INTRODUCTION:

Pregnancy is a state of acceptance of fetus because Pregnancy is an immunological balancing act, in which mother’s immune system has to remain tolerant to fetal/paternal antigens and yet maintain normal immune competence for defence against microorganisms. Sir peter brain Medawar first thought that fetus is a semi allograft.

He gave three postulates for survival of this allograft in mother ^{1, 2}. They were:

-Anatomical separation of fetus from its mother

- Antigenic immaturity of fetus

- Immunological inertness of mother.

Why doesn’t mother reject fetus?

Maternal fetal immunologic relationship is unique. Tolerance of fetus by maternal immune system is active mechanism, where by fetal tissues are prevented by being recognized as foreign and/ or from being rejected by cells of maternal immune system. (Figure-I)

Figure-I, Maternal fetal immunologic relationship, source-women-health info .com

Factors for non rejection of fetus by mother:-

v Pregnant uterus is an immune privileged site: -

Immune privileged site means that antigens in the tissues are not exposed to immune system because of mechanical barrier. For e.g. Lens in the eye is an immune privileged site .It has a capsule all around as mechanical barrier. Similarly blood has blood brain barrier. Pregnant uterus have mechanical barrier that is syncytiotrophoblast surrounds all around fetus (intervillous space) which is direct contact between maternal and fetal blood ^{3, 4}.

This trophoblast-immune interaction involves three stages³: (figure-II)

1) Attraction:- trophoblast cells secrete chemokine that can recruit immune cells to the implantation site

2) Recruitment/Education: - trophoblast cells produce regulatory cytokines that modulate the differentiation process of immune cells.

3) Response: - immune cells educated by trophoblast cells respond to signals of the local microenvironment in a unique way.

Figure-II- trophoblast-immune interaction stages

v Immunological concept of trophoblast-

The process of blastocyst implantation is a series of interactions between the blastocyst and maternal tissues. The purpose of this process is

- To provide nourishment to the embryo for developmental growth in appropriate physiological and endocrinological environment until a placenta is established, and

- To protect the (semi-)allogeneic embryo from any attacks from the maternal immune system.

To facilitate successful implantation, therefore, these two aspects of the embryonic demand must be satisfied in the embryo-maternal interface throughout the entire process of implantation ⁴.

Ø The first concept is that blastocyst implantation essential factors (BIEFs) have dual functions: one, for structural and functional modification of the endometrium to accommodate the developing embryo and provide nourishment and suitable environment for its development, and the other, for modulation, directly or indirectly, of the maternal immune system to prevent attacks by the maternal immune system ^5.

Ø The second concept is that BIEFs convert the endometrium (or uterus) from an immunologically non-privileged site to a privileged site. This endometrial (uterine) conversion is the immunological aspect of the blastocyst implantation process. When the endometrium has become receptive for blastocyst implantation, it signifies that the immunological conversion of the endometrium by BIEFs has been sufficiently attained to let the embryo start contacting maternal tissues ^{5, 6.}

During the early stages of placentation, as the trophoblast cells differentiate and make their way to the maternal blood vessels to establish the placenta, BIEFs continuously provide nourishment and immunological protection to the developing embryo. The immunological protection of the embryo/fetus from potential attacks by the maternal immune system appears to reach a peak at the time of establishment of the placenta. Thus, clarification of the roles of BIEFs in both the physiological/endocrinological aspect as well as the immunological aspect is essential for understanding the biological process of implantation. Trophoblast (fetal tissue), during the process of implantation invades maternal uterine decidua, so that fetus does not make direct contact with mother. This trophoblast gets differentiated into villous and extra villous⁵.

Villous: - it covers all chorionic villus of definitive placenta .It comes in direct contact with maternal blood. Interestingly, it is immunologically inert containing human leukocyte antigen [HLA] class1and class2 negative).It interacts with maternal systematic immune response.

