Immunogenesis of preeclampsia: lessons from donor gametes

Background: Preeclampsia remains an important complication of pregnancy. It is associated with mortality and morbidity for both maternal and fetal/newborn patients. Although major inroads have been made in understanding the pathophysiology of preeclampsia in recent decades, the initial primary cause of its occurrence in some women and not others has escaped clarification.

Review: There have been a number of clinical clues pointing to an immune genesis of this disease, including most recently the use of donor gametes in assisted reproductive technology (ART). Despite a number of confounding variables, most studies investigating the addition of donor ova to the ART environment point in the direction of an immune genesis due to the burden of an increasingly foreign fetal allograft on the maternal host. A review of a selection of these studies and a contemporary review of our own Maternal Fetal Medicine practice observations in this regard was completed.

Conclusions: This retrospective evidence suggests a highly likely association. A more basic understanding of the immune interactions at the maternal-fetal interface is required before a final solution to this problem will be at hand and targeted remedies can be formulated.     

The partner's role in the etiology of preeclampsia

The etiology of preeclampsia is often considered to be purely maternal, i.e. maternal constitutional factors that impair maternal cardiovascular/endothelial mechanisms normally required to cope with the specific pregnancy demands, being primarily a generalised inflammatory response and a hyperdynamic circulation. Recent data strongly indicate an important role for the male partner in the causation of this common pregnancy disorder. The aim of this review is to discuss the relevant literature and to explain how paternal, relational and sexual factors play an important role in the etiology of preeclampsia.     

Pathophysiology of preeclampsia

Preeclampsia is a multisystem disorder affecting about 5-10% of all pregnancies. It is a major cause of maternal, fetal and neonatal mortality and morbidity. Despite intensive research the etiology of this disease still remains unknown. Until now the inadequate transformation of the smooth-muscle cells of spiral arteries in the placental bed caused by an insufficient endovascular invasion of the trophoblast has been considered to be the major reason for the development of preeclampsia. Maternal-fetal (paternal) immune maladaptation is implicated in the insufficient trophoblast invasion, which leads to an imbalance of angiogenic and antiangiogenic factors at the maternal-fetal interface. This review summarizes the actual knowledge of important pathophysiological basic principles of preeclampsia.     

Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response

Preeclampsia is characterized by generalized endothelial dysfunction as a result of an inappropriate maternal immune response against the fetus. It has been postulated that the adaptive immune system plays a key role in the etiology of preeclampsia by generating a pro-inflammatory Th1 type immune reaction. In this review, recent studies on Th1 and Th2 type cytokine mapping in preeclampsia are reviewed, as well as on the sources of pro-inflammatory cytokines and the role of regulatory cytokines and chemokines. In addition, we discuss the possible role of Toll-like receptors of the innate immune system in the pathophysiology of preeclampsia. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the newer concepts related to the pathogenesis of preeclampsia and explain the role of the maternal immune system and the role of pro-inflammatory and regulatory cytokines and chemokines in the pathophysiology of the disease.     

Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex

OBJECTIVE: The aim of the present study was to evaluate the effects of fetal gender on serum human chorionic gonadotropin (hCG) and testosterone in normotensive and preeclamptic pregnancies. METHODS: The study consisted of 137 women with singleton pregnancies in the third trimester. Seventy-three pregnancies were uncomplicated; among those were 35 male and 38 female fetuses. Sixty-four pregnancies were complicated by preeclampsia; among those were 33 male and 31 female fetuses. Human chorionic gonadotropin and total testosterone were measured in maternal peripheral blood. RESULTS: In male-bearing pregnancies, maternal hCG and testosterone serum levels were significantly higher in preeclamptic than normotensive mothers (P <.001). In female-bearing pregnancies, testosterone levels were significantly higher in preeclamptic than normotensive mothers (P <.001), whereas the hCG levels were not significantly different. Male-bearing preeclamptic women had significantly higher testosterone levels than female-bearing preeclamptic women (P <.02), whereas the hCG levels were not significantly different. In uncomplicated pregnancies the hCG levels were significantly higher in female-bearing than in male-bearing mothers (P <.005), whereas the testosterone levels were not significantly different. CONCLUSION: In preeclamptic pregnancies with male fetuses, the maternal serum hCG levels were significantly higher than in uncomplicated pregnancies. Total testosterone levels were significantly higher in pregnancies with either gender and significantly higher in male-bearing than in female-bearing pregnancies. This may indicate an androgen influence on the pathophysiologic mechanism of preeclampsia.     

