Clinical significance of predictive and diagnostic indices of fetal pathology associated with placental insufficiency in women with endometriosis

BACKGROUND: Modern achievements of pharmacology, surgery and reproductive medicine have determined an increase in the implementation of reproductive function in endometriosis of various localization. The onset of pregnancy in presence of impaired endometrial receptivity and progesterone resistance, pro-inflammatory and pro-thrombotic status, abnormal functioning of the immune system, structural changes in the reproductive organs leads to impaired formation of the embryo (feto) placental system, early reproductive losses, complicated pregnancy and adverse perinatal outcomes. In this regard, the endometriosis and pregnancy issue requires close study and specific proposals to optimize pregnancy management. AIM: The aim of this study was to develop predictive (PIs) and diagnostic (DIs) indices of placenta-associated fetal pathology in pregnant women with endometriosis, to determine their prognostically and diagnostically significant parameters. MATERIALS AND METHODS: This prospective study in the dynamics of gestation included a comprehensive clinical and laboratory examination of 175 pregnant women with endometriosis (100 subjects with adenomyosis and 75 subjects with ovarian endometriosis). To develop PIs and DIs, two comparison groups with fetal pathology due to placental insufficiency were retrospectively identified, depending on the location of endometriosis. Group I consisted of 49 pregnant women with adenomyosis and placental insufficiency isolated from other pregnancy complications, accompanied by growth retardation and/or chronic fetal hypoxia; Group II comprised 29 pregnant women with ovarian endometriosis and placental insufficiency isolated from other pregnancy complications, accompanied by growth retardation and/or chronic fetal hypoxia. The control group (Group III) included 30 healthy pregnant women with a normal course of gestation. The examination was performed at 10-14 weeks, 20-24 weeks, and 28-34 weeks of gestation and included an assessment of placental insufficiency markers such as placental growth factor (PlGF), placental -1-microglobulin (PAMG-1), tumor necrosis factor (TNF), lymphocytes with membrane receptor FasR (L CD95+), C-reactive protein, placental alkaline phosphatase (PAPh), and fetal hemoglobin (HbF). The information value of individual parameters and indices was determined by ROC analysis, odds ratio, and clinical epidemiology tests. RESULTS: Pregnancy in presence of endometriosis in 100% of cases was complicated by placental insufficiency of varying severity (with fetal pathology in 81.5% of cases), the frequency of which had statistically significant differences between the groups of pregnant women with adenomyosis and ovarian endometriosis (2 = 4.06, p = 0.04). To predict growth retardation and / or chronic fetal hypoxia, we have developed PI I (PlGF / TNF 100) and PI II (PAMG-1 / PlGF 100), which characterize the state of placental angio-and vasculogenesis depending on systemic inflammatory response level. For early diagnosis of fetal pathology, we have proposed DI I (CRP / PAPh 100), DI II (HbF / PlGF 100) and DI III (L CD95+ / PAPh 100), which allow for diagnosing placental alterations with impaired placental energy supply due to an increase in inflammatory status. Evaluation of prognostic and diagnostic significance of PIs and DIs showed that the most informative tools are PI I (Se = 86.1%, Sp = 80.5%) and DI I (Se = 88.3%, Sp = 83.7%). CONCLUSIONS: The use of PIs allows for risk stratification of pregnant women from the 1st trimester of gestation to address the issue of the prevention method. The clinical capabilities of DIs optimize obstetric tactics for the timely prescription of therapy for placental insufficiency and targeted diagnosis of fetal pathology. Pregnant women with endometriosis should be classified as a high perinatal risk group, and therefore the proposed PIs and DIs should be included in the dynamic examination complex.

CHROMOSOMAL PATHOLOGY MARKERS IN FETUS AT THE AGE OF 10-13 WEEKS + 6 DAYS

The most complete information about chromosomal pathology presence in fetuses of thefirst trimester of pregnancy is provided by the use of complex markers: PAPP-A (plasmaprotein-A associated with pregnancy) + free β-hCG (human β chorionic gonadotropin)ultrasound (CP - collar space + nasal bone) for the 10-14th week of development.Purpose of the work – determination of the risk of chromosomal pathology in fetuses inthe first trimester of pregnancy based on markers: biochemical testing of PAPP + freeβ-hCG from the 10-14th week of pregnancy; Ultrasound investigation (US): measurementof the collar space and nasal bone presence.Material and methods: 258 pregnant women with a high risk of chromosomalabnormalities in the first trimester were examined by means of markers: biochemicaltesting of PAPP + free β-hCG and measurements of the collar space. The values ofthe measured markers are expressed as a constituent of the expected median for thecorresponding gestational term. Medians, the 5th and 95th percentiles, percentage outsidethe expected 5th and 95th percentiles, as well as percentage outside the expected 5th /95th percentiles to establish fetal pathology. The study was performed on an ultrasoundscanner Voluson Expert 8 using a transducer with 3-4D transabdominal RAB 4-8D, RAB6-D, and transvaginal RIC 5-9D. Medical Center "EKHOMED" is engaged in expertultrasound envestigations, as well as invasive examinations, which are required for verification of fetal pathology, is the base of Danylo Halytsky Lviv Medical University,DPGE, Department of Radiation Diagnostