Preeclampsia and human reproduction. An essay of a long term reflection

Hypertensive disorders of pregnancy (HDP: pregnancy-induced hypertension, preeclampsia, eclampsia) affect approximately 10% of human births. Women are at increased risk for HDP during their first conception; and/or when the conception is with a new partner (new paternity); when conception occurs very shortly after the beginning of their sexual relationship. A primary cause of preeclampsia is the defect of the normal human-specific deep endovascular invasion of trophoblast, which is a consequence of the nutritional demands of growth of the human fetal brain. The occurrence of preeclampsia represents a reproductive disadvantage unique to humans compared with other mammals. As such, it may have played a significant role in shaping human reproduction and, therefore, human sexuality. This deep implantation/preeclampsia phenomenon may explain many anthropological mysteries of human sexuality that do not exist in other mammalian species (and primates). These include: very low fertility rate, concealed ovulation, all year long 'apparent-waste-of-efficiency' sexuality, absence of sperm competition in human females at the time of conception, and the unexplained testicle size in human males compared with relevant primates. Further, this deep trophoblastic implantation (and its failure in preeclampsia) in humans might be a decisive condition of hominization between great apes and all the other Homo genuses. This frontier might even have occurred inside these Homo lineages: because of their relatively small brains, the first species of Homo might not have presented the deep trophoblastic invasion described in Homo sapiens.     

Reproductive strategies for human survival

Reproductive strategies for the human species have basically remained unaltered since Homo sapiens first appeared, probably in the valleys of Africa: males have always attempted to pass their genes to the largest feasible number of females, selecting those females capable of providing the best quality of oocytes; females invariably have sought a male capable of providing the best means of survival for herself and her offspring. This meant that human sexuality has been essentially conceptive, although it is reasonable to suppose that it began to lose this 'exclusive' connotation early in the cultural evolution of the species. Then, during the 20th century, major revolutions occurred: first, with the advent of contraception, sex without reproduction became a reality; then, with assisted reproduction technology, humans devised reproduction without sex; finally, very recently, women have begun to reproduce even in menopause. Additional strategies will, no doubt, soon be available, although we cannot as yet clearly see whether, or when, reproduction without sex and gametes, or in-vitro gestations will become available.     

Fetal head molding. Diagnosis by ultrasound and a review of the literature

Head molding refers to changes in cranial bone relationships that occur in response to external compression force. In the normal term labor with vertex presentation, the suboccipito-bregmatic diameter shortens and the mentovertical diameter lengthens. This is accomplished partially through the unbending or straightening of the parietal bones rather than the frequently taught mechanism of overlapping sutures. The occipital and frontal bones may also contribute by an inward movement of their apex, using their basal portions as a hinge. A locking mechanism may occur in protracted labors as the free edges of the cranial bones are forced into one another, preventing further molding and providing more protection for the fetal brain. The preterm skull has weaker material properties and wider sutures. Thus, more molding at lower pressures is possible and the protective effect of "locking" may not be operational. A case of extreme antenatal preterm fetal head molding discovered at ultrasound is presented as an introduction to review the literature regarding molding.     

Abnormal iron parameters in the pregnancy syndrome preeclampsia

OBJECTIVE: Our purpose was to investigate iron status parameters in preeclampsia with a view to exploring their possible contribution to the etiology. STUDY DESIGN: In prepared serum samples from 40 preeclamptic women and matched pregnant control subjects at the John Radcliffe Hospital, Oxford, a number of iron status parameters were measured. Statistical analysis was by the Wilcoxon signed rank test and linear regression. RESULTS: Serum iron concentration, ferritin, and percent saturation of transferrin were significantly higher in the preeclamptic patients than in control subjects, whereas unsaturated iron-binding capacity and apotransferrin levels were significantly lower. No difference was found in hemopexin concentrations in the two groups. Gestational age at the time of sampling was correlated (positively) with only two parameters, total and unsaturated iron-binding capacity, but only in the preeclampsia group. Eighteen percent of preeclamptic subjects had percent transferrin saturation levels in the region associated with iron overload. CONCLUSION: Released iron species in preeclampsia may contribute to the etiology and will exacerbate lipid peroxidation and endothelial cell injury. Given the high prevalence of heterozygosity for hemochromatosis with the associated reduced ability to exclude ingested iron, it would seem inadvisable, in the absence of evidence of iron deficiency, to give iron supplements to pregnant women at high risk for preeclampsia.     

