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Abstract

Reproductive failure in a variety of forms, whether it be infertility, miscarriage, pre-eclampsia, prematurity or intrauterine growth restriction, may aggregate within individuals. This observation, although rarely studied, suggests that single pathophysiologies may be associated with a variety of reproductive morbidities. In this review, hyperimmune responsiveness to pregnancy is provided as one example of a process leading to a multitude of adverse impacts on healthy childbearing. Further research on reproductive failure as a spectrum is warranted.

Keywords

infertility inflammation pre-eclampsia pregnancy preterm delivery

Successful pregnancy requires profound maternal physiologic adaptation. Failure to adapt to and support a growing placenta and fetus may result in adverse reproductive outcomes including infertility, pregnancy loss, pre-eclampsia, intrauterine growth restriction (IUGR), and prematurity. The purpose of this review is to consider the intersections between a range of reproductive and perinatal disorders, such as reproductive disorders in aggregate. Although direct examination of this concept is rare, the available data are presented herein. Moreover, the author reviews one line of evidence in its favor; that single pathophysiologies are common to a variety of types of reproductive failure. In particular we focus on the links between hyperimmunity and reproductive disorders.

The literature presented is not a systematic review, but does represent an unbiased analysis of research related to the hypothesis that immune excess is associated with multiple types of reproductive failure.

Adverse pregnancy outcomes cluster

Adverse pregnancy outcomes are clearly recurrent in particular women. Recurrent preterm delivery was common in a large population-based study: among women whose first pregnancy ended in a preterm delivery, 20% of white women and 26% of black women had a preterm delivery in their second pregnancy. Among those whose first pregnancy was very premature (delivery after 20–27 weeks), 29% of white women and 37% of black women had a subsequent preterm delivery [1]. In a case–control comparison, predictors of preterm delivery recurrence included preterm labor and a short interpregnancy interval, but much of the risk of recurrence remained elusive [2]. Similarly, women who experience pre-eclampsia in a first pregnancy have an approximately 25% risk of hypertension in their second pregnancy, as compared with a less than 2% risk of pre-eclampsia in second pregnancies overall [3]. Repetitive intrauterine growth restriction is also common, with as many as a third of nonsmoking women experiencing recurrent growth retardation [4,5]. Finally, a subset of women will have recurrent spontaneous abortions.

Different adverse pregnancy outcomes may also cluster in individual women. For example, women with infertility who give birth to a single child after the use of assisted reproductive technology are at an elevated risk of having a low birthweight baby [6]. This appears to represent maternal predisposition and not a medication effect, as surrogate mothers do not manifest an excessively low birthweight risk. Moreover, of women who are subfertile (generally defined as taking more than a year to conceive), data from over 55,000 singleton live births indicate a 50% increase in preterm birth in primiparas and a 90% increase in preterm birth among multiparas, with the use of infertility treatment only adding to the risk in multiparas [7]. In the same cohort, longer time-to-pregnancy increased the risk of pre-eclampsia by 50% among primiparas and 2.5-fold among multliparas [8]. Moreover, longer time-to-pregnancy among women planning their pregnancy increased the risk for neonatal death in a duration-dependent fashion [9]. Finally, many studies have shown that women with pre-eclampsia are more likely to have babies with IUGR [10,11]. Although IUGR may be a result of pre-eclampsia in this situation, this might also demonstrate a common pathophysiology in these two conditions. Although links between various types of reproductive failure in a given woman have not been commonly studied, these examples suggest that further research into this premise would be warranted.

Observing correlations between adverse pregnancy outcomes is only one way to demonstrate the intersection of reproductive morbidities. Another is to demonstrate that a single physiologic process relates to a multitude of reproductive morbidities. The hypothesis that this plethora of adverse reproductive consequences stems from immune imbalance will now be considered. Immune imbalance is but one of many pathophysiologic processes that might have been used to show that a common pathway may lead to many types of reproductive failure. Another example would be abnormal maternal vessel remodeling, which is common to some women with IUGR, pre-eclampsia and preterm delivery. However, rather than touching briefly on many pathophysiologies, one process will be described in detail. The purpose of this more detailed discussion is to provide convincing evidence that a given physiologic aberration may relate to a spectrum of adverse reproductive and perinatal outcomes.

