Immunological Causes Associated to Foetal Death: An Update

Authors

  • Alejandra Comins Boo Department of Clinical Immunology, Hospital Clínico San Carlos, Madrid, Spain
  • Juliana Ochoa Grullón Department of Clinical Immunology, Hospital Clínico San Carlos, Madrid, Spain
  • Pluvio Coronado Department of Obstetrics & Gynecology, Hospital Clínico San Carlos, Madrid, Spain
  • Miguel Ángel Herráiz Department of Obstetrics & Gynecology, Hospital Clínico San Carlos, Madrid, Spain
  • Silvia Sánchez-Ramón Department of Clinical Immunology, Hospital Clínico San Carlos, Madrid, Spain

DOI:

https://doi.org/10.14205/2309-4400.2014.02.01.7

Keywords:

Foetal loss, antiphospholipid syndrome, immunological causes.

Abstract

Up to 5% of couples at reproductive age suffer from at least two consecutive miscarriages, and around 1% experience three or more consecutive gestational losses, most of them during the first ten weeks of pregnancy, resulting in a significant personal, social and economic public health burden. The pregnancy losses occurring after the twentieth gestational week, namely foetal death or stillbirth, are even more emotionally and psychologically devastating for the couple. In almost half of these cases there is not any known cause of foetal death. In the last years, significant progress in the identification and treatment of the risk factors associated to foetal death has been made: advanced maternal age, obesity, pre-existing maternal diseases or acquired infections during pregnancy; and associated immunological disorders. Among the latter, the most common cause is the obstetric antiphospholipid syndrome, autoimmune disease that can present with placental infarction, thrombosis in the utero-placental circulation and foetal loss. Here we review the evidence of other immunological disorders that have been associated with intrauterine foetal death: non-diagnosed celiac disease, peripheral expansion of natural killer cells and diverse autoimmune or inflammatory abnormalities. The detection and control of such abnormalities in women with history of prior foetal death may lead to a successful subsequent pregnancy.

References

Barfield WD. Standard terminology for fetal, infant, and perinatal deaths. Pediatrics 2011;128(1):177-181. http://dx.doi.org/10.1542/peds.2011-1037

Lawn JE, Blencowe H, Pattinson R, Cousens S, Kumar R, Ibiebele I, et al. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011;377(9775):1448-1463. http://dx.doi.org/10.1016/S0140-6736(10)62187-3

Confidential Enquiry into Maternal and Child Health (CEMACH). Perinatal Mortality 2007: United Kingdom. 2009

Cousens S, Blencowe H, Stanton C, Chou D, Ahmed S, Steinhardt L, et al. National, regional, and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis. Lancet 2011;377(9774):1319-1330. http://dx.doi.org/10.1016/S0140-6736(10)62310-0

Pierangeli SS, Chen PP, Raschi E, Scurati S, Grossi C, Borghi MO, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost 2008;34(3):236-250. http://dx.doi.org/10.1055/s-0028-1082267

Cesarman-Maus G, Rios-Luna NP, Deora AB, Huang B, Villa R, Cravioto Mdel C, et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood 2006;107(11):4375-4382. http://dx.doi.org/10.1182/blood-2005-07-2636

Di Prima FA, Valenti O, Hyseni E, Giorgio E, Faraci M, Renda E, et al. Antiphospholipid Syndrome during pregnancy: the state of the art. J Prenat Med 2011;5(2):41-53.

Agar C, van Os GM, Morgelin M, Sprenger RR, Marquart JA, Urbanus RT, et al. Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. Blood;116(8):1336-1343.

de Groot PG, Meijers JC. beta(2) -Glycoprotein I: evolution, structure and function. J Thromb Haemost 2011;9(7):1275- 1284. http://dx.doi.org/10.1111/j.1538-7836.2011.04327.x

Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011;7(6):330-339. http://dx.doi.org/10.1038/nrrheum.2011.52

Pennings MT, Derksen RH, van Lummel M, Adelmeijer J, VanHoorelbeke K, Urbanus RT, et al. Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2'. J Thromb Haemost 2007;5(2):369-377. http://dx.doi.org/10.1111/j.1538-7836.2007.02310.x

Cuadrado MJ, Buendia P, Velasco F, Aguirre MA, Barbarroja N, Torres LA, et al. Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome. J Thromb Haemost 2006;4(11):2461-2469. http://dx.doi.org/10.1111/j.1538-7836.2006.02193.x

Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002;195(2):211-220. http://dx.doi.org/10.1084/jem.200116116

Meroni PL, Gerosa M, Raschi E, Scurati S, Grossi C, Borghi MO. Updating on the pathogenic mechanisms 5 of the antiphospholipid antibodies-associated pregnancy loss. Clin Rev Allergy Immunol 2008;34(3):332-337. http://dx.doi.org/10.1007/s12016-007-8055-9

Rand JH, Wu XX, Quinn AS, Taatjes DJ. The annexin A5- mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus 2010;19(4):460-469. http://dx.doi.org/10.1177/0961203310361485

Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 2007;29(2):95-113. http://dx.doi.org/10.1007/s00281-007-0069-0

Meroni PL, Tedesco F, Locati M, Vecchi A, Di Simone N, Acaia B, et al. Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus 2010;19(4):453-456. http://dx.doi.org/10.1177/0961203309361351

Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol 2005;32(9):1709-1712.

Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv 2011;66(10):639-653. http://dx.doi.org/10.1097/OGX.0b013e318239e1ee

Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for pregnancy loss in lupus. Obstet Gynecol 2006;107(2 Pt 1):293-299. http://dx.doi.org/10.1097/01.AOG.0000194205.95870.86

Petri M. Sex hormones and systemic lupus erythematosus. Lupus 2008;17(5):412-415. http://dx.doi.org/10.1177/0961203308090026

Magid MS, Kaplan C, Sammaritano LR, Peterson M, Druzin ML, Lockshin MD. Placental pathology in systemic lupus erythematosus: a prospective study. Am J Obstet Gynecol 1998;179(1):226-234. http://dx.doi.org/10.1016/S0002-9378(98)70277-7

Royal_College_of_Obstetricians_and_Gynaecologists, Royal_College_of_Pathologists. Late Intrauterine Fetal Death and Stillbirth. 2010

Buyon JP, Kalunian KC, Ramsey-Goldman R, Petri MA, Lockshin MD, Ruiz-Irastorza G, et al. Assessing disease activity in SLE patients during pregnancy. Lupus 1999;8(8):677-684. http://dx.doi.org/10.1191/096120399680411272

Hulstein JJ, van Runnard Heimel PJ, Franx A, Lenting PJ, Bruinse HW, Silence K, et al. Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. J Thromb Haemost 2006;4(12):2569-2575. http://dx.doi.org/10.1111/j.1538-7836.2006.02205.x

Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD. Advances in the pathophysiology of pre-eclampsia and related podocyte injury. Kidney Int 26 Feb 2014. http://dx.doi.org/10.1038/ki.2014.17

Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM, et al. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 2007;49(3):612-617. http://dx.doi.org/10.1161/01.HYP.0000256565.20983.d4

Xia Y, Kellems RE. Is preeclampsia an autoimmune disease? Clin Immunol 2009;133(1):1-12. http://dx.doi.org/10.1016/j.clim.2009.05.004

Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010;63(6):601-610. http://dx.doi.org/10.1111/j.1600-0897.2010.00852.x

Lynch AM, Murphy JR, Byers T, Gibbs RS, Neville MC, Giclas PC, et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol 2008;198(4):385 e381- 389.

Dekker G, Robillard PY. Pre-eclampsia: Is the immune maladaptation hypothesis still standing? An epidemiological update. J Reprod Immunol 2007;76(1-2):8-16. http://dx.doi.org/10.1016/j.jri.2007.03.015

Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol 2004;286(4):H1389- 1393. http://dx.doi.org/10.1152/ajpheart.00298.2003

Mihu D, Costin N, Mihu CM, Seicean A, Ciortea R. HELLP syndrome - a multisystemic disorder. J Gastrointestin Liver Dis 2007;16(4):419-424.

Steinborn A, Rebmann V, Scharf A, Sohn C, Grosse-Wilde H. Soluble HLA-DR levels in the maternal circulation of normal and pathologic pregnancy. Am J Obstet Gynecol 2003;188(2):473-479. http://dx.doi.org/10.1067/mob.2003.55

Sziller I, Hupuczi P, Normand N, Halmos A, Papp Z, Witkin SS. Fas (TNFRSF6) gene polymorphism in pregnant women with hemolysis, elevated liver enzymes, and low platelets and in their neonates. Obstet Gynecol 2006;107(3):582-587. http://dx.doi.org/10.1097/01.AOG.0000195824.51919.81

Alijotas-Reig J, Melnychuk T, Gris JM. Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: New therapeutic challenging opportunities. Med Clin (Barc) 2014

Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta 2014;35(4):241-248. http://dx.doi.org/10.1016/j.placenta.2014.02.004

Hsu P, Nanan RK. Innate and Adaptive Immune Interactions at the Fetal-Maternal Interface in Healthy Human Pregnancy and Pre-Eclampsia. Front Immunol 2014;5(125.

Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 2004;112(1):38-43. http://dx.doi.org/10.1111/j.1365-2567.2004.01869.x

Zenclussen AC. Regulatory T cells in pregnancy. Springer Semin Immunopathol 2006;28(1):31-39. http://dx.doi.org/10.1007/s00281-006-0023-6

Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 2013;110(3):E231-240. http://dx.doi.org/10.1073/pnas.1206322110

Moffett A, Colucci F. Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest 2014;124(5):1872-1879. http://dx.doi.org/10.1172/JCI68107

Morales M, Berney T, Jenny A, Morel P, Extermann P. Crohn's disease as a risk factor for the outcome of pregnancy. Hepatogastroenterology 2000;47(36):1595-1598.

Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: an evolving story. Thyroid 2001;11(1):57-63. http://dx.doi.org/10.1089/10507250150500676

Gynaecologists RCoOa. Late Intrauterine Fetal Death and Stillbirth. October 2010

Kent J, Farrell AM, Soothill P. Routine administration of AntiD: the ethical case for offering pregnant women fetal RHD genotyping and a review of policy and practice. BMC Pregnancy Childbirth 2014;14(87.

Illanes SE. Management of haemolytic disease of the foetus & newborn: steps to improve the outcomes. Indian J Med Res 2013;138(11-12.

Liumbruno GM, D'Alessandro A, Rea F, Piccinini V, Catalano L, Calizzani G, et al. The role of antenatal immunoprophylaxis in the prevention of maternal-foetal anti-Rh(D) alloimmunisation. Blood Transfus 2010;8(1):8-16.

Vega-Ostertag ME, Pierangeli SS. Mechanisms of aPLmediated thrombosis: effects of aPL on endothelium and platelets. Curr Rheumatol Rep 2007;9(3):190-197. http://dx.doi.org/10.1007/s11926-007-0031-0

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2014-06-30

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