Inflammation in Complicated Pregnancy and Its Outcome

Abstract Background Normal pregnancy relies on a careful balance between immune tolerance and suppression. It is known that strict regulation of maternal immune function, in addition to components of inflammation, is paramount to successful pregnancy, and any imbalance between proinflammatory and anti-inflammatory cytokines and chemokines can lead to aberrant inflammation, often seen in complicated pregnancies. Inflammation in complicated pregnancies is directly associated with increased mortality and morbidity of the mother and offspring. Aberrant inflammatory reactions in complicated pregnancies often lead to adverse outcomes, such as spontaneous abortion, preterm labor, intrauterine growth restriction, and fetal demise. The role of inflammation in different stages of normal pregnancy is reviewed, compared, and contrasted with aberrant inflammation in complicated pregnancies. The complications addressed are preterm labor, pregnancy loss, infection, preeclampsia, maternal obesity, gestational diabetes mellitus, autoimmune diseases, and inflammatory bowel disease. Aim This article examines the role of various inflammatory factors contributing to aberrant inflammation in complicated pregnancies. By understanding the aberrant inflammatory process in complicated pregnancies, novel diagnostic tools and therapeutic interventions for modulating it appropriately can be identified.

[1]  D. Kapoor,et al.  Inflammatory bowel disease in pregnancy , 2016 .

[2]  T. Cotechini,et al.  Aberrant maternal inflammation as a cause of pregnancy complications: A potential therapeutic target? , 2015, Placenta.

[3]  D. Zawieja,et al.  Suppression of aldosterone and progesterone in preeclampsia , 2015, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[4]  R. Levy,et al.  Understanding and Managing Pregnancy in Patients with Lupus , 2015, Autoimmune diseases.

[5]  J. Keelan,et al.  Drugs to Block Cytokine Signaling for the Prevention and Treatment of Inflammation-Induced Preterm Birth , 2015, Front. Immunol..

[6]  T. Kuehl,et al.  Pre-eclampsia has an adverse impact on maternal and fetal health. , 2015, Translational research : the journal of laboratory and clinical medicine.

[7]  E. Kamali-Sarvestani,et al.  Differences in the expression of TLRs and inflammatory cytokines in pre-eclamptic compared with healthy pregnant women. , 2014, Iranian journal of immunology : IJI.

[8]  O. S. Bicer,et al.  Prematurity, infection, mortality, morbidity and interleukins: the reason or the result of preterm labor? , 2014, Minerva pediatrica.

[9]  L. Jara,et al.  Risk factors of systemic lupus erythematosus flares during pregnancy , 2014, Immunologic Research.

[10]  J. Ehrig,et al.  Cardiotonic steroids induce anti-angiogenic and anti-proliferative profiles in first trimester extravillous cytotrophoblast cells. , 2014, Placenta.

[11]  D. Zawieja,et al.  Hyperglycemia impairs cytotrophoblast function via stress signaling. , 2014, American journal of obstetrics and gynecology.

[12]  R. Romero,et al.  Prevalence and Clinical Significance of Sterile Intra‐amniotic Inflammation in Patients with Preterm Labor and Intact Membranes , 2014, American journal of reproductive immunology.

[13]  Yan Zhao,et al.  Maternal Circulating Concentrations of Tumor Necrosis Factor-Alpha, Leptin, and Adiponectin in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis , 2014, TheScientificWorldJournal.

[14]  M. Vickers,et al.  Maternal Obesity, Inflammation, and Developmental Programming , 2014, BioMed research international.

[15]  P. Chatterjee,et al.  Regulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy , 2014, Front. Immunol..

[16]  Catherine Kim,et al.  Maternal outcomes and follow‐up after gestational diabetes mellitus , 2014, Diabetic medicine : a journal of the British Diabetic Association.

[17]  C Andrew Combs,et al.  Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. , 2014, American journal of obstetrics and gynecology.