Susceptibility of red blood cell lipids to in vitro oxidation and antioxidant status in preeclampsia

Objective

To investigate susceptibility of red blood cell (RBC) lipids to oxidation and antioxidant status in preeclampsia.

Study design

Twenty-one women with mild preeclampsia, 21 women with severe preeclampsia, and 20 healthy pregnant women were included in this cross-sectional study. Susceptibility of RBC to oxidative stress was determined by measuring RBC-malondialdehyde levels after incubation with hydrogen peroxide. Vitamins E and C, total carotenoids and erythrocyte superoxide dismutase and glutathione peroxidase (GPx) activities and serum total antioxidant capacity (TAC) were determined spectrophotometrically. One-way analysis of variance and correlation analysis were used for statistical analyses.

Results

Compared with the normal pregnant women, susceptibility of RBC to oxidation was enhanced in the mild (p < 0.05) and severe (p < 0.01) preeclampsia groups, TAC was lower in the mild (p < 0.01) and severe (p < 0.001) preeclampsia groups. Vitamin C level was decreased in severe preeclampsia and total carotene level was decreased in mild and severe preeclampsia groups (p < 0.05). GPx activity was also decreased in the mild (p < 0.01) and severe (p < 0.05) preeclampsia groups.

Conclusion

The results of the present study supported the oxidative stress hypothesis of preeclampsia and it is possible that RBC play a role in the pathophysiology of the disease.     

Preeclampsia: Diagnosis and management of the atypical presentation.

Preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome remain as major obstetric problems that plague a large percentage of women resulting in an equally large percentage of maternal and perinatal morbidities. It is important that a clinician makes the most accurate diagnosis possible to prevent these adverse maternal and perinatal outcomes. In general, most women will have a classical presentation of preeclampsia (hypertension and proteinuria) at >20 weeks gestation and <48 hours postpartum. However, recent studies have suggested that some women will develop preeclampsia without the classical findings. The purpose of this review is to increase awareness of the non-classical and atypical features of preeclampsia, eclampsia, and HELLP syndrome and their respective management. Atypical cases are those that develop before 20 weeks, beyond 48 hours postpartum and those that present with some of the signs and symptoms of preeclampsia without the usual hypertension or proteinuria. By formulating a rational stepwise approach towards diagnosis, we may prevent the costly consequence of a missed diagnosis and its eventual possible fatalities.     

Cytokine-related genes and oxidation-related genes detected in preeclamptic placentas

Purpose

To investigate cytokine- and oxidation-related genes for preeclampsia using DNA microarray analysis.

Methods

Placentas were collected from 13 normal pregnancies and 13 patients with preeclampsia. Gene expression was studied using DNA microarray. Among significantly expressed genes, we focused on genes associated with cytokines and oxidation, and the results were confirmed using quantitative real time-polymerase chain reaction (QRT-PCR).

Results

415 genes out of 30,940 genes were altered by ≥2-fold in the microarray analysis. 121 up-regulated genes and 294 down-regulated genes were found to be in preeclamptic placenta. Six cytokine-related genes and 5 oxidation-related genes were found from among the 121 up-regulated genes. The cytokine-related genes studied included oncostatin M (OSM), fms-related tyrosine kinase (FLT1) and vascular endothelial growth factor A (VEGFA), and the oxidation-related genes studied included spermine oxidase (SMOX), l cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), acetate dehydrogenase A (LDHA). These six genes were also significantly higher in placentas from patients with preeclampsia than in those from women with normal pregnancies. The placental tissue of patients with preeclampsia showed significantly higher mRNA expression of these six genes than the normal group, using QRT-PCR.

Conclusion

DNA microarray analysis is one of the great methods for simultaneously detecting the functionally associated genes of preeclampsia. The cytokine-related genes such as OSM, FLT1 and VEGFA, and the oxidation-related genes such as LDHA, CYP26A1 and SMOX might prove to be the starting point in the elucidation of the pathogenesis of preeclampsia.     