Gene expression of the constant region of the heavy chain of immunoglobulin G (IgG CRHC) is down-regulated in human decidua in association with preeclampsia

An aberrant interaction at the maternal/fetal interface between the genetically distinct fetal trophoblast cells and cells of the maternal decidua has been proposed as an initiating factor in one of the major complications of human pregnancy, preeclampsia. Biochemical and epidemiological studies suggest that the immune system plays an important role in preeclampsia. Thus, the aim of this study was to determine the decidual gene expression status in preeclampsia of one of the key components of the adaptive immune system. Total RNA was extracted from decidua collected from women with normal pregnancies and those complicated by preeclampsia. Reverse Northern analysis was performed on 72 cDNAs from human decidua and differentially expressed genes identified were analysed further using semi-quantitative RT-PCR and Northern blot analysis. Expression of the gene encoding the constant region of the heavy chain of immunoglobulin G (IgG CRHC) was shown to be down-regulated in association with preeclampsia. These data support the hypothesis that immune maladaptation may play an important role in the pathogenesis of preeclampsia.     

Comparison of interleukin-6 levels in maternal and umbilical cord blood in early- and late-onset preeclampsia

Purpose: Increased inflammatory response and cytokines are claimed to play a significant role in the etiology of preeclampsia. Interleukin-6 (IL-6) is a proinflammatory cytokine. Limited number of studies evaluating IL-6 levels in preeclamptic patients have produced conflicting results. Therefore, the present study sought to compare maternal and umbilical cord serum levels of IL-6 in early- and late-onset preeclamptic pregnancies as well as in normal pregnancies. Materials and methods: A total of 69 participants were enrolled in the study. The control group consisted of 24 participants with normal pregnancies. Preeclampsia group consisted of 45 participants. The preeclampsia group was further classified into the subgroups of early- and late-onset preeclampsia. Late-onset preeclampsia group consisted of 24 women whereas early-onset preeclampsia group consisted of 21 women. Serum and umbilical cord samples of IL-6 were compared. Results: There was no significant difference between maternal and umbilical cord serum IL-6 concentrations between the preeclampsia and control group. No significant difference was observed in maternal and umbilical cord serum IL-6 levels between early- and late-onset preeclampsia groups. Conclusion: Our results do not support an increase in IL-6 levels in patients with early- and late-onset preeclampsia. The clinical relevance of our findings needs to be further investigated.     

Placental villitis of unclear etiology during ovum donor in vitro fertilization pregnancy

OBJECTIVE: Preliminary observations by a single pathologist at our institution revealed a 75% incidence of villitis of unexplained etiology in ovum donor in vitro fertilization pregnancies. Because the incidence of villitis of unexplained etiology in the general population is approximately 10%, we conducted a controlled study to compare the incidence of villitis of unexplained etiology in ovum donor in vitro fertilization pregnancies to that in in vitro fertilization pregnancies that do not use donated ova. STUDY DESIGN: Placental specimens of ovum donor in vitro fertilization pregnancies were matched randomly with pregnancies that resulted from both fresh and frozen/thawed native oocyte in vitro fertilization from March 5, 1995, to October 10, 2001, and examined in a blinded fashion by a single pathologist (D. J. R.) for villitis of unexplained cause. The incidence of villitis of unexplained etiology was analyzed in 27 patients who underwent ovum donor in vitro fertilization versus 37 patients who underwent native oocyte in vitro fertilization. RESULTS: Villitis of unexplained cause occurred in 22.2% of ovum donor in vitro fertilization pregnancies, 10.8% of native oocyte in vitro fertilization pregnancies (fresh and frozen/thawed combined), and 14.3% of frozen/thawed cycles (P=.21). CONCLUSION: Although the incidence was not statistically different than in in vitro fertilization that used native maternal oocytes, there was a 2-fold increase in villitis of unexplained cause in the ovum donor in vitro fertilization placentas, which suggests that immune-related disorders may be increased in ovum donor pregnancies.     