[18]  E. Norwitz,et al.  Human Fetal Membranes Generate Distinct Cytokine Profiles in Response to Bacterial Toll-Like Receptor and Nod-Like Receptor Agonists1 , 2014, Biology of reproduction.

[19]  M. Koucký,et al.  Progesterone, inflammation and preterm labor , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  T. Cotechini,et al.  Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia , 2014, The Journal of experimental medicine.

[21]  G. Wallukat,et al.  Endothelin-1, Oxidative Stress, and Endogenous Angiotensin II: Mechanisms of Angiotensin II Type I Receptor Autoantibody–Enhanced Renal and Blood Pressure Response During Pregnancy , 2013, Hypertension.

[22]  J. Granger,et al.  Recent advances in the understanding of the pathophysiology of preeclampsia. , 2013, Hypertension.

[23]  J. Martin,et al.  Progesterone blunts vascular endothelial cell secretion of endothelin-1 in response to placental ischemia. , 2013, American journal of obstetrics and gynecology.

[24]  Z. Tabka,et al.  Inflammation and impaired endothelium-dependant vasodilatation in non obese women with gestational diabetes mellitus: preliminary results , 2013, Lipids in Health and Disease.

[25]  Yang Xia,et al.  Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond. , 2013, Circulation research.

[26]  A. Blanc,et al.  New Findings for Maternal Mortality Age Patterns: Aggregated Results for 38 Countries , 2013, PloS one.

[27]  Bethany J Figg,et al.  National Institute of Child Health and Human Development , 2013 .

[28]  S. Hooper,et al.  The Consequences of Chorioamnionitis: Preterm Birth and Effects on Development , 2013, Journal of pregnancy.

[29]  C. Redman,et al.  Review: Preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses. , 2013, Placenta.

[30]  K. Cleary,et al.  Pravastatin for the Prevention of Preeclampsia in High-Risk Pregnant Women , 2013, Obstetrics and gynecology.

[31]  S. Lye,et al.  Physiologic Uterine Inflammation and Labor Onset , 2013, Reproductive Sciences.

[32]  Haibin Wang,et al.  Deciphering the molecular basis of uterine receptivity , 2013, Molecular reproduction and development.

[33]  S. Saha,et al.  Safety and efficacy of immunomodulators and biologics during pregnancy and lactation for the treatment of inflammatory bowel disease , 2012, Expert opinion on drug safety.

[34]  D. Zawieja,et al.  Pathogenesis of pre-eclampsia: marinobufagenin and angiogenic imbalance as biomarkers of the syndrome. , 2012, Translational research : the journal of laboratory and clinical medicine.

[35]  D. MacIntyre,et al.  The Th1:Th2 Dichotomy of Pregnancy and Preterm Labour , 2012, Mediators of inflammation.

[36]  D. MacIntyre,et al.  Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 , 2012, Mediators of inflammation.

[37]  S. Sifakis,et al.  Role of Adipokines and Other Inflammatory Mediators in Gestational Diabetes Mellitus and Previous Gestational Diabetes Mellitus , 2012, International journal of endocrinology.

[38]  G. Wallukat,et al.  CD19+CD5+ Cells as Indicators of Preeclampsia , 2012, Hypertension.

[39]  S. A. Akbari,et al.  Correlation between high-risk pregnancy and developmental delay in children aged 4–60 months , 2012, The Libyan journal of medicine.

[40]  M. Fasshauer,et al.  Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre‐eclampsia , 2012, Clinical endocrinology.

[41]  G. Wallukat,et al.  Hypertension in response to IL-6 during pregnancy: role of AT1-receptor activation. , 2011, International journal of interferon, cytokine and mediator research.

[42]  V. Chatterjee,et al.  Interleukin 10 Deficiency Exacerbates Toll-Like Receptor 3–Induced Preeclampsia-Like Symptoms in Mice , 2011, Hypertension.

[43]  K. Wallace,et al.  IL-6-induced pathophysiology during pre-eclampsia: potential therapeutic role for magnesium sulfate? , 2011, International journal of interferon, cytokine and mediator research.

