Obstetric Syndrome Research Articles

Pregnancy disorders in Africa and the obstetric dilemma.

The high neonatal and maternal morbidity and mortality associated with the extremes of birth weight is referred to as the obstetric dilemma. Pre-eclampsia and other conditions that lead to low birth weight are considered as the Great Obstetrical Syndromes (GOS). At the other extreme is high birth weight resulting in obstructed labour. Fetal weight largely depends on placental function and defective placentation is a common feature of the GOS. There is evidence that the local uterine immune system (KIR and HLA-C) regulates placentation, with racial differences noted. These differences may be responsible for the striking obstetric dilemma in Africans.

IFPA award in placentology lecture: Phylogenomic origins and evolution of the mammalian placenta

The placenta has had the most dynamic evolutionary history of all mammalian organs. It has undergone massive shifts in anatomy, physiology, and the way in which uterine and fetal tissue interact with one another during pregnancy. The human placenta is arguably the best studied amongst mammals, yet much about its function during pregnancy is not understood. The purpose of this paper is to outline the evolutionary history of the placenta, and to point out major gaps in the current state of knowledge. I also propose novel theoretical, experimental, and computational approaches that are likely to provide insight into the normal process of placentation and the role the placenta plays in the great obstetrical syndromes.

Novel 3D light microscopic analysis of IUGR placentas points to a morphological correlate of compensated ischemic placental disease in humans.

The villous tree of the human placenta is a complex three-dimensional (3D) structure with branches and nodes at the feto-maternal border in the key area of gas and nutrient exchange. Recently we introduced a novel, computer-assisted 3D light microscopic method that enables 3D topological analysis of branching patterns of the human placental villous tree. In the present study we applied this novel method to the 3D architecture of peripheral villous trees of placentas from patients with intrauterine growth retardation (IUGR placentas), a severe obstetric syndrome. We found that the mean branching angle of branches in terminal positions of the villous trees was significantly different statistically between IUGR placentas and clinically normal placentas. Furthermore, the mean tortuosity of branches of villous trees in directly preterminal positions was significantly different statistically between IUGR placentas and clinically normal placentas. We show that these differences can be interpreted as consequences of morphological adaptation of villous trees between IUGR placentas and clinically normal placentas, and may have important consequences for the understanding of the morphological correlates of the efficiency of the placental villous tree and their influence on fetal development.

Autonomic denervation: A new aetiological framework for clinical obstetrics and gynaecology

The hypothesis is that many clinical conditions in obstetrics and gynaecology result from the diverse and varying consequences of injuries to pelvic autonomic nerves. These injuries result from difficult first labours, persistent physical efforts during defaecation, and, medical and surgical techniques for evacuation of the uterus. The neuro-immunohistochemical “signatures” of these injuries are variations of the Dixon–Robertson–Brosens (DRB) lesion in preeclampsia, where there is hyperplasia of the tunica intima and media of arterioles with narrowing of the lumen of the vessel. In stage IV, nulliparous “endometriosis” (and other gynaecological conditions) there are circumferential layers of abnormal nerves around a narrowed arteriole, whereas in early-onset preeclampsia (and other obstetric conditions) there are similar histological findings in uterine arterioles but there is no sign of injured nerves. During pregnancy there is elongation of blood vessels but no elongation of injured nerves leading to relative denervation of the myometrium. These lesions are detectable in most of the “great” obstetric syndromes, and, across the spectrum of gynaecological syndromes. They provide a coherent explanation of the natural history and clinical presentations of many of these syndromes. Clinical features vary with the site, nature and extent of the injury; a minor injury may enable pregnancy though it is complicated by late-onset pre-eclampsia whereas a more extensive injury may prevent pregnancy and present with chronic pelvic pain with, or without, endometriosis.

Chronic Hepatitis B Infection is Associated with Decreased Risk of Preeclampsia: A Meta-Analysis of Observational Studies

Background/Aims: Preeclampsia is a complex multi-system obstetric syndrome and remains one of the leading causes contributing to maternal and perinatal mortality and morbidity. Previous epidemiological studies regarding the association between chronic hepatitis B virus (CHB) infection and the risk of preeclampsia have reported inconsistent results. Therefore, we conducted a meta-analysis to investigate the association between CHB infection and preeclampsia. Methods: The electronic database was searched until January 1st, 2016. Relevant studies reporting the association between CHB infection and the risk of preeclampsia were included and for further evaluation. Statistical analysis was performed using Stata 10.0 (Stata Corp). Results: Three observational cohort studies and eight case-control studies, including 11566 preeclampsia patients, were identified. A significant negative association between CHB infection and preeclampsia was observed (odds ratio = 0.77, 95% confidence interval, 0.65- 0.90, P=0.002, fixed-effect model). Conclusions: Findings from our meta-analysis indicate that CHB infection may decrease the risk of preeclampsia in Asian population. Future prospective cohorts in different countries with larger sample sizes are warranted to ascertain the causality and pathophysiological studies are required to explore the possible biological mechanisms involved.