Impaired fetal thymic growth precedes clinical preeclampsia: a case-control study

In preeclampsia the maternal adaptive immune system undergoes specific changes, which are different from the physiological processes associated with healthy pregnancy. Whether preeclampsia also affects the fetal immune system is difficult to investigate, due to limited access to the fetus. We hypothesized that if preeclampsia affects the fetal adaptive immune system this might be associated with early changes in thymic growth. In this case-control study, 53 preeclamptic and 120 healthy control pregnancies were matched for maternal age, gestational age and smoking. Fetal thymus diameter was measured as the greatest width perpendicular to a line connecting sternum and spine based on ultrasound images taken at 17-21 weeks gestation. Independent of fetal and maternal anthropometric measures, thymuses were found to be smaller in preeclamptic pregnancies than healthy controls (16.2 mm versus 18.3 mm, respectively, mean difference=2.1 mm, 95% CI: 0.8-3.3, p<0.001), and the odds of developing preeclampsia was estimated to be 0.72 (95% CI: 0.60-0.86, p<0.001) lower for each 1 mm increase in thymus diameter. There was no correlation between the onset of preeclampsia and fetal thymus size. This is the first study to suggest that fetal thymus growth is reduced before the clinical onset of preeclampsia and precedes any described fetal anomalies or maternal immunological changes associated with preeclampsia. We propose that the fetal adaptive immune system is either passively affected by maternal processes preceding clinical preeclampsia or is actively involved in initiating preeclampsia in later pregnancy.     

Pre-eclampsia in pregnancies from donor inseminations

The outcome of 584 AID pregnancies was analysed in order to examine the possible role of immune mechanisms in the development of pre-eclampsia (PE). The overall incidence of PE was high (9.3%) compared with the expected incidence of 0.5–5.0%. The incidence was similar in both multigravid and primigravid women. The expected protective effect of a previous pregnancy was not seen, with a 47-fold increase in PE (observed versus expected) in AID pregnancies after a previous full-term pregnancy and a 15-fold increase after a previous pregnancy of short duration. In the context of AID pregnancies these findings tend to support the proposed ‘fresh mating’ concept of PE although the incidence is lower in multigravidas after a full-term (4.7%) than after a partial pregnancy (15.7%). This suggests that it may only be a full-term pregnancy which protects against the development of PE.The category and duration of infertility and the duration of marriage did not affect the incidence of PE except where the male partner was oligozoospermic. In this case the incidence of PE was higher where infertility was 3 years or longer.Further analysis of the findings failed to provide clear evidence to discriminate the role of HLA and tissue-specific non-HLA antigens in the feto-maternal relationship as determinants of the development of PE. Neither did the results support the operation of immunological enhancement induced by prior coital antigen exposure in the genesis of PE, but raised instead the possibility of the operation of a mechanism of sensitisation of the female partner to seminal components over a long period of time when the husband was oligozoospermic compared with one whose husband was azoospermic.     

Placental Microparticles,DNA, and RNA in Preeclampsia

Preeclampsia is a common disorder of the second half of pregnancy that complicates 2% to 7% of all pregnancies worldwide and remains a major cause of maternal and fetal morbidity and mortality. Although the origin of the disease is still elusive, population-based studies have suggested that it might implicate genetic, immunologic, or physiologic factors. On the other hand, there is no doubt that the placenta plays an important role in its development. In preeclampsia, the shedding of placenta debris, such as syncytiotrophoblast microparticles (STBMs) and DNA and messenger RNA molecules, into the maternal peripheral blood is increased. The analysis of this material may give new insight into placentation and the underlying etiology of this disorder, as well as yield new tracks of research for the understanding of the molecular mechanisms, leading to the generation of the clinical symptoms.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between 'self' and 'non-self'. Accordingly, the fetus activates the mother's immune system because the fetus is in part 'non-self'. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint. Instead, the danger model suggests that normal pregnancy, regardless of the expression of 'non-self' antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome. Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Indications of an altered immune balance in preeclampsia: a decrease in in vitro secretion of IL-5 and IL-10 from blood mononuclear cells and in blood basophil counts compared with normal pregnancy