Immune adaptation to normal pregnancy

Inflammation is necessary for normal placental implantation, occurring as part of an endometrial inflammatory response at the site of placenta implantation [12,13]. A modulated inflammatory response is critical for implantation and early embryonic survival. The cytokines tumor growth factor (TGF)-β and tumor necrosis factor (TNF)-α have been proposed to play a role in normal implantation [14,15]. Abnormal functioning of TGF-β and other cytokines may modify the behavior of trophoblasts, which then express integrins, a key feature of the switch for the invasive behavior necessary for sufficiently deep endometrial placentation [16]. Perhaps it is not surprising, then, that periconceptual aspirin use, which interferes with cytokine function, has been associated with spontaneous abortion [17]. During a healthy pregnancy, a woman tolerates a fetus carrying paternal major histocompatibility complex (MHC) and minor antigens that are foreign to her. Moreover, the mother produces an excess of pregnancy-associated circulating activated macrophages, effectors of the innate immune system and markers of oxidative stress [18 –21]. Nonetheless, if all goes well, the fetus will not be rejected.

An impediment to fetal immune rejection are fetal defense mechanisms. Fetal placental trophoblasts do not express MHC proteins, the foreign antigen recognition sites that upregulate the immune response. Instead, the trophoblasts express human leukocyte antigen G (HLA-G), a molecule that inhibits maternal natural killer (NK) cells from becoming cytotoxic [22]. Fetal trophoblasts also express decay accelerating factor (DAF), an inhibitor of cytotoxic killing by NK cells and a regulator of complement activation. Finally, fascilin (FAS)-ligand, a molecule that regulates the apoptosis of immune cells, is highly concentrated in the placenta [23,24].

However, the placental barrier is not complete. Even months or years after delivery, fetal antigens and maternal antibodies to paternal MHC proteins are present in the mother's circulation [22,25]. The syndrome of rhesus (Rh)-incompatibility demonstrates the potential for Rh-positive fetuses to immunize Rh-negative mothers, resulting in maternal Rh-antibodies crossing the placenta and attacking fetal red blood cells [26]. Nonetheless, most fetal MHC antigens of paternal origin do not elicit a uniformly antagonistic maternal immune response. One possible mediator of immune downregulation involves soluble pregnancy-specific β₁-glycoproteins (PSGs) [27 –29]. These proteins both inhibit maternal pro-inflammatory T-cell responses and appear to be required for early communication between the embryo and the endometrial tissues, with aberrant expression leading to recurrent spontaneous abortion.

Overall, a degree of inflammation is normal in pregnancy and maternal and fetal mechanisms protect against excess inflammation. Indeed, excess inflammation, specifically a maternal genotypic/phenotypic susceptibility to hyperinflammation, is associated with reproductive failure, a point made in the sections to follow.

Inflammation, pelvic inflammatory disease & tubal infertility

Women with overly aggressive inflammatory responsiveness may be susceptible to reproductive failure after a sexually transmitted infection. Neisseria gonorrhea and Chlamydia trachomatis are sexually transmitted pathogens that can ascend from the cervix to the upper genital tract where they initiate inflammation characteristic of pelvic inflammatory disease (PID) [30]. PID causes tubal obstruction and pelvic adhesions and leads to infertility and ectopic pregnancy [31]. The mechanism by which chlamydia causes chronic pelvic inflammation is understood to involve a heat-shock protein (hsp) antibody that is expressed on the chlamydial cell wall (Chsp) and cross-reacts with the hsp expressed ubiquitously on human cells (Hhsp60). Antibodies to Hhsp60 and chlamydial Chsp60 share 48% of their amino acid sequences [32]. In macaques, chronic persistent fallopian tube C. trachomatis infection results in severe inflammatory pathology and a strong, long-lasting Chsp60 response [33]. In women, antibodies to Chsp60 are found in 6–25% of fertile women with a positive serology for chlamydia, 48–60% of women with chlamydial PID, and 80–90% of women with chlamydia-associated tubal infertility [30,34]. Women with particular human leucocyte antigen (HLA) phenotypes, including HLA-A31 and HLA DQA ^*301, appear to be at elevated risk for gonococcal and chlamydial cervicitis, endometritis, PID and tubal infertility [35,36]. It is likely that such women launch a more profound immunologic response to Chsp60, a more severe cross-reaction to Hhsp60 and more intense immune-related structural damage. Thus, innate immune hyper-responsiveness in conjunction with sexually transmitted infections may increase the risk of tubal infertility and reduce reproductive potential.