Методология профилактики больших акушерских синдромов

Методология профилактики больших акушерских синдромов

591: Maternal total cell free DNA in preeclampsia and IUGR: evidence for differences in maternal and fetal response for abnormal implantation

591: Maternal total cell free DNA in preeclampsia and IUGR: evidence for differences in maternal and fetal response for abnormal implantation

The physiologic anticoagulant and anti-inflammatory role of heparins and their utility in the prevention of pregnancy complications.

Accumulating evidence supports the concept of increased thrombin generation, placental vascular lesions, and inflammation as crucial points in the development of the great obstetrical syndromes [preeclampsia, intrauterine growth restriction (IUGR), preterm labor (PTL), preterm prelabor rupture of membranes (PROM), fetal demise and recurrent abortions]. In light of this, the role of heparins for primary or secondary prevention of these syndromes is becoming more and more apparent, mainly due to the antithrombotic and anti-inflammatory effects of heparins. There is agreement regarding the use of heparin in the prevention of gestational complications in patients with antiphospholipid syndrome, while its use for other obstetrical complications is under debate. In the present review we will describe the physiologic role of heparins on coagulation and inflammation and we will discuss current evidence regarding the use of heparins for the prevention/treatment of obstetrical syndromes.

Functional glycosylation in the human and mammalian uterus.

BackgroundGlycosylation is the most common and structurally diverse of all the post-translational modifications of proteins. Lipids and extracellular matrices are also often glycosylated. The mammalian uterus is highly enriched in glycoconjugates that are associated with the apical surfaces of epithelial cells and the secretions released by both epithelial and stromal cells. These glycoconjugates interact primarily with sperm, the implanting embryo, the fetus, and any pathogen that happens to gain entry into the uterus. Secretions of the endometrial glands increase substantially during the luteal phase of the menstrual cycle. These secretions are highly enriched in glycoproteins and mucins that promote specific uterine functions.FindingsLectins and antibodies have been employed in the majority of the studies focused on uterine glycosylation have employed to define the expression of carbohydrate sequences. However, while these studies provide insight about potential glycosylation, precise information about glycan structure is lacking. Direct sequencing studies that employ biochemical or mass spectrometric methods are far more definitive, but have rarely been employed with uterine glycoproteins. Both lectin/antibody binding and direct carbohydrate sequencing studies that have been focused on the mammalian uterus are reviewed. The primary functional role of the eutherian uterus is to facilitate fertilization and nurture the developing embryo/fetus. Trophoblasts are the primary cells that mediate the binding of the embryo and placenta to the uterine lining. In mammals that utilize hemochorial placentation, they invade the decidua, the specialized endometrial lining that forms during pregnancy. Trophoblasts have also been analyzed for their lectin/antibody binding as a complement to the analysis of the uterine cells and tissues. They will also be reviewed here.ConclusionsThe functional roles of the glycans linked to uterine and trophoblast glycoconjugates remain enigmatic. Another major question in the human is whether defects in placental or uterine glycosylation play a role in the development the Great Obstetrical Syndromes. More recent findings indicate that changes in glycosylation occur in trophoblasts obtained from patients that develop preeclampsia and preterm birth. The functional significance of these changes remain to be defined. Whether such shifts happen during the development of other types of obstetrical syndromes remains to be determined.

Association of maternal anemia with other risk factors in occurrence of Great obstetrical syndromes at university clinics, Kinshasa, DR Congo.