[44]  J. Morris,et al.  A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. , 2011, Reproduction.

[45]  L. Cordero,et al.  Maternal Preeclampsia and Neonatal Outcomes , 2011, Journal of pregnancy.

[46]  Sarah M. Barr,et al.  Placental structure and inflammation in pregnancies associated with obesity. , 2011, Placenta.

[47]  G. Mor,et al.  Inflammation and pregnancy: the role of the immune system at the implantation site , 2011, Annals of the New York Academy of Sciences.

[48]  J. Puschett,et al.  Marinobufagenin, resibufogenin and preeclampsia. , 2010, Biochimica et biophysica acta.

[49]  Sarah M. Barr,et al.  Obesity, pregnancy, inflammation, and vascular function. , 2010, Reproduction.

[50]  J. Puschett,et al.  Contribution of Angiogenic Factors in a Rat Model of Pre-Eclampsia , 2010, American Journal of Nephrology.

[51]  J. Keelan.  Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. , 2010, Journal of reproductive immunology.

[52]  M. Mitchell,et al.  Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I‐κB kinase (IKK) inhibitors , 2010, British journal of pharmacology.

[53]  L. Iaccarino,et al.  Hormones, immune response, and pregnancy in healthy women and SLE patients. , 2010, Swiss medical weekly.

[54]  B. LaMarca,et al.  The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. , 2010, Minerva ginecologica.

[55]  G. Mor,et al.  REVIEW ARTICLE: The Immune System in Pregnancy: A Unique Complexity , 2010, American journal of reproductive immunology.

[56]  T. Shima,et al.  REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T‐Cell Paradigm in Pregnancy , 2010, American journal of reproductive immunology.

[57]  D. Schust,et al.  REVIEW ARTICLE: The Contribution of Macrophages to Normal and Pathological Pregnancies , 2010, American journal of reproductive immunology.

[58]  J. Puschett,et al.  Resibufogenin Prevents the Manifestations of Preeclampsia in an Animal Model of the Syndrome , 2010, Hypertension in pregnancy.

[59]  S. Blackwell,et al.  Angiotensin Receptor Agonistic Autoantibody Is Highly Prevalent in Preeclampsia: Correlation With Disease Severity , 2010, Hypertension.

[60]  J. Puschett,et al.  Alterations in the Renin-Angiotensin System in a Rat Model of Human Preeclampsia , 2009, American Journal of Nephrology.

[61]  G. Mor,et al.  REVIEW ARTICLE: Inflammation and Implantation , 2009, American journal of reproductive immunology.

[62]  Yang Xia,et al.  Is preeclampsia an autoimmune disease? , 2009, Clinical immunology.

[63]  A. Gruber,et al.  Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model , 2009, Journal of cellular and molecular medicine.

[64]  S. Amini,et al.  Monocyte chemoattractant protein-1 (MCP-1): an overview. , 2009, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[65]  J. Puschett,et al.  Marinobufagenin causes endothelial cell monolayer hyperpermeability by altering apoptotic signaling. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[66]  J. Shapiro,et al.  Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets , 2009, Pharmacological Reviews.

[67]  B. Tharakan,et al.  Vascular Leak in a Rat Model of Preeclampsia , 2009, American Journal of Nephrology.

[68]  M. Knöfler,et al.  Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium. , 2009, Placenta.

[69]  A. L. Seager,et al.  Expression and Activity of Toll-Like Receptors 1–9 in the Human Term Placenta and Changes Associated with Labor at Term , 2009, Biology of reproduction.

[70]  E. Lakatta,et al.  Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension , 2008, Journal of hypertension.

[71]  Steffen Jung,et al.  Uterine DCs are crucial for decidua formation during embryo implantation in mice. , 2008, The Journal of clinical investigation.

[72]  Tiejuan Mi,et al.  Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice , 2008, Nature Medicine.

[73]  S. Glaser,et al.  Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function* , 2008, Journal of Biological Chemistry.

[74]  Rong Li,et al.  Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. , 2008, Fertility and sterility.

[75]  Asif Ahmed,et al.  Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling , 2008, Hypertension.

[76]  G. Mor.  Inflammation and Pregnancy , 2008, Annals of the New York Academy of Sciences.

[77]  C. Morris,et al.  Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells. , 2008, Placenta.

[78]  S. Hauguel-de Mouzon,et al.  Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. , 2008, Placenta.

[79]  J. Nelson,et al.  Autoimmune Disease During Pregnancy and the Microchimerism Legacy of Pregnancy , 2008, Immunological investigations.

[80]  P. Cohen,et al.  The selectivity of protein kinase inhibitors: a further update. , 2007, The Biochemical journal.

[81]  Gillian D Bryant-Greenwood,et al.  Relaxin and the Human Fetal Membranes , 2007, Reproductive Sciences.

[82]  F. Ghezzi,et al.  The fetal inflammatory response syndrome. , 2007, American journal of obstetrics and gynecology.

[83]  S. Mandel,et al.  Therapy Insight: management of Graves' disease during pregnancy , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[84]  H. Masuyama,et al.  Expression and potential role of peroxisome proliferator-activated receptor gamma in the placenta of diabetic pregnancy. , 2007, Placenta.

[85]  G. Mor,et al.  Trophoblast–Macrophage Interactions: a Regulatory Network for the Protection of Pregnancy , 2007, American journal of reproductive immunology.

[86]  P. Tekkis,et al.  A meta-analysis on the influence of inflammatory bowel disease on pregnancy , 2006, Gut.

[87]  C. Morris,et al.  Marinobufagenin impairs first trimester cytotrophoblast differentiation. , 2006, Placenta.

[88]  J. Hanna,et al.  Decidual NK cells regulate key developmental processes at the human fetal-maternal interface , 2006, Nature Medicine.

[89]  J. Puschett,et al.  Resibufogenin Corrects Hypertension in a Rat Model of Human Preeclampsia , 2006, Experimental biology and medicine.

[90]  J. Hiller,et al.  Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. , 2005, The New England journal of medicine.

[91]  M. Wolf,et al.  INFLAMMATION AND GLUCOSE INTOLERANCE: A PROSPECTIVE STUDY OF GESTATIONAL DIABETES MELLITUS. , 2003, Journal of Investigative Medicine.

[92]  I. Sargent,et al.  Pre-eclampsia, the placenta and the maternal systemic inflammatory response--a review. , 2003, Placenta.

[93]  S. Kane.  Inflammatory bowel disease in pregnancy. , 2003, Gastroenterology clinics of North America.

[94]  Jonathan M Morris,et al.  Pregnancy is associated with suppression of the nuclear factor kappaB/IkappaB activation pathway in peripheral blood mononuclear cells. , 2003, Journal of reproductive immunology.

[95]  K. Takakuwa,et al.  Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? , 2002, Human reproduction.

[96]  W. Ferrell,et al.  Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. , 2002, The Journal of clinical endocrinology and metabolism.

[97]  S. Mizutani,et al.  Possible activation of the renin-angiotensin system in the feto-placental unit in preeclampsia. , 2002, The Journal of clinical endocrinology and metabolism.

[98]  G. Wallukat,et al.  The upregulation of angiotensin II receptor AT1 in human preeclamptic placenta , 2001, Molecular and Cellular Endocrinology.

[99]  S. Fisher,et al.  Implantation and the survival of early pregnancy. , 2001, The New England journal of medicine.

[100]  A. Kung,et al.  Epitope mapping of tsh receptor-blocking antibodies in Graves' disease that appear during pregnancy. , 2001, The Journal of clinical endocrinology and metabolism.

[101]  J. Lieberman,et al.  Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain , 2001, Schizophrenia Research.

[102]  M. Aitkenhead,et al.  Serum Levels of Vascular Endothelial Growth Factor in Preeclamptic and Normotensive Pregnancy , 2000, Hypertension.