Inflammation & pre-eclampsia

Pre-eclampsia is a systemic maternal disease, characterized by hypertension and proteinuria, and is potentially fatal to both mother and fetus [3,37]. Endothelial dysfunction, probably mediated by oxidative stress, is generally observed in affected women and thought to cause the systemic maternal disease. Redman and colleagues have argued that excessive inflammation provides the oxidative insult to the endothelium seen in pre-eclampsia [18]. Granulocyte and monocyte subsets, characteristic of acute sepsis, are elevated in pre-eclampsia [19,20]. Pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-6 and soluble phospholipase A₂, as well as activated clotting and complement pathways, have also been observed at higher levels in pre-eclamptic than in normal pregnancies [38].

Pre-eclampsia may be more common in placentas where there is a greater dissimilarity between paternal and maternal antigens. Arguably, this might explain the association between large placentas and pre-eclampsia [39]. For example, pre-eclampsia is common among women bearing gestational trophoblastic neoplasms or molar pregnancies, imprinted by the father and representing trophoblastic cells, in the absence of fetal tissue. Twin pregnancies, which have larger placentas than singleton pregnancies, are also more likely to result in pre-eclampsia. Furthermore, the risk for pre-eclampsia is higher in immunologically vulnerable placentas, in particular those with reduced or absent HLA-G expression [40,41]. Finally, it has been proposed that women with more limited exposure to the paternal sperm either by virtue of in vitro fertilization, shorter sexual cohabitation or use of barrier contraception, may be less tolerant and thus mount a more robust immunologic reaction to the sperm, resulting in pre-eclampsia [42].

Direct markers of upregulated immune responsiveness are seen in pre-eclampsia. Although data are limited, mothers carrying a genetic polymorphism that leads to the production of high levels of TNF-α were at increased risk for pre-eclampsia [43]. Additionally, various infections, which would stimulate the maternal immune response, have been linked to pre-eclampsia, including urinary tract infections, malaria and C. pneumoniae [18,44]. Moreover, a recent report showed that women with HIV-1 infection who received no antiretroviral therapy, and thus had suppressed immune function, had markedly reduced rates of pre-eclampsia [45]. In contrast, women taking immune restorative retroviral therapy had pre-eclampsia rates that did not differ from controls. Finally, as discussed in more detail below, women with systemic lupus erythematosus (SLE) are more likely to develop pre-eclampsia [46]. Thus, a greater burden of fetal (placental) antigens, a less well-defended placenta, in addition to an excessive maternal inflammatory response, is associated with pre-eclampsia.

Preterm birth & immune response to infection

Preterm birth, particularly when it involves infants born at less than 32 weeks and weighing less than 1500 g, is a major determinant of perinatal mortality and neonatal morbidity [47]. Evidence of infection (bacteria isolated from the placenta, choriamnion, amniotic fluid or fetus) or of inflammation (histologic chorioamnionitis, decidual inflammation or elevations in systemic inflammatory markers) is found in up to 70–80% of very early preterm deliveries [48,49]. Prostaglandins and proinflammatory cytokines, including IL-1, TNF-α and IL-6, produced in response to infection, are thought to trigger preterm premature rupture of membranes or premature labor. That is, the immediate antecedent of preterm delivery is inflammation.

Several lines of evidence suggest that immune hyper-responsiveness plays a role in preterm delivery. First, low-virulence microorganisms, such as Ureaplasma urealyticum, Mycoplasma hominis, and Fusobacteria spp., persisting for weeks or even months in the upper genital tract, are associated with preterm delivery [50]. Furthermore, aproximately 30% of cases of preterm labor are initiated at relatively low levels (less than 10⁵ colony forming units/mm) of bacterial growth [49]. That premature delivery can be caused by relatively benign bacteria, sometimes having had relatively limited growth, suggests that the damage from the bacteria may be less important than the immunologic response to the bacteria. Second, up to a fifth of women with medically indicted, rather than spontaneous, preterm deliveries, have evidence of upper genital tract infection [48]. That these infections do not initiate preterm deliveries again suggests that predisposition to a pathologic immune response must interact with in utero infection to induce an adverse pregnancy outcome.

Systemic lupus erythematosus, autoimmune diseases & adverse pregnancy outcomes

Until now, the examples in this review have focused on adverse reproductive outcomes and their association with immune upregulation. It will now proceed to a class of examples whereby immune dysregulation relates to a series of poor pregnancy outcomes. Autoimmune diseases are a class of disorders in which a lack of immune tolerance is combined with an immune hyper-responsiveness. SLE, one of the most studied of autoimmune diseases, is characterized by an attack on the nuclei, cytoplasm or membranes of the host's cells and is associated with pre-eclampsia and poor birth outcomes [46]. The incidence of pre-eclampsia among women with SLE ranges from 5–38%, compared with rates generally no higher than 3–7% in most unaffected populations [51]. Women with more severe SLE, in particular those with lupus nephritis and antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), seem to be at particularly high risk of developing pre-eclampsia [52 –54]. Idiosyncratically, prednisone treatment will often worsen pre-eclampsia, perhaps revealing as yet unknown aspects of how auto-immunity promotes the pathophysiology of pre-eclampsia.

Fetal demise, still births, preterm deliveries and IUGR are also common among women with SLE. A number of predictors for fetal loss have been proposed including lupus nephritis, the presence of antiphospholipid antibodies, antibodies to anti-SSA (Ro) or anti-SSB (La), maternal hypertension and history of fetal death [55 –58]. A common pathology leading to adverse pregnancy outcomes in women with these autoantibody types is thought to involve abnormal clotting mechanisms; including interference with the release of arachidonic acid, inhibition of prostaglandin (PGI)₂ production, interference with protein C and disturbance of fibrinolysis [59]. Antiphospholipid antibodies commonly cause venous, and even arterial thrombosis, particularly during pregnancy. In the two largest case series to follow women with antiphospholipid antibodies during pregnancy, the rates of thrombosis or stroke ranged from 5–12% [60,61]. Placentas from affected women also have evidence of infarctions and necrosis. However, a recent study suggested that the placental lesion in first trimester pregnancy losses among women with antiphospholipid antibody syndrome was due to defective trophoblast invasion, perhaps since antiphospholipid antibodies can bind to receptors on trophoblasts and alter their behaviour [62]. Since abnormal trophoblast invasion is also a hallmark of pre-eclampsia and IUGR, this early placental lesion may help to link SLE to these pregnancy complications.

Although less is known about pregnancy outcomes among women with other autoimmune conditions, they too appear to be at high risk for poor reproductive outcomes. In two large, prospective studies, rheumatoid arthritis was associated with an increased risk of pre-eclampsia, preterm delivery and babies who were small for their gestational age [63,64]. In patients whose disease was active, birthweights of babies were lower. Women with autoimmune thyroiditis also have reproductive abnormalities including menstrual irregularities and reductions in fertility rates [65]. In addition, a large literature implicates anti-ovary antibodies (antibodies to selfantigens in the ovary) in infertility [66]. Finally, although not generally considered an autoimmune disease, women with endometriosis have many characteristics of autoimmunity including clonal B-cell production and the concurrence of other autoimmune conditions [67,68]. Infertility is a prominent feature of endometriosis, both in populations of women and in animal models, and assisted reproductive technologies have been less successful in women with endometriosis than in women with other forms of infertility [69].

Summary & future perspectives

Individual adverse pregnancy outcomes are recurrent. Whether different adverse pregnancy outcomes cluster is a subject requiring further research, but it is plausible. Moreover, it is quite possible that single pathophysiologies may contribute to more than one type of reproductive failure. In this article, consideration was given to a single pathophysiologic mechanism, hyperimmunity, in association with several reproductive morbidities. There are many other examples where a risk factor is associated with numerous types of reproductive morbidity. To name only a few, these include:

Age in association with infertility

Spontaneous abortion

Growth restriction and congenital malformations

Elevated circulating corticotrophin-releasing hormone in association with growth restriction

Pre-eclampsia and premature birth

Obesity in association with macrosomia

Pre-eclampsia and infertility

Diabetes in association with macrosomia, congenital malformations, pre-eclampsia and infertility

Much additional research is needed to understand the mechanisms by which these common links occur.

The notion that a single susceptibility or environmental factor may influence multiple adverse pregnancy outcomes challenges us to consider that when a given factor is involved in one type of reproductive failure, it may also be associated with other, seemingly divergent adverse pregnancy outcomes. It also raises the question of why, given a single exposure, some women experience one type of morbidity and some women another. Clearly, this suggests the possibility of gene–environment, gene–gene, or environment–environment interactions. Clinically, the notion that various adverse reproductive/perinatal morbidities cluster and that single pathophysiologies relate to many outcomes may ultimately suggest that clinicians be alert to a spectrum of risk within an individual woman.

Executive summary

Excessive inflammatory responsiveness has been associated with diverse types of reproductive failure including pre-eclampsia, intrauterine growth restriction, preterm delivery and tubal infertility.

Some women may have a genotype/phenotype that codes for excessive pro-inflammatory responsiveness and these women may be at excess risk for reproductive failure.

Different types of reproductive failure, such as pre-eclampsia, intrauterine growth restriction, preterm delivery and recurrent miscarriage, may be linked through common pathophysiologies, an assertion that requires additional verification.

References

Adams

Elam-Evans

Wilson

Gilbertz

: Rates of and factors associated with recurrence of preterm delivery. JAMA 283, 1591–1596 (2000).

Documents recurrence rates of preterm delivery.

Krymko

Bashiri

Smolin

: Risk factors for recurrent preterm delivery Eur. J. Obstet. Gynecol. Reprod. Biol. 113, 160–163 (2004).

Ness

Roberts

: Heterogeneous causes constituting the single syndrome of pre-eclampsia: a hypothesis and its implications. Am. J. Obstet. Gynecol. 175, 1365–1370 (1996).

Review and hypothesis suggesting links between cardiovascular risk, abnormal placentation and pre-eclampsia.

Bakketeig

Hoffman

Jacobsen

Hagen

Storvik

: Intrauterine growth pattern by the tendency to repeat small-for-gestational-age births in successive pregnancies. Acta. Obstet. Gynecol. Scand. 165(Suppl.), S3–S7 (1997).

Rasmussen

Irgens

Albrechtsen

Dalaker

: Predicting pre-eclampsia in the second pregnancy from low birth weight in the first pregnancy. Obstet. Gynecol. 96(5 Pt 1), 696–700 (2000).

Schieve

Meikle

Ferre

Peterson

Jeng

Wilcox

: Low and very low birth weight in infants conceived with use of assisted reproductive technology. N. Engl. J. Med. 346, 731–737 (2002).

Large registry study showing that births from assisted reproduction are more likely to be have a low birth weight.

10.

Basso

Baird

: Infertility and preterm delivery, birthweight, and caesarean section: a study within the Danish National Birth Cohort. Hum. Reprod. 18, 2478–2484 (2003).

11.

Basso

Weinberg

Baird

Wilcox

Olsen

: Danish National Birth Cohort. Am. J. Epidemiol. 157, 195–202 (2003).

12.

Basso

Olsen

: Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. Br. Med. J. 330, 393–394 (2005).

13.

Demonstration of a link between subfecundity and neonatal mortality.

