Pregnancy Immunology

The immune system plays an essential role in various processes throughout a woman’s life (e.g. menstruation, ovulation, among others). The central focus of this review is the role of the immune system during pregnancy, as well as, the function that immunological structural barriers play between a mother and her child. The placenta, a transitory structure, is the principal immunological barrier between maternal and fetal blood. The trophoblasts are the most important fetal cells that are in contact with the maternal cells¹. There are three types of trophoblasts that can be identified within the fetus that are exposed to maternal cells. These populations are: the villous cytotrophoblasts, synciotrophoblasts, and the non-villous cytotrophoblasts. These early cells induce the first noticeable change in the maternal immune system, an increase in peripheral white blood cell count ¹.

Pregnancy is generally seen as a symbiotic natural state, the maternal innate immune system is activated by the presence of embryonic cells². Embryonic and fetal cells express paternal Major Histocompatability Complexes, essentially, labeling them as foreign to maternal cells. The innate immune cells, such as the natural killer (NK) cells, macrophages, and dendritic cells accumulate around the invading trophoblast, increase in population, and finally acquire an activated phenotype during pregnancy ². It has been found that an increase of 18%, or greater, in maternal NK cells is associated with abortions, demonstrating that the immune response mounted a response against the embryo/fetus ¹.

Although the innate immune system is active during pregnancy, the maternal immune system makes several measures to tolerate the presence of the fetus. Dendritic cells, one of the most potent antigen presenting cells, play an essential role in maternal-fetal tolerance. These cells catabolize tryptophan by using the enzyme indoleamine 2,3 dioxygenase, which leads to the suppression of the T lymphocytes. Experiments in mice demonstrate when the gene, which codes for this enzyme, is blocked there is a increased risk of abortion ³.

Tolerance of foreign tissue is a positive asset for the fetus. However, studies demonstrate that down-regulation of the adaptive immune response causes pregnant women to be more susceptible to a wide variety of pathogens ⁴. On a positive note, thanks to the mothers’ innate immune response, she will still poses a defense line to deter invading pathogens. Pregnant women have a higher number of activated peripheral blood monocytes and granulocytes than non-pregnant women ⁴.

Lastly, studies indicate that stimulation by sex hormones play an important part in the activation of the innate immune system during pregnancy. Studies have shown that elevation of estrogen levels can lead to the activation of phagocytic macrophages, while progesterone and prolactin stimulate the launch of macrophage cytotoxic mechanisms through the release of reactive oxygen species⁴.

Clinical Applications

Maternal-Fetal Blood Related Pathologies: Erythroblastosis Fetalis and ABO Incompatibility.

Erythroblastosis Fetalis

Erythroblastosis Fetalis is a pathology in which an Rh-negative sensitized pregnant woman activates her immune system, producing immunoglobulins due to the presence of an Rh-positive fetus. This particular condition most commonly occurs during the mother’s second pregnancy. According to Arraut, “the primary goal of caring for an Rh D-negative pregnant woman who is nonimmunized is prevention of alloimmunization”⁵. If a paternity test reveals the father is Rh- positive and mother is Rh-negative, she is a candidate for anti-D IgG prophylaxis as immunological treatment for the child.

Anti-d IgG prophylaxis is a treatment known to work as an antibody-mediated immune suppression. The most likely description of this mechanism is explained as follows: “via central inhibition, wherein Rh-D IgG coats fetal erythrocytes, which are then sequestered in the spleen and lymph nodes. The local increase in antigen-antibody complexes interrupts the commitment of B cells to plasma cell clones, thereby suppressing the primary immune response. Additionally, these antigen-antibody complexes stimulate the release of cytokines by immune effector cells that inhibit the proliferation of antigen-specific B cells” ⁵.

ABO Incompatibility

ABO incompatibility is “a reaction of the immune system that occurs if two different and not compatible blood types are mixed together”⁶. Incompatibility of the ABO blood type between mother and child is a condition present in 15-25% of pregnancies and is commonly known as ABO Hemolytic Disease of the Newborn (ABO HDN). ABO HDN occurs when maternal Ig antibodies specific for ABO blood antigens cross the placenta and induce hemolysis of fetal red blood cells. In contrast with Rh disease, ABO HDN can happen during the first pregnancy and it does not become more severe in future pregnancies. The problems caused by ABO HDN are numerous. These include anemia with possible hydrops fetalis, hyperbilirunemia encephalopathy (kernicterus), hepatomegaly, and splenomegaly.⁸ The problems caused by ABO HDN are due to true ABO alloimmunization, or immunization against an antigen belonging to a member of the same species, which occurs in approximately 1 out of 150 births. As reported by Senterre and colleges⁷ ABO alloimmunization can lead to severe hemolytic disease (destruction of red blood cells) of the newborn leading to hyperbilirubinemia, severe anemia, and other complications. For this reason, pre- diagnosis and adequate care are necessary to prevent complications in ABO incompatibility.