Extra villous :- At tips of chorionic villi, cytotrophoblast cells breaks through syncytium and fix villi to underlying uterine decidua .This cytotrophoblast migrates all along placenta to encircle entire embryonic sac( anchoring cytotrophoblast ) few of them migrate into myometrium ,whereas endovascular cytotrophoblast erodes and alters structure of maternal arterioles to render the vessel dilated and non-contractile ,which is required for continuation of normal pregnancy and is absent in conditions like pre-eclampsia and IUGR.

v Active Protection of the Trophoblast Against Viral Infection

The trophoblast, the cellular unit of the placenta, not only recognizes microorganisms and initiates an immune response; it may also produce anti-microbial peptides and, therefore, actively protect itself against pathogens. Studies have demonstrated the expression of the anti-microbial human beta defensing 1 and 3 by trophoblast cells. Secretory leukocyte protease inhibitor (SLPI), which is a potent inhibitor of HIV infection and inducer of bacterial lysis, has also been found in trophoblast cells ⁵. The expression of TLR-3, TLR-7, TLR-8 and TLR-9 by trophoblast cells may explain how the placenta regulates the expression of these anti-microbial factors. Stimulation of first trimester trophoblast cells through TLR-3 promotes the production and secretion of SLPI and IFN-β, two important anti-viral factors. These factors provide the first line of defense against viral infections and have the potential to activate multiple intracellular pathways. IFN-β and SLPI production by trophoblast cells, in response to a viral infection at the maternal-fetal interface, may represent a potential mechanism by which the placenta prevents transmission of viral infection (e.g. HIV) to the fetus during pregnancy. These data suggest that the placenta represents an active immunological organ, (innate immune system), capable of recognizing and responding to pathogens. However, it also indicates that the placenta is prone to infections from microorganisms, which in its absent (non-pregnant) would never take place ^3.

v Alternations in immune system during pregnancy:-

Mother’s host defense mechanism undergoes various alternations during pregnancy to tolerate fetus ‘which in turn makes her more prone for infection.Alternations in her immune system also influences course of chronic disorders such as autoimmune disorders.The mothers body recognizes the fetus as no self and prohibits an immune response as if it were an infection. By adjusting the immune system during pregnancy, maternal homeostasis is achieved by creating a stable environment for fetal development .In pregnancy the innate immune response is activated, while the adaptive immune system is depressed ⁶.

Ø Alternation in innate immunity response during pregnancy:-There is an increase in total WBC counts especially polymorph nuclear neutrophils (PMN).This results in increase of ability of phagocytosis that prevents mother and fetus from infection. But it has been seen that these PMN have altered metabolic activity and decreased chemo taxis that protects from rejection, but results in delay in initial response to infection especially against gram-negative organisms.Also there is improved expressions that leads to enhanced phagocytic recognition and destruction of antigen-antibody complexes which gives protection to mother and fetus from infection ⁶.

-Natural killer (NK) cell activity: - Its cytolytic activities is down regulated during pregnancy that may assist in maternal tolerance of fetus by protecting the trophoblast from destruction also they produce growth promoting cytokinesis required for growth of trophoblasts ^{7 .}

-Fibronectin: - There is an increase in fibronectin during pregnancy which is glycoprotein with opsonic and clot stabilizing properties, resulting in augmented maternal response infection.

Ø Alternation in adaptive immune response during pregnancy:-There is depressed adaptive immune response during pregnancy.

*Alternation in cell mediated immunity: There is a Th1-Th2 shift which alters cell mediated immunity.Th1 responses are related with graft host reaction, reduction of which leads to prevention of fetus from rejection but in return it risks mother for increased mycotic and other opportunistic infection ⁷.

*Alternation in antibody mediated immunity: There is decreased responsiveness of B cell to antigen stimulation during pregnancy, which makes mother prone for streptococcal and staphylococcal infection. Level of maternal IgG antibody falls as gestation progresses mainly attributed to hemodilutions, loss of IgG in urine and transfer of maternal IgG to fetus in last trimester which protects fetus ⁷.

v Alteration in complement system:-

Alterations in complement system start as early as 11 weeks gestation. Complement system basically comprises of two types of pathways, classical and alternative pathways ⁸.

-Classical pathway is involved in graft rejection whereas alternate pathway has action against infection. Complements involved in classical pathway (C1, C2, and C4) are decreased during pregnancy that favors decreased chance of rejection. Complements involved in alternative pathway increases so less chance of rejection.