14.

Sibai

Caritis

Thom

: Prevention of pre-eclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N. Engl. J. Med. 329, 1213–1218 (1993).

15.

Sentinel clinical trial of aspirin for prevention of pre-eclampsia.

16.

Sibai

Lindheimer

Hauth

: Risk factors for preeclampsisa, abruption placentae, and adverse neonatal outcomes among women with chronic hypertension. N. Engl. J. Med. 339, 667–671 (1998).

17.

Starkey

Sargent

Redman

: Cell populations in human early pregnancy deciduas: characterization and isolation of large granular lymphocytes by flow cytometry. Immunology 65, 129–134 (1988).

18.

Labarrere

Faulk

: Anchoring villi in human placental basal plate: lymphocytes, macrophages and coagulation. Placenta 12, 173–182 (1991).

19.

Caniggia

Grisaru-Gravnoski

Kuliszewski

Post

Lye

: Inhibition of TGF-β3 restores the invasive capability of extravillous trophoblast in preeclamptic pregnancies. J. Clin. Invest. 103, 1641–1650 (1999).

20.

Pijnenborg

McLaughlin

Vercruysse

: Immunolocalization of tumor necrosis factor-α (TNF-α) in the placental bed of normotensive and hypertensive human pregnancies. Placenta 19, 231–239 (1998).

21.

Caniggia

Winter

: Adriana and Luisa Castelluci Award Lecture 2001. Hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies – a review. Placenta 23(S), S47–S57 (2002).

22.

Excellent review of hypoxia inducible factor, immunology and abnormal placentation in pre-eclampsia.

23.

Liu

Odouli

: Exposure to nonsteroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. Br. Med. J. 327, 368 (2003).

24.

Novel observation of an association between nonsteroidal anti-inflammatory drugs and miscarriage.

25.

Redman

Sacks

Sargent

: Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am. J. Obstet. Gynecol. 180, 499–506 (1999).

26.

Excellent review and proposal of the hypothesis that abnormal immune function plays a role in the genesis of preeclampsia.

27.

Sacks

Studena

Sargent

Redman

: Normal pregnancy and pre-eclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am. J. Obstet. Gynecol. 197, 80–86 (1998).

28.

Luppi

Haluszczak

Betters

Richard

Trucco

DeLoia

: Monocytes are progressively activated in the circulation of pregnancy women. J. Leukoc. Biol. 72, 874–884 (2002).

29.

Sacks

Sargent

Redman

: An innate view of human pregnancy. Immunol. Today 20, 114–118 (1999).

30.

Hanson

: The mother–offspring dyad and the immune system. Acta Paediatr. 89, 252–258 (2000).

31.

Hunt

Vassmer

Ferguson

: Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J. Immunol. 158, 4122–4128 (1997).

32.

Wegmann

Lin

Guilbert

: Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol. Today 14, 353–356 (1993).

33.

Nelson

: Microchimerism and HLA relationships of pregnancy: implications for autoimmune diseases. Curr. Rheumatol. Reports 3, 222–229 (2001).

34.

Bukowski

Saade

: Hydrops fetalis. Clin. Perinatol. 27, 1007–1031 (2000).

35.

Arnold

Rone

Trivadi

Chan

: Effect of pregnancy-specific β1-Glycoprotein on the development of preimplantation embryo. Proc. Soc. Exp. Biol. Med. 220(3), 169–177 (1999).

36.

Snyder

Wessner

Wessells

: Pregnancy-specific glycoproteins function as immunomodulators by inducing secretion of IL-10, IL-6 and TGF-β1 by human monocytes. Am. J. Reprod. Immunol. 45(4), 205–216 (2001).

37.

Jurisicova

Antenos

Kapasi

Meriano

Casper

: Variability in the expression of trophectodermal markers β-human chorionic gonadotrophin, human leukocyte antigen-G and pregnancy specific β-1 glycoprotein by the human blastocyst. Hum. Reprod. 14(7), 1852–1858 (1999).

38.