[103]  James J. Walker,et al.  Pre-eclampsia , 2000, The Lancet.

[104]  S. Lye,et al.  Endocrine and paracrine regulation of birth at term and preterm. , 2000, Endocrine reviews.

[105]  R. Ansari,et al.  Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells. , 2000, Hypertension.

[106]  J. Kwok,et al.  Changes in cytokine production during pregnancy in patients with Graves' disease. , 2000, Thyroid : official journal of the American Thyroid Association.

[107]  A. Nielsen,et al.  Current topic: the uteroplacental renin-angiotensin system. , 2000, Placenta.

[108]  G. Wallukat,et al.  AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. , 2000, Circulation.

[109]  B. Eskenazi,et al.  Association of prenatal maternal or postnatal child environmental tobacco smoke exposure and neurodevelopmental and behavioral problems in children. , 1999, Environmental health perspectives.

[110]  G. Robinson,et al.  The localization and expression of the renin-angiotensin system in the human placenta throughout pregnancy. , 1999, Placenta.

[111]  O. Fedorova,et al.  Effects of two putative endogenous digitalis‐like factors, marinobufagenin and ouabain, on the Na+,K+‐pump in human mesenteric arteries , 1998, Journal of hypertension.

[112]  C. Craven,et al.  Human spiral artery renin-angiotensin system. , 1998, Hypertension.

[113]  Roberto Romero,et al.  The fetal inflammatory response syndrome. , 1998, American journal of obstetrics and gynecology.

[114]  B. Korelitz.  Inflammatory bowel disease and pregnancy. , 1998, Gastroenterology clinics of North America.

[115]  Roberto Romero,et al.  GROα in the Fetomaternal and Amniotic Fluid Compartments During Pregnancy and Parturition , 1996 .

[116]  R. Romero,et al.  The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice. , 1992, American journal of obstetrics and gynecology.

[117]  J. Whitworth,et al.  Renin-aldosterone relationships in pregnancy-induced hypertension. , 1992, American journal of hypertension.

[118]  R. Romero,et al.  Systemic administration of interleukin-1 induces preterm parturition in mice. , 1991, American journal of obstetrics and gynecology.

[119]  T. Musci,et al.  Preeclampsia: an endothelial cell disorder. , 1989, American journal of obstetrics and gynecology.

[120]  W. Hsueh,et al.  Increased fetoplacental active renin production in pregnancy-induced hypertension. , 1987, American journal of obstetrics and gynecology.

[121]  E. M. Symonds,et al.  CHANGES IN THE RENIN‐ANGIOTENSIN SYSTEM IN PRIMIGRAVIDAE WITH HYPERTENSIVE DISEASE OF PREGNANCY , 1975, British journal of obstetrics and gynaecology.

[122]  E. M. Symonds,et al.  Analysis of changes in the renin-angiotensin system during pregnancy. , 1972, Clinical science.

[123]  R. Abdul-karim,et al.  Pressor response to angiotonin in pregnant and nonpregnant women. , 1961, American journal of obstetrics and gynecology.

[124]  M. Uddin,et al.  Diabetes Mellitus and Preeclampsia , 2014 .

[125]  A. Caughey,et al.  Progesterone supplementation and the prevention of preterm birth. , 2011, Reviews in obstetrics & gynecology.

[126]  R. Romero,et al.  The Role of Inflammation and Infection in Preterm Birth , 2007, Seminars in reproductive medicine.

[127]  L. Stevenson.  Exercise in pregnancy. Part 1: Update on pathophysiology. , 1997, Canadian family physician Medecin de famille canadien.

[128]  F. Ghezzi,et al.  GRO alpha in the fetomaternal and amniotic fluid compartments during pregnancy and parturition. , 1996, American journal of reproductive immunology.

[129]  R. Bradley.  Diabetic pregnancy. , 1990, British journal of hospital medicine.