Clinical implications:-

Preeclampsia:-It is multisystem complex disorders with main event pathogenesis being vascular endothelialcell injury. Exact cause of damage is not clear but immunological basis has been suggested .This altered immunological response is due to deficient HLA-G expression on extra villous trophoblast. This leads to 3 abnormal responses ⁹.

· Th1-Th2 shift does not occur which is required for normal pregnancy. In pre-eclampsia, Th1 response is more so all inflammatory cytokines are more than normal resulting in all manifestations of pre-eclampsia.

· Cytotoxic activity of NK cells doesn’t get suppressed because of deficient HLAG expression .There is increased circulating cytokines in preeclampsia.

· Because of decreased HLA-G expression there is poortrophoblastic invasionwhich is required for fetal growth. It results in partial retention of blood in the muscular layer of myometrium .This leads to high conductance in the vessels that is required for proper development of feto-placental unit.

All this leads to cellular dysfunction, endothelial dysfunction and placental ischemia leading to release of free radicals and factor X which result in preeclampsia and IUGR.

Intrauterine growth restriction:-Pathophysiology of IUGR is similar to that of preeclampsia. Both have decreased HLA-G expression. But surprisingly both may not occur simultaneously ¹⁰.

Recurrent pregnancy loss:-Immunological factor causing RPL constitute 20-50% of all the causes. Causes are mainly divided into allo-immune and auto- immune factors ¹⁰.

The allo-immune factors which causes RPL are-

· Th1>Th2

· Deficient HLA-G expression

· Absence of anti-paternal / blocking antibody

· Increased abnormal forms of IL-1 ( normal forms of IL-1 is required for trophoblastic invasion)

· Close HLA compatibility between mother and fetus (as HLA incompatibility is essential to develop anti paternal antibody which is required to prevent graft rejection).

The auto immune factor causing RPL mainly three factors are of utmost importance:

· Antiplatelet antibody(APL) causes Antiphospholipid antibody syndrome ( APS)

· Antithyroid antibody causes Autoimmune thyroid disorders ( Grave’s disease and Hashimoto’s disease)

· Antinuclear antibodies causes Systematic lupuserythematosis.

RH- Alloimmunization-Alloimmunization 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 mechanism can result in pathophysiologic processes during the perinatal period .This disorder is caused by transplacental passage of maternal IgG antibody that reacts with antigen on the fetal RBCs and leads to cell lysis. The fetal neonatal effects may be minimal or may include severe anemia , congestive heart failure and death ^10,11.

Factor that influence the intensity of that reaction between maternal antibody and fetal antigens include the presence of antigens on fetal tissue that are not found in maternal tissue, distribution of antigens in fetal tissue, strength and quantity of antigen, efficacy of maternal immune response, presence or absence of previous exposure and sensitization to the antigen, and the type of antibody produced by the mother.

With the development of Rh Ig (a human gamma globulin concentrate of anti-D) initial immunization of most women can be prevented .The incidence of Iso-immunization during pregnancy is 1.6%, decreasing to 0.18 % with administration of both antenatal and postpartum Rh Ig, which acts by destroying fetal RBCS in mother system before the foreign D antigen on these cells can be recognized by her immune system and can trigger formation of antibodies and more importantly memory cells.

ABO- incompatibility:-The potential for isoimmunization also exists with ABO compatibility .It is 3 times more common than RH alloimmunization .Previous exposure and immunization are not necessarily with ABO incompatibility because mother already has naturally occurring bodies against fetal RBCs antigens. The most common situation where ABO incompatibility is with type O mother and a type A or less frequent type B infant .The simultaneously occurrence of Rho (D) and ABO alloimmunization has protective effect that reduces the likelihood of maternal Rho-D sensitization. ABO alloimmunization and probably Rho-D isoimmunization don’t occur in opposite direction (i.e. from baby to mother) because fetal antibodies tend to be in a macroglobulin form that can’t cross the placenta^{10, 11}.