It has been suggested that maladaptation of the maternal immune response during pregnancy might be a causal factor for preeclampsia. This study was designed to examine the systemic immune status at both the innate level and the adaptive level in pregnancies complicated by preeclampsia (n=15) and normal pregnancies (n=15). Spontaneous and in vitro-induced secretion of IL-5, IL-6, IL-10, IL-12, IL-13 and TNF-alpha, in response to paternal blood cells and the vaccination antigens purified protein derivate of tuberculin (PPD) and tetanus toxoid (TT), was detected in cell culture supernatants from blood mononuclear cells by ELISA. Preeclamptic women showed reduced numbers of basophil granulocytes in the blood (p=0.004) and lower spontaneous secretion of IL-5 from blood mononuclear cells (p=0.016). In addition, paternal antigen-induced secretion of IL-10 was decreased in preeclampsia compared with normal pregnancy (p=0.012). No further differences between preeclampsia and normal pregnancy were found for any stimuli or cytokines. The present findings of reduced basophil numbers and lower spontaneous in vitro secretion of IL-5 in preeclampsia compared with normal pregnancy indicate a decrease in systemic Th2 immunity in preeclampsia. Furthermore, the decrease in paternal antigen-induced secretion of the immunosuppressive cytokine IL-10 in preeclampsia indicates a fetus-specific decrease in immunosuppression mediated by blood mononuclear cells. Whether these systemic changes are a cause or a consequence of preeclampsia remains to be elucidated.     

Human chorionic gonadotropin in cord blood and peripheral maternal blood in singleton and twin pregnancies at delivery

The influence of fetal sex on human chorionic gonadotropin (hCG) in cord and peripheral maternal blood was studied at delivery in 57 twin and 66 singleton uncomplicated pregnancies. In twin pregnancies the hCG levels were about twice as high in female-female and in female-male vis-à-vis male-male combinations in both maternal and cord blood. In singleton pregnancies the hCG levels were significantly higher in maternal and in cord blood in cases of female vis-à-vis male infants. The ratio of maternal hCG/placental weight was also highest in the twin pregnancies when one or both infants were female. This suggests a "female effect", possibly genetically based.     

Preeclampsia Due to Fetal Non-immune Hydrops: Mirror Syndrome and Review of Literature

Objective.?Mirror syndrome (Ballantyne's syndrome) refers to the association of fetal hydrops and maternal preeclampsia. The aim of this study was to determine the relation and incidence between fetal hydrops and preeclampsia in our clinic.?Methods.?A retrospective review of patients associated with fetal hydrops and findings with preeclampsia was used. Seventy-five cases with single pregnancy and diagnoses with nonimmune hydrops fetalis were found. According to the data 4 cases were found related with preeclampsia.?Results.?Mirror syndrome is rarely encountered and underdiagnosed. We found a frequency of 5.3% (4 cases in 75 affected pregnancies) for single non-immune hydrops cases in which maternal hypertension occurred. Fetal outcome is depending on etiology and prognosis is mainly very low. Maternal symptoms and laboratory findings are resolving after intrauterine fetal death or delivery. Conclusion. Hydrops fetalis must be considered as a potential risk factor for preeclampsia. It is important that this clinical condition has a potential of about 5% for proceeding preeclampsia.     

Outcomes of pregnancies achieved by donor egg in vitro fertilization--a comparison with standard in vitro fertilization pregnancies

OBJECTIVE: Prior studies on donor egg in vitro fertilization (DE-IVF) outcomes have been limited by the lack of an appropriate control group. Here, we review the obstetric and perinatal outcomes of pregnancies achieved by DE-IVF and compare these pregnancies with those of women who also needed similar assisted reproductive techniques, of similar socioeconomic status, and cared for by a small group of 8 physicians applying consistent diagnostic and treatment approaches. STUDY DESIGN: A retrospective review of 50 consecutive pregnancies achieved by DE- IVF and 50 consecutive pregnancies achieved by standard IVF (STD-IVF) was performed. Comparisons were made for demographic and medical confounding factors and for outcome measures. RESULTS: The 2 groups were nearly identical for gravidity, parity, and multiple gestations but did vary in maternal age. Average age of patients receiving DE-IVF was 41.9(+/-5.1), whereas the STD-IVF averaged 37.7(+/-3.6) years ( P < .001). Key obstetric outcomes did not differ between the 2 groups with the exception of pregnancy-induced hypertension. In patients with DE-IVF, 26% had pregnancy-induced hypertension (PIH) develop, whereas this occurred in only 8% of the STD-IVF group ( P = .02). Examining nulliparous patients only, 37.1% of DE-IVF had PIH develop, whereas only 8% of STD-IVF group achieved that diagnosis ( P < .003). An analysis with a multiple logistic regression in nulliparous patients found odds ratios of 7.1 (95% CI, 1.4-36.7) in DE versus STD-IVF, odds ratio 4.9 (95% CI, 1.3-18.3) for multiple gestation versus singleton, and odds ratio 1.0 (95% CI, 0.9-1.1) for maternal age. CONCLUSION: Nulliparous pregnancies achieved by DE-IVF are associated with an increased risk of PIH; however, excellent outcomes can still be expected.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between ‘self’ and ‘non-self’. Accordingly, the fetus activates the mother's immune system because the fetus is in part ‘non-self’. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint.Instead, the danger model suggests that normal pregnancy, regardless of the expression of ‘non-self’ antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome.Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