Ultrastructural aspects of preeclampsia. II. Mitochondrial changes

Biopsy specimens were obtained under direct vision at the time of cesarean section from 47 patients (35 with preeclampsia and 12 normotensive patients) and from four women with cesarean section hysterectomies (all normotensive) as an extension of previous work. Tissues were obtained from the myometrium near the placental bed and from the opposite side of the uterus. Skin biopsies were also obtained from eight women with preeclampsia and liver biopsies were obtained from two patients with acute microvesicular fatty change of pregnancy (one with and one without concomitant preeclampsia). Specimens were examined histologically and by electron microscopy. Mitochondrial changes in small vessels, principally venules, in myometrial smooth muscle, myometrial interstitial cells, circulating leukocytes, epidermal and dermal cells, and hepatocytes were examined and compared between women with preeclamptic and normotensive pregnancies. These findings were then compared with mitochondria from 500 biopsies over the same 3-year interval to assess the possible role of delay in tissue fixation. There were 12 other biopsies from nonpregnant women of childbearing age. As further control on artifact, other specimens were initially sampled immediately in the operating room and then serially for up to 2 hours later. Artifact as a basis for the mitochondrial changes was ruled out by these procedures. Normal mitochondria undergo a morphologic conformational sequence with physiologic changes in substrate, oxygen consumption, adenosine diphosphate, and respiratory rate. The mitochondria of preeclamptic tissues show a central disruption that is outside this normal sequence or cycle. This disruption occurs more often and is more severe in preeclampsia than in normotensive pregnancies. In addition, the hypertrophic smooth muscle of the pregnant uterus has a complex of cytoplasmic organelles in a paranuclear location, usually apical, that contains a variable mixture of glycogen, the Golgi apparatus, endoplasmic reticulum, mitochondria, and small unidentified microvesicles. This complex has the location and appearance suggestive of a myometrial "power pack" of significance in metabolism and contraction. The presence of similar mitochondrial changes in a limited sample of nonuterine tissues is suggestive of a systemic metabolic disorder as an important feature of preeclampsia.     

Complement Factor H Variant Y402H is Not a Risk Factor for Preeclampsia in the Finnish Population

Objective: Variations in complement factor H, which down-regulates the activity of the alternative complement pathway, have been associated with different vascular disorders. Here we examine whether factor H variation is involved in the etiology of preeclampsia. Methods: We studied 110 women with preeclampsia and 99 controls for complement factor H variations by sequencing. Results: No significant differences in the genotype or allele frequencies of the Y402H variant were detected between the two groups. No sequence variations were detected in the short consensus repeat domain 20 of the gene. Conclusions: Neither the Y402H variant, nor mutations in the short consensus repeat domain 20 of the gene is associated with preeclampsia. For examination of possible links to other polymorphisms or detection of small genotypic effects, studies in larger sample sets are warranted.     

高龄孕产妇子痫前期的特点与处理难点

随着"二孩政策"的全面放开,高龄孕产妇人数急剧上升,产科面临巨大挑战。高龄妊娠并发子痫前期患者病情复杂且严重,孕产妇不良妊娠结局明显增加。本文就高龄妊娠子痫前期的特点及处理难点进行讨论。     

Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia

Preeclampsia is a human pregnancy-specific disorder that is diagnosed by the new appearance of hypertension and proteinuria after 20 weeks' gestation. It is a leading cause of perinatal morbidity and mortality, and the only intervention that effectively reverses the syndrome is delivery. Oxidative stress of the placenta is considered to be a key intermediary step in the pathogenesis of preeclampsia, but the cause for the stress remains unknown. Hypoxia-reoxygenation (H/R) injury, as a result of intermittent placental perfusion secondary to deficient trophoblast invasion of the endometrial arteries, is a possible mechanism. In this review, we present evidence to show that there is a plausible basis from which to assume that blood flow in the intervillous space will be intermittent in all normal pregnancies. The intermittency will be exacerbated by impaired conversion of the spiral arteries, or by the presence of atherotic changes that reduce their caliber as seen in preeclampsia. Placental oxidative stress can be the consequences of fluctuations in oxygen concentrations after H/R through the actions of reactive oxygen species. On this basis, there will be a complete spectrum of placental changes among the normal, the late onset and the early onset preeclamptic states. Viewing the syndrome as a continuum of H/R insults provides new insight into the pathophysiology of pregnancy that will hope fully lead to improved clinical interventions.     

Preeclampsia: Diagnosis and management of the atypical presentation

Preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome remain as major obstetric problems that plague a large percentage of women resulting in an equally large percentage of maternal and perinatal morbidities. It is important that a clinician makes the most accurate diagnosis possible to prevent these adverse maternal and perinatal outcomes. In general, most women will have a classical presentation of preeclampsia (hypertension and proteinuria) at >20 weeks gestation and <48 hours postpartum. However, recent studies have suggested that some women will develop preeclampsia without the classical findings. The purpose of this review is to increase awareness of the non-classical and atypical features of preeclampsia, eclampsia, and HELLP syndrome and their respective management. Atypical cases are those that develop before 20 weeks, beyond 48 hours postpartum and those that present with some of the signs and symptoms of preeclampsia without the usual hypertension or proteinuria. By formulating a rational stepwise approach towards diagnosis, we may prevent the costly consequence of a missed diagnosis and its eventual possible fatalities.     

Development and use of quality of care indicators for obstetric care in women with preeclampsia, severe preeclampsia, and severe morbidity.

OBJECTIVE: To develop indicators for evaluating the quality of care in managing preeclampsia. METHODS: An expert group helped to develop and validate the following indicators for evaluating quality of care: availability of intensive care; completeness of laboratory tests; appropriateness of drug treatment at admission and before delivery (antihypertensive drugs, anticonvulsants, and dexamethasone); gestational age at which pregnancy should be interrupted; and type of delivery. By using these indicators, it was possible to evaluate the quality of care in 432 patients with preeclampsia. RESULTS: A significant percentage of patients with preeclampsia and "near misses" received low quality of care, regardless of disease severity. CONCLUSION: A number of interventions are needed to increase the quality of care to help avert maternal deaths in patients with preeclampsia.     

Prediction of preeclampsia in type 1 diabetes in early pregnancy by clinical predictors: a systematic review

Purpose: The purpose of this study is to evaluate the prevalence and possible clinical predictors of preeclampsia present in early pregnancy among women with type 1 diabetes.

Methods: A systematic search of PubMed was conducted in April 2017. Inclusion criteria were largely unselected cohort, including at least 100 women with type 1 diabetes, dealing with either the prevalence of preeclampsia or possible clinical predictors of preeclampsia identified in early pregnancy.

Results: Based on 11,518 pregnancies in 11 articles, the prevalence of preeclampsia in women with type 1 diabetes was 17%, five to six times more than in the background population. In early pregnancy, the following clinical predictors were associated with increased prevalence of preeclampsia: diabetic nephropathy (OR 3.7–23.5), microalbuminuria (OR 3.8–11.7), diabetic retinopathy (OR 1.9–2.9) and pre-existing hypertension (OR 3.8–17.1) as well as high blood pressure within the normotensive range. HbA1C, body mass index and nulliparity were positively associated with preeclampsia, but not consistently.

Conclusion: The prevalence of preeclampsia in women with type 1 diabetes was 17%. In early pregnancy pre-existing hypertension and high blood pressure within the normotensive range as well as presence of microangiopathy were predictors of preeclampsia. Poor glycaemic control, obesity and nulliparity probably also contribute to the increased risk.     

The epidemiology of preterm labour

Although the definition of preterm birth is birth before 37 completed weeks, the major transition in terms of needing special care occurs between 34 and 37 weeks. The Homo sapiens neonate is born much more immature than other anthropoid species, perhaps because earlier birth has evolved to avoid the large head of the human fetus becoming impacted in the small pelvis of the mother, who has become adapted to a bipedal gait. The main burden of preterm birth exists in developing countries. There are no accurate recent worldwide data, but estimates of preterm birth rates range from 5% in developed countries to 25% in developing countries. The preterm delivery rate has been relatively stable at 5–10% in developed countries for many years. The North Thames database of 517,381 pregnancies demonstrates significant ethnic variation in preterm birth rates, with higher rates in black women. This is associated with an accelerated rate of maturity in the black fetus and neonate, with correspondingly lower gestation-specific neonatal mortality rates below 38 weeks, and higher at 38 weeks of gestation and beyond. Ethnic differences can explain only a very small proportion of global preterm births. The greatest aetiological factor worldwide is infection, mainly due to malaria and HIV. In developed countries, iatrogenic delivery is responsible for almost half of the births between 28 and 35 weeks; hypertension and pre-eclampsia are the major pathologies. Other factors include multiple pregnancy, intrauterine growth restriction, maternal stress and heavy physical work.     