Immunization during pregnancy:-

Preconception immunization of pregnant women to prevent disease in the offspring, when practical, is preferred to vaccination of pregnant women .It should occur at least 3 months before conception. Potential risk of immunization during pregnancy includes fetal viremia, teratogens interference with development of infant’s response to immunizations during childhood and maternal side effects that might compromise uteroplacental function ¹².

Vaccines which are contraindicated during pregnancy are

· Measles

· Mumps,

· Rubella,

· Poliomyelitis,

· Yellow fever,

· Varicella

Vaccines, which are benefit, outweigh risks during pregnancy are:

· Tetanus,

· Influenza,

· Rabies,

· Hepatitis B,

· Hepatitis A,

· Pneumococcus,

· Meningococcal,

· Typhoid.

Post exposure prophylaxes which can be given during pregnancy are:

· Hepatitis B ,

· Rabies,

· Tetanus ,

· Varicella,

· Hepatitis A.

Nursing implications

Ø One of the first tasks is to investigate the educational requirements of nurses to assess the immunological concept and its influence on pregnancy.

Ø Assessment of professional and ethical issues faced by nurses while caring for women with immunological disorders can be considered as a part of nursing practice.

Ø Counseling the mother with previous history of immunological disturbance and plan for future pregnancy is a focused area of nursing.

Ø The nurse must be prepared to help the pregnant women with immune suppression disorders and overcome the future complications. The caring aspects of professional nursing are an essential component of meeting the special needs of these patients.

Ø In the management–care environment, a nurse can begin the investigation and decide which patient requires more advanced assessment and treatment. Helping the pregnant women through early diagnosis is a professional rewarding experience.

Ø A nurse is in a unique position to help a pregnant woman through thorough assessment and evaluate pregnancy outcome.

Ø Much of the basic work for assessment and examination of pregnancy could be accomplished by a nurse practitioner .Hence it can create a new field for midwifery nurse to expand her role towards immunological complications and its management area.

Ø It is a challenging attitude of midwifery nurse to undertake various research studies on immunological aspects of pregnancy.

CONCLUSIONS:

Thus all this suggests that pregnancy is not just adaptive response that is required for maternal fetal tolerance but also innate immune response produced by macrophages and NK cells in pregnant in endometrium.Infect recent data proposes pregnancy is characterized by marked changes immune regulation with enhanced innate immunity and suppressed adaptive immunity.

REFERENCES:

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2. Fest S, Abrahams VM, et al. Trophoblast-macrophage interactions. A regulatory network for the protection of pregnancy. American Journal of Reproductive Immunology. 57(1); 2007:55–66.

3. Harris LK. Review: trophoblast. Vascular cell interactions in early pregnancy. How to remodel a vessel. Placenta.31;2010:S93–S98

4. Von Rango U. Fetal tolerance in human pregnancy-A crucial balance between acceptance and limitation of trophoblast invasion. Immunology Letters. . 115(1); 2008:21–32.

5. Houser BL, et al. Two unique human decidual macrophage populations. Journal of Immunology.186(4) ;2011:2633–2642

6. Yoshinaga K. Research on Blastocyst Implantation Essential Factors (BIEFs) Am J Reprod Immunol. 63; 2010:413–424.

7. Shimada S, et al. Natural killer, natural killer T, helper and cytotoxic T cells in the decidua from sporadic miscarriage. Am J Reprod Immunol; 56; 2006:193–200.

8. Makrigiannakis A. et al. Fetomaternal immune tolerance. American Journal of Reproductive Immunology. 60(6); 2008:482–496.

9. Guilbert, L.J. There is a bias against type 1 cytokine expression and function in pregnancy. Indian Journal of Maternal and Child Health. 2(2); 2000: 105-110.

10. Billington, W.D.The immunological problem of pregnancy. International Journal of Obstetrics. 60(1);2003 :1-11

11. Rani Akhil Bhat, Meenakshi Dua. The Immunology of Pregnancy. Asian Journal of OBG and Gynae Practice. 11(1); 2007:13-19

12. Luppi, P. How immune mechanisms are affected by pregnancy vaccine. Indian Journal of Obstetrics. 43(2); 2003:87.

Received on 22.04.2013 Modified on 15.05.2013

Asian J. Nur. Edu. and Research 3(3): July-Sept., 2013; Page 183-187