 Neonatal B cells in response to vaccine antigens tend to differentiate into memory B cells rather than antibody-producing plasma B cells.

The total amount of immunoglobulin at birth is 55% to 80% of adult values, and primarily consists of IgG from the mother.⁸² Levels of serum immunoglobulins after birth are illustrated in Figure 13-9. Neonatal IgG values reflect the IgG acquired from the mother either transplacentally or via breast milk.⁸⁹ The newborn can produce IgG₁ in a manner similar to that of an adult; however, IgG₂ production is reduced to about 2 years. IgG₂ is important for defense against polysaccharide antigens such as are seen with GBS, K1 forms of E. coli, Haemophilus influenzae, pneumococcus, and meningococcus.⁸² Development of antibody responses is primarily dependent on postbirth age rather than Post-menstrual age.⁵⁷

IgG is important for immunity to bacteria, especially gram-negative organisms, bacterial toxins, and viruses.^70,174 Neonatal values depend on gestational age because placental transfer of IgG increases during the third trimester. Thus preterm infants may have inadequate protection. For example, cord blood values of IgG are minimal in infants born at 24 to 25 weeks’ gestation and average 400 mg/dL (4.0 g/L) at 32 weeks and 1500 mg/dL (15 g/L) at term.^114,174,180 Term IgG levels are 90% to 95% of adult values and 5% to 10% higher than maternal values.^70,140 Levels of IgG are lower in SGA infants, possibly due to impaired placental transport of maternal IgG.⁸⁹ After birth, levels fall gradually as maternal IgG is catabolized. Because significant production of IgG by the infant does not occur until after 6 months, all infants experience a transient “physiologic hypogammaglobulinemia” (see Physiologic Hypogammaglobulinemia) in the first 6 months. However, as a result of IgG transfer in breast milk, the neonate continues to get antibodies against infectious agents for which the mother has circulating antibodies because of previous exposure or immunization (see Table 5-4).

IgA is important for localized immunity in the GI and respiratory tracts. As stated above, IgA does not cross the placenta in significant amounts. Neonatal (term and preterm) values are low (0.1 to 5 mg/dL [0.001 to 0.05 g/L], which is less than 2% of adult values). Elevated IgA is found in cord blood after maternal-fetal transfusion and occasionally with intrauterine infection, although IgM is seen more commonly after fetal infection.¹¹⁴ sIgA is not found in neonates at birth but can be detected in saliva, tears, and intestinal mucosa by 2 weeks to 2 months.⁸² sIgA occurs as a monomer or is attached to a polypeptide chain (secretory component). The polypeptide chain provides resistance to pH changes and protects the IgA molecule from proteolytic digestion in the GI tract.

IgM, which also does not cross the placenta, is important for protection against blood-borne infections and can trigger multiple effector functions of the classical complement cascade.¹⁷⁴ IgM is the major immunoglobulin synthesized in the first month of life.^5,66,122 IgM levels increase rapidly by 2 to 4 days after birth, probably secondary to stimulation from environmental antigens, although neonatal values are low (5 to 15 mg/dL [0.05 to 0.15 g/L]), with means of 6 mg/dL (0.06 g/L) at 28 weeks’ gestation and 11 mg/dL (0.11 g/L) at term, which is approximately 10% of adult values.^70,89 The fetus is capable of producing significant IgM in response to exposure to certain antigens, such as the TORCH organisms, after 19 to 20 weeks’ gestation, which may be due to activation of the fetal B1a cells.¹¹⁴ However, neonatal IgM has less specificity than adult IgM in responding to specific antigens, which may hinder the initial recognition of pathogenic organisms. IgE and IgD do not cross the placenta in significant amounts, and newborn values are less than 10% of adult values.⁶⁶

Few B cells that have differentiated into immunoglobulin-secreting cells (IgSCs) are seen in the first 5 days after birth, and those that are found are mostly IgM-secreting cells. By a month of age, two thirds of neonates have IgSCs, most of which are IgA-secreting cells. Increased IgSCs are more common in both term and preterm infants with intrauterine infection. Low serum concentrations of IgG in preterm infants may also be due to a decreased ability of their B cell to switch immunoglobulin isotype forms.¹⁷⁴