BackgroundMaternal anemia, a common situation in developing countries, provokes impairment of nutrients/oxygen supply to the placenta-fetus unit that leads to Great obstetrical syndromes (GOS). In our setting, however, occurrence of GOS has been found also depending on variables existing prior to pregnancy such as diabetes in family, hypertension in family, previous macrosomia, stillbirth, SGA and pre-eclampsia as well as overweight/obesity. Our study thus aimed to determine the magnitude of maternal anemia and its association with these pre-pregnancy high-risk variables in occurrence of GOS.MethodsThis is a cross-sectional study including women delivered at the University Clinics of Kinshasa, DR Congo, 12. during 18 months. Anemia was stated at hemoglobin blood concentration < 10 g/dL. Sampled women were checked for pregnancy high-risk factors and pregnancy complications. Odds ratios (95 % confidence intervals) were calculated to establish associations of anemia with various variables. Multivariate calculations aimed to isolate variables influencing these associations. The p <0.05 was considered significant.ResultsThe study sample included 412 women, among whom 220 (53.4 %) were diagnosed anemic. Anemia was found significantly linked to malaria, urinary infection, cesarean section, prematurity, SGA and stillbirth whose risk was 1.6 – 6.1 times augmented. Anemia was also found linked to pre-pregnancy high-risk factors such as age < 18 and ≥ 35 years, previous miscarriage, grand multiparity, diabetes in family, previous prematurity, overweight/obesity, previous cesarean section and previous pre-eclampsia, all of them enhancing the link of maternal anemia with complications.ConclusionMaternal anemia is very prevalent among pregnant women of our setting. It strongly contributes to worsening of morbidities that act with pregnancy high-risk factors in raising the risk of cesarean section, prematurity, SGA and stillbirth.

Menstrual preconditioning for the prevention of major obstetrical syndromes in polycystic ovary syndrome

The presence of multiple ovarian cysts, anovulation, and endometrial progesterone resistance in the neonate seems remarkably similar to ovarian and endometrial features of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the absence of cyclic menstruations after menarche, the neonatal progesterone resistance is likely to persist and adversely affect young women with PCOS at the time of pregnancy after induction of ovulation, because any persisting defect in progesterone response can interfere with the process of decidualization and trophoblast invasion. The primigravid woman with PCOS therefore is likely to be at risk of defective deep placentation as manifested by the increased risk of major obstetric syndromes. A recent, large epidemiologic study has demonstrated that the risk of preeclampsia and preterm delivery is elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year old group. It is proposed therefore that induction of ovulation in the infertile nulligravid woman with PCOS should be preceded by a period of progesterone withdrawal bleedings to achieve full endometrial progesterone response by the time of pregnancy. The cyclic administration of clomiphene citrate for a period to be determined by vascular response may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual preconditioning.

Galectins: Double-edged Swords in the Cross-roads of Pregnancy Complications and Female Reproductive Tract Inflammation and Neoplasia.

Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes.

Full-Length Human Placental sFlt-1-e15a Isoform Induces Distinct Maternal Phenotypes of Preeclampsia in Mice

ObjectiveMost anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.MethodsPregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.ResultsUltrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).ConclusionsA mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the in vivo pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.

A review of inter- and intraspecific variation in the eutherian placenta.

The placenta is one of the most morphologically variable mammalian organs. Four major characteristics are typically discussed when comparing the placentas of different eutherian species: placental shape, maternal-fetal interdigitation, intimacy of the maternal-fetal interface and the pattern of maternal-fetal blood flow. Here, we describe the evolution of three of these features as well as other key aspects of eutherian placentation. In addition to interspecific anatomical variation, there is also variation in placental anatomy and function within a single species. Much of this intraspecific variation occurs in response to different environmental conditions such as altitude and poor maternal nutrition. Examinations of variation in the placenta from both intra- and interspecies perspectives elucidate different aspects of placental function and dysfunction at the maternal-fetal interface. Comparisons within species identify candidate mechanisms that are activated in response to environmental stressors ultimately contributing to the aetiology of obstetric syndromes such as pre-eclampsia. Comparisons above the species level identify the evolutionary lineages on which the potential for the development of obstetric syndromes emerged.

The perinatal origins of major reproductive disorders in the adolescent: Research avenues

The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies.

The potential perinatal origin of placentation disorders in the young primigravida

The fetus is exposed to high plasma concentrations of unbound estrogens and progesterone throughout pregnancy. However, secretory or decidual changes in the fetal uterus occur relatively infrequently before birth, suggesting a variable endometrial progesterone response at the time of birth. Arguably, partial progesterone resistance that persists into adolescent years may compromise the physiological transformation of the spiral arteries and predispose for defective placentation in the case of pregnancy. Decidualization of the endometrial stromal compartment and junctional zone myometrium precedes trophoblast invasion. It represents the first step in the process of spiral artery remodeling needed to establish effective uteroplacental blood flow by midpregnancy. The major obstetric syndromes caused by impaired placental bed spiral artery remodeling are prevalent in teenage pregnancies, including preeclampsia, fetal growth restriction, and spontaneous preterm labor. Preconditioning of the uterus in response to cyclic menstruation during adolescence may be critical to achieve full uterine responsiveness to hormonal cues. Understanding the mechanisms of functional maturation of the uterus during the early reproductive years may yield novel insights into the major obstetric syndromes.