子痫前期孕妇血清中氧化应激产物H_2O_2对sHLA-G表达的影响

目的:探讨子痫前期患者血清中氧化应激产物H2O2对可溶性人类白细胞抗原G(sHLA-G)表达的影响,分析早发型及晚发型子痫前期的病因。方法:选择早发型和晚发型子痫前期孕妇各15例为研究组,以同期正常孕妇15例为对照组。采用比色法及ELISA法分别检测3组研究对象血清中H2O2含量和sHLA-G表达,并进行相关性分析。结果:(1)早发型及晚发型子痫前期组孕妇血清中H2O2呈高水平表达[(58.43±3.56)μmol/L,(29.84±7.67μmol/L)],与正常妊娠组相比[(21.61±4.25)μmol/L],差异均有统计学意义(P均<0.05);早发型子痫前期组孕妇血清中H2O2含量显著高于晚发型子痫前期组(P<0.05)。(2)早发型及晚发型子痫前期组孕妇血清中sHLA-G呈低水平表达[(28.65±9.16)U/ml,(51.84±8.67)U/ml],与正常妊娠组[(98.13±13.26)U/ml]相比,差异有统计学意义(P均<0.05);早发型子痫前期组孕妇血清中sHLA-G表达量显著低于晚发型子痫前期组(P<0.05)。(3)正常妊娠、子痫前期孕妇血清中的H2O2水平与sHLA-G表达呈负相关(r=-0.835,P<0.05)。结论:早发型子痫前期发病早,受氧化应激损伤更严重,血清中sHLA-G表达量更低;氧化应激产物H2O2可能潜在下调sHLA-G表达,与子痫前期发病及病情轻重程度相关。     

Fetal-Maternal Conflict,Trophoblast Invasion,Preeclampsia, and the Red Queen

The much publicized conflict hypothesis for understanding fetal-maternal interaction during pregnancy often invokes a ‘battle’ metaphor, rather than a well orchestrated interplay occurring as a series of well controlled moves and counter-moves as happens in a game of chess. Such stepwise interaction is particularly obvious in the spiral artery remodelling process, and it would be interesting to trace the history of the successive steps in histological adaptation throughout primate phylogeny. The restricted invasion observed in a few species on a ‘lower’ evolutionary scale suggests a tendency of progressive deeper invasion during primate evolution. Unfortunately, our knowledge of invasive processes in the placental bed in nonhuman primates is highly inadequate. A paradigm underscoring the stepwise interaction between mother and fetus may be provided by the Red Queen hypothesis, which is a useful model to explain co-evolutionary processes between different species. The apparent association between preeclampsia and restricted endovascular trophoblast invasion, combined with the absence of the disease in primate species showing shallow invasion, suggests that preeclampsia may result from a failure in one or more interactive steps necessary for deeper invasion. Evidence for a genetic component invokes the puzzling question as to why “preeclampsia genes” are not eliminated from human populations. As in other fields of medicine, a proper understanding of Darwinian selection processes may throw some light on the causes of preeclampsia.     

15-羟廿碳四烯酸对子痫前期脐动脉环的收缩作用及机制

目的探讨15-羟廿碳四烯酸(15-HETE)在子痫前期患者的离体脐动脉环的作用。 方法分析2011年1月至6月期间,就诊于哈尔滨医科大学附属第一医院28例孕妇资料,正常妊娠组12例,子痫前期组16例。在剖宫产术中胎儿娩出后,立即收集脐带用于脐动脉张力研究。采用组织浴槽血管环法观察15-HETE对两组患者离体脐动脉环的收缩作用。两组脐动脉环血管张力和脐动脉环收缩力的比较采用两样本均数t检验进行统计学处理。 结果(1)15-HETE以浓度依赖方式(10^－8～10^－6 mol/L)使游离脐动脉环张力增加,在子痫前期组,血管张力值分别为145.37±7.65, 205.42±4.99, 268.00±6.25,而正常妊娠组的张力值为107.41±3.90, 127.83±5.23, 140.04±6.57。因此,15-HETE对子痫前期脐动脉环张力作用更为明显,与正常妊娠组相比差异有统计学意义(t＝－12.769,－31.909,－48.856;P<0.05)。(2)脐动脉的血管收缩作用在正常妊娠组被10^－6 mol/L硝苯地平阻断前后的血管张力值为140.04±6.57和128.89±6.16(t＝3.087,P<0.05);子痫前期组脐动脉的血管收缩作用被10^－6 mol/L硝苯地平阻断前后的血管张力值为268.00±6.25和166.96±3.42(t＝40.419,P<0.05)。(3)脐动脉的血管收缩作用在正常妊娠组被1,4,5-三磷酸肌醇(IP3)受体阻断剂2-氨基乙基二苯硼酸酯(2-APB)阻断前后的血管张力值为140.04±6.57和91.87±3.33(t＝20.491, P<0.05);子痫前期组脐动脉的血管收缩作用被IP3受体阻断剂2-APB阻断前后的血管张力值为268.00±6.25和93.14±4.97(t＝58.804,P<0.05)。 结论在子痫前期,15-HETE可能通过增加细胞内钙离子浓度导致脐动脉的收缩。