蜕膜化缺陷在子痫前期发病机制中的研究进展

子痫前期是一种严重影响孕产妇和胎儿健康的妊娠期高血压疾病。其病因和发病机制至今尚未阐明,如何有效地预测、诊断和治疗子痫前期,一直是妇产科学界关注的焦点。子宫内膜的蜕膜化为胚胎着床和胚胎发育提供必需的营养和免疫豁免基质。而蜕膜细胞的生物学功能（增殖、分化、凋亡、血管发生和能量代谢等）紊乱所致的蜕膜化缺陷,可影响滋养层细胞的侵袭、炎症抵抗、氧化应激及免疫保护,影响胚胎着床和妊娠维持,从而调控子痫前期的发生、发展。充分了解蜕膜细胞的生物学功能异常所致的蜕膜化缺陷在子痫前期发病机制中的作用,将有助于为预测及诊治子痫前期提供更多的理论依据。     

Impact of fetal sex in pregnancy-induced hypertension and preeclampsia in Japan

The male antigen (HY), the elevated level of fetal antigen in twin pregnancies, and the increased number of MHC mismatches in dizygotic twin pregnancies might affect immunological tolerance during pregnancy. Using the Perinatal Database of the Japanese Society for Obstetrics and Gynecology, we studied the occurrence of pregnancy-induced hypertension (PIH) and preeclampsia in mothers delivering singleton babies and in those delivering monochorionic diamniotic (MD) twin pregnancies and dichorionic diamniotic (DD) twin pregnancies at 125 centers of the perinatal network in Japan from 2001 through 2005. In singleton pregnancies, pregnant women carrying female fetuses had a significantly higher incidence of PIH and preeclampsia compared with those carrying male fetuses. In MD twin pregnancies, compared with mothers carrying male-male fetuses, those carrying female-female fetuses had significantly higher incidences of PIH and preeclampsia and a marked difference was observed in primiparous cases. In DD twin pregnancies, the incidences of PIH and preeclampsia were significantly higher in mothers with female-female fetuses than those with male-male fetuses, while those with male-female fetuses had intermediate values. The incidence of PIH and preeclampsia in MD twin pregnancies was similar to that in DD twin pregnancies with male-male fetuses or female-female fetuses. The male antigen and the increased number of MHC mismatches in DD twin pregnancies were not a risk factor for PIH and preeclampsia. Female fetal sex was a risk factor for PIH and preeclampsia.     

Review: Alterations in placental glycogen deposition in complicated pregnancies: Current preclinical and clinical evidence

Normal placental function is essential for optimal fetal growth. Transport of glucose from mother to fetus is critical for fetal nutrient demands and can be stored in the placenta as glycogen. However, the function of this glycogen deposition remains a matter of debate: It could be a source of fuel for the placenta itself or a storage reservoir for later use by the fetus in times of need. While the significance of placental glycogen remains elusive, mounting evidence indicates that altered glycogen metabolism and/or deposition accompanies many pregnancy complications that adversely affect fetal development. This review will summarize histological, biochemical and molecular evidence that glycogen accumulates in a) placentas from a variety of experimental rodent models of perturbed pregnancy, including maternal alcohol exposure, glucocorticoid exposure, dietary deficiencies and hypoxia and b) placentas from human pregnancies with complications including preeclampsia, gestational diabetes mellitus and intrauterine growth restriction (IUGR). These pregnancies typically result in altered fetal growth, developmental abnormalities and/or disease outcomes in offspring. Collectively, this evidence suggests that changes in placental glycogen deposition is a common feature of pregnancy complications, particularly those associated with altered fetal growth.