Cohen

Brunham

: Pathogenesis of chlamydia induced pelvic inflammatory disease. Sex Transm. Infect. 75, 21–24 (1999).

39.

Westrom

Eschenback

: Pelvic inflammatory disease. In: Sexually Transmitted Diseases. Holmes

Sparling

Mardh

P-A

(Eds). McGraw-Hill, NY, USA 783–810 (1999).

40.

Outstanding review of the epidemiology of pelvic inflammatory disease.

41.

Witkin

Askienazy-Elbhar

Henry-Suchet

: Circulating antibodies to a conserved epitope of the Chlamydia trachomatis 60 kDa heat shock protein (hsp60) in infertile couples and its relationship to antibodies to C. trachomatis surface antigens and the Escherichia coli and human HSP60. Hum. Reprod. 13, 1175–1179 (1998).

42.

Peeling

Patton

Cosgrove DL

Sweeney

: Antibody response to the chlamydial heat-shock protein 60 in an experimental model of chronic pelvic inflammatory disease in monkeys. J. Infect. Dis. 180, 774–779 (1999).

43.

Demonstration in primates of the link between the heat shock protein of Chlamydia and chronic inflammation related to pelvic inflammatory disease.

44.

Peeling

Kimani

Plummer

: Antibody to chlamydial hsp60 predicts an increased risk for chlamydial pelvic inflammatory disease. J. Infect. Dis. 175, 1153–1158 (1997).

45.

Human demonstration of the associations between Chlamydia, heat shock protein and pelvic inflammatory disease.

46.

Kimani

Maclean

Bwayo

: Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex workers in Nairobi, Kenya. J. Infect. Dis. 173, 1437–1444 (1996).

47.

Ness

Brunham

Shen

Bass

: For the PID Evaluation and Clinical Health (PEACH) Study Investigators. Associations among human leukocyte antigen (HLA) class II DQ variants, bacterial sexually transmitted diseases, endometritis, and fertility among women with clinical pelvic inflammatory disease. Sex. Transmis. Dis. 31, 301–304 (2004).

48.

Lain

Roberts

: Contemporary concepts of the pathogenesis and management of preeclampsia. JAMA 287, 3183–3186 (2002).

49.

Excellent review of etiology and clinical aspects of pre-eclampsia.

50.

Benyo

Smarason

Redman

Sims

Conrad

: Expression of inflammatory cytokines in placentas from women with preeclampsia. J. Clin. Endocrinol. Metabol. 86, 2505–2512 (2001).

51.

Haig

: The quarterly review of biology: genetic conflicts in human pregnancy. Q. Rev. Biol. 68(4), 495–532 (1993).

52.

Sentinel hypothesis of maternal–fetal conflict as an evolutionary construct related to pregnancy.

53.

O'Brien

McCarthy

Jenkins

: Altered HLA-G transcription in preeclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease. Cell. Mol. Life Sci. 58, 1943–1949 (2001).

54.

Goldman-Wohl

Ariel

Greenfield

: Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with preeclampsia. Mol. Hum. Reprod. 6, 88–95 (2000).

55.

Dekker

Sibai

: The immunology of preeclampsia. Sem. Perinatol. 23, 24–33 (1999).

56.

Chen

Wilson

Wong

Zheng

Walker

McKillop

: Tumor necrosis factor α (TNF-α) gene polymorphism and expression in preeclampsia. Clin. Exp. Immunol. 104, 154–159 (1996).

57.

Heine

Ness

Roberts

: Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Obstet. Gynecol. (2005) (In press).

58.

Wimalasundera

Larbalestier

Smith

: Preeclampsia, antiretroviral therapy, and immune reconstitution. Lancet 360, 1152–1154 (2002).

59.

Mok

Wong

RWS

: Pregnancy in systemic lupus erythematosus. Br. Med. J. 77, 157–165 (2001).

60.

Slattery

Morrison

: Preterm delivery. Lancet 360, 1489–1497 (2002).

61.

Hauth

Andrews

Goldenberg

: Infection-related risk factors predictive of spontaneous preterm birth. Prenat. Neonat. Med. 3, 86–90 (1998).

62.

Gomez

Romero

Edwin

David

: Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect. Dis. Clin. N. Am. 11, 136–176 (1997).

63.

Goldenberg

Hauth

Andrews

: Mechanisms of disease: intrauterine infection and preterm delivery. N. Engl. J. Med. 342, 1500–1507 (2000).

64.

Excellent review of preterm delivery and its link to infection.

65.

Kitridou

: The mother in systemic lupus erythematosus. In: Dubois' lupus erythematosus (5th edition). Wallace

Hahn

, (Eds), Williams & Wilkins, Baltimore, MD, USA 967–1002 (1997).

66.

Oviasu

Hicks

Cameron

: The outcome of pregnancy in women with lupus nephritis. Lupus 1, 19–25 (1991).

67.

Packham

Lam

Nicholls

: Lupus nephritis and pregnancy. Q. J. Med. 83, 315–324 (1992).

68.

Julkunen

Kaaja

Palosuo

: Pregnancy in lupus nephropathy. Acta Obstet. Gynecol. Scand. 72, 258–263 (1993).

69.

Martinez-Rueda

Acre-Salinas

Kraus

Alcoer-Varela

Alarcon-Segovia

: Factors associated with fetal losses in severe systemic lupus erythematosus. Lupus 5, 113–119 (1996).

70.

Rahman

Gladman

Urowitz

: Clinical predictors of fetal outcome in systemic lupus erythematosus. J. Rheumatol. 25, 1526–1530 (1998).

71.

Lockshin

Druzin

Goei

: Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N. Engl. J. Med. 313, 152–156 (1985).

72.

Out

Bruinse

Christiaens

: A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 167, 26–32 (1992).

73.

Loizou

Byron

Englert

David

Hughes

Walport

: Association of quantitative anticardiolipin antibody levels with fetal loss and time of loss in systemic lupus erythematosus. Q. J. Med. 68, 525–531 (1988).

74.

Branch

Silver

Blackwell

: Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet. Gynecol. 80, 614–620 (1992).

75.

Lima

Khamashta

Buchanan

: A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin. Exp. Rheumatol. 131–136 (1996).

76.

Sebire

Fox

Backos

Rai

Paterson

Regan

: Defective endovascular trophoblast invasion in primary antiphopholipid antibody syndrome-associated early pregnancy failure. Hum. Reprod. 17, 1067–1071 (2002).

77.

Bowden

Barrett

Fallow

Silman

: Women with inflammatory polyarthritis have babies of lower birth weight. J. Rheumatol. 28, 355–359 (2001).

78.

Skornsvoll

Ostensen

Irgens

Baste

: Obstetrical and neonatal outcome in pregnant patients with rheumatic disease. Scand. J. Rheumatol. 27, 109–112 (1998).

79.

Krasses

: Thyroid disease and female reproduction. Fertil. Steril. 74(6), 1063–1070 (2000).

80.

Luborsky

: Ovarian autoimmune disease and ovarian autoantibodies. J. Womens Health 11, 585–599 (2002).

81.

Gleicher

el-Roeiy

Confino

Friberg

: Is endometriosis an autoimmune disease? Obstet. Gynecol. 70, 115–122 (1987).

82.

Overview of the literature suggesting that aberrant immunity accompanies endometriosis.

83.

Sinaii

: Autoimmune and related diseases among women with endometriosis: a survey analysis. Hum. Reprod. 17, 2715–2724 (2002).

84.

Vignali

Infantino

Matrone

: Endometriosis: novel etiopathogenetic concepts and clinical perspectives. Fertil. Steril. 78, 665–678 (2002).

Intersections between Adverse Pregnancy Outcomes

Abstract

Keywords

Adverse pregnancy outcomes cluster

Immune adaptation to normal pregnancy

Inflammation, pelvic inflammatory disease & tubal infertility

Inflammation & pre-eclampsia

Preterm birth & immune response to infection

Systemic lupus erythematosus, autoimmune diseases & adverse pregnancy outcomes

Summary & future perspectives

References