• Here is a video that describes bilirubin metabolism that illustrates the details in the process of newborns becoming jaundiced due to hemolysis.

http://www.youtube.com/watch?feature=player_embedded&v=JNbca1vxa5c - at=68

Perinatal HIV

“Recommendations regarding HIV screening and treatment of pregnant women and prophylaxis for perinatal HIV transmission have evolved considerably in the United States over the last 25 years” ¹¹. Without intervention, between 25-40% of babies born to HIV-infected mothers, in the most severely affected countries, are also infected. With appropriate interventions, transmission rates can be reduced to less than 1%. “In 2007, approximately 12 million children had been orphaned by HIV.” ¹².

Typical impairment of cellular immune defenses found in HIV infected children usually present symptoms such as: recurrent bacterial infections, oral candidiasis, failure to thrive, developmental delay, SCID, etc. This is why early diagnosis of HIV infection is crucial and ideally, should occur postnatally where mothers are known to be HIV-positive. This allows for early detection and prophylaxis against opportunistic infection in neonates. “These tests/screening procedures include: PCR of viral DNA in infants, CD4 count/monitoring, baseline HIV resistance, viral load, and serology for hepatitis A-C, herpes simplex, mumps, rubella, etc.” ¹²

HIV infection of young children most commonly arises as a result of mother to child transmission (MTCT). MTCT can occur inside the uterus, during labor, after labor, and through breastfeeding¹³. MTCT most commonly occurs during labor¹³. The exact mechanism of transmission is still unclear. However, recent studies relate perinatal infection with increased viral load and allogenic stimulation¹⁴. “The study suggests that allogenic stimulation by the fetus promotes vertical transmission via activation and proliferation of latent infected cells in the mother’s plasma”¹⁴.

For these reasons, the prevention of vertical transmission focuses on reducing the viral load of the mother by means of anti-retroviral therapy before, during and after delivery¹⁵. The most common anti-retroviral therapy used for the prevention of perinatal infection is Zidovudine¹³. HIV screening, avoidance of breastfeeding, and elective caesarian delivery are also important tools in preventing perinatal HIV transmission¹³.

Multiple Choice Questions:

1) A primagravida mother comes to her OB GYN with concerns about her fetus. She mentions that she has not drunk alcohol nor smoked. She indicates that her mother had complications during the primagravida’s mother birth. Is a primagravida fetus susceptible to Erythroblastosis Fetalis?

A. Yes

B. No

C. Yes, only if the mother drinks and smokes.

D. More information is needed to answer the question.

2) A newborn begins developing accentuated jaundice soon after birth. The attending obstetrician suspects ABO incompatibility and orders an agglutination test. If the issue in this case turned out to be ABO incompatibility, what test results would you expect from maternal blood (Sample 1) vs. neonatal blood (Sample 2)?

		Anti-A	Anti-b
a.	Sample 1	+	-
	Sample 2	+	-
b.	Sample 1	-	-
	Sample 2	+	-
c.	Sample 1	-	+
	Sample 2	+	-
d.	Sample 1	-	-
	Sample 2	-	-
e.	Sample 1	-	-
	Sample 2	+	+
f.	Sample 1	+	+
	Sample 2	+	+

3) Who is required to offer HIV counseling and testing?

A. Physicians

B. Nurses

C. Any healthcare professional involved in providing care to the pregnant woman.

D. Her husband.

E. The peeping-tom neighbor.

Discussion Questions:

Bri1.Briefly explain the mechanism of treatment to prevent erythroblastosis fetalis?

2. Why is phototherapy a viable option for treatment of ABO incompatibility?

3. What counseling and testing services must providers offer to pregnant women?

Answers to the multiple choice questions:

1) B

2) C

3) C

Discussion Questions Answers:

1) Central inhibition, wherein Rh D IgG coats fetal erythrocytes, which are then sequestered in the spleen and lymph nodes. The local increase in antigen-antibody complexes interrupts the commitment of B cells to plasma cell clones, thereby suppressing the primary immune response.

2) Since ABO incompatibility causes hemolysis, and by effect, jaundice, the infant's body is simply overwhelmed by the amount of bilirubin in the blood. Unconjugated bilirubin cannot be excreted until it is conjugated by the liver and turned into a salt. Phototherapy is the use of UV rays to turn bilirubin into lumirubin and photobilirubin (both isomers of bilirubin). These two compounds can be eliminated by the body without being processed by the liver, reducing the threat of liver damage and deposition of bilirubin in the brain.

3) Medical counseling aimed at the neonate in reducing the risk infection. Includes tests/screening procedures include: PCR of viral DNA in infants, CD4 count/monitoring, baseline HIV resistance, viral load, and serology for hepatitis A-C, herpes simplex, mumps, rubella, etc.

Prevention of HIV: Zidovudine, an anti-retroviral therapy, administered before, during, and after delivery and the avoidance of breastfeeding to prevent transmission of HIV to neonate. For the mother, regular usage of condoms during sexual intercourse and for her partner to be tested regularly to reduce the risk of spreading the virus.

References:

1. A.L. Veenstra van Nieuwenhiven, Heineman M.J., et al. The immunology of successful pregnancy. Human Reproductive Update. Department of Gynecology, University of Groningen, The Netherlands. 2003; 9(4):347-357.

2. Koga K. and Mor G. Toll-Like Receptors at the Maternal-Fetal Interface in Normal Pregnancy and Pregnancy Disorders. Allergy and Clinical Immunology. . 2010 June; 63(6): 587–600.

3.Somerset D., Zheng Y., et al. Normal pregnancy is associated with an elevation in the immune suppresser CD25+ CD4+ regulatory T-cell subset. Immunology. 2004, May; 112 (1):38-42.

4.Osorio Y., Bonilla D., among others. Pregnancy enhances the innate immune response in experimental cutaneous leishmaniasis through hormone-modulated nitric oxide production. Journal of Leukocyte Biology. 2008 Jun;83(6):1413-22.

5. Arraut, Amaryllis MD; Caughey, Aaron B, MD: Tran, Susan H, MD. Erythrocyte Alloimmunization and Pregnancy. emedicine from WebMD. http://emedicine.medscape.com/article/273995-overview. Accessed March, 23, 2011.

6. ABO Incompatibility.MedlinePlus. Retrieved from http://www.nlm.nih.gov/medlineplus/ency/article/001306.htm. February 28, 2011. Accesed March 22, 2011.

7. Senterre T., Minon JM, and Rigo J. Neonatal ABO incompatibility underlies a potentially severe hemolytic disease of the newborn and requires adequate care. Arch Pediatr. 2011 March ;18(3):279-282.

8. Bilirubin encephalopathy. WrongDiagnosis. http://www.wrongdiagnosis.com/medical/bilirubin_encephalopathy.htm. January 26,2011. Accessed March 22, 2011.

9. Virgina Commonwealth University. Introduction: Jaundice and kernicterus. Kernicterus & Newborn Jaundice Online. http://www.kernicterus.org/. Accessed March 22, 2011.

10. Adam Cloe. How Phototherapy Works on Jaundice.Livestrong.com. http://www.livestrong.com/article/79481-phototherapy-works-jaundice/. February 4, 2011. Accessed March 22, 2011.

11. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 2010, May 24; pp 1-117. http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed March 28, 2011.

12. Willacy, H. and Knott, L. Congenital HIV and Childhood AIDS.Patient.co.uk. http://www.patient.co.uk/doctor/Congenital-HIV-Infection-and-its-Prevention.htm. February 14, 2011. Accessed March 28, 2011.

13. US Centers for Disease Control. Mother to child (Perinatal) HIV transmission and prevention. 2007 CDC HIV/AIDS Fact Sheet. http://www.cdc.gov/hiv/topics/perinatal/resources/factsheets/pdf/perinatal.pdf Accessed on March 23, 2011.

14. Wang G, Izadpanah N, Kitchen C, Bernstein HB. Fetal allostimulation of maternal cells: A potential mechanism for perinatal HIV transmission following obstetrical hemorrhage. AIDS Research and Human Retriviruses. 2008; 24(12): 1545-54.doi: 10.1089/aid.2008.0007

15. McGowan JP, Shah SS. Prevention of perinatal HIV transmission during pregnancy. J. Antimicrob. Chemother. 2000; 46(5): 657-668.doi: 10.1093/jac/46.5.657

16. Illinois Perinatal HIV Prevention Act FAQ. Illinois Perinatal HIV Hotline. http://www.hivpregnancyhotline.org/preventionact/faq.aspx. accessed march 29, 2011.