The physiologic and therapeutic role of heparin in implantation and placentation

Implantation, trophoblast development and placentation are crucial processes in the establishment and development of normal pregnancy. Abnormalities of these processes can lead to pregnancy complications known as the great obstetrical syndromes: preeclampsia, intrauterine growth restriction, fetal demise, premature prelabor rupture of membranes, preterm labor, and recurrent pregnancy loss. There is mounting evidence regarding the physiological and therapeutic role of heparins in the establishment of normal gestation and as a modality for treatment and prevention of pregnancy complications. In this review, we will summarize the properties and the physiological contributions of heparins to the success of implantation, placentation and normal pregnancy.

Oral Infection as a Risk Factor for Preeclampsia

Preeclampsia is a common obstetric syndrome affecting approximately 5-10% of pregnant women leading to significant maternal mortality and morbidity. Preeclampsia accounts for 25% of preterm deliveries resulting in adverse neonatal outcome. It is also the third most common direct cause of maternal death in the United Kingdom [1,2]. Preeclampsia is characterized by new onset hypertension exceeding 140/90 mmHg and proteinuria exceeding 300 mg in a 24 hour urine sample, after 20 weeks of gestation in a previously normotensive woman. It is characterized by abnormal vascular response to placentation, reduced organ perfusion, vasospasm, activation of the coagulation system, inflammatory like response, oxidative stress and some perturbation in volume and blood pressure control, affecting the placenta, kidney liver and brain [3-5].

Placental vascular pathology and increased thrombin generation as mechanisms of disease in obstetrical syndromes.

Obstetrical complications including preeclampsia, fetal growth restriction, preterm labor, preterm prelabor rupture of membranes and fetal demise are all the clinical endpoint of several underlying mechanisms (i.e., infection, inflammation, thrombosis, endocrine disorder, immunologic rejection, genetic, and environmental), therefore, they may be regarded as syndromes. Placental vascular pathology and increased thrombin generation were reported in all of these obstetrical syndromes. Moreover, elevated concentrations of thrombin-anti thrombin III complexes and changes in the coagulation as well as anticoagulation factors can be detected in the maternal circulation prior to the clinical development of the disease in some of these syndromes. In this review, we will assess the changes in the hemostatic system during normal and complicated pregnancy in maternal blood, maternal–fetal interface and amniotic fluid, and describe the contribution of thrombosis and vascular pathology to the development of the great obstetrical syndromes.

The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion*

Objective: Acute atherosis is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. However, the frequency of acute atherosis in the great obstetrical syndromes is unknown. The purpose of this study was to determine the frequency and topographic distribution of acute atherosis in placentas and placental bed biopsy samples obtained from women with normal pregnancy and those affected by the “great obstetrical syndromes”. We also examined the relationship between acute atherosis and pregnancy outcome in patients with preeclampsia. Material and methods: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women’s Hospital/Detroit Medical Center was conducted to examine 16 345 placentas. Patients were classified into the following groups: (1) uncomplicated pregnancy; (2) spontaneous preterm labor (sPTL) and preterm prelabor rupture of membranes (PPROM); (3) preeclampsia; (4) gestational hypertension; (5) small-for-gestational age (SGA); (6) chronic hypertension; (5) fetal death; (6) spontaneous abortion and (7) others. A subset of patients had placental bed biopsy. The incidence of acute atherosis was compared among the different groups. Results: (1) The prevalence of acute atherosis in uncomplicated pregnancies was 0.4% (29/6961) based upon examination of nearly 7000 placentas; (2) the frequency of acute atherosis was 10.2% (181/1779) in preeclampsia, 9% (26/292) in fetal death, 2.5% (3/120) in midtrimester spontaneous abortion, 1.7% (22/1,298) in SGA neonates and 1.2% (23/1,841) in sPTL and PPROM; (3) among patients with preeclampsia, those with acute atherosis than in those without the lesion had significantly more severe disease, earlier onset, and a greater frequency of SGA neonates (p < 0.05 all) and (4) the lesion was more frequently observed in the decidua (parietalis or basalis) than in the decidual segment of the spiral arteries in patients with placental bed biopsies. Conclusions: Acute atherosis is rare in normal pregnancy, and occurs more frequently in patients with pregnancy complications, including preeclampsia, sPTL, preterm PROM, midtrimester spontaneous abortion, fetal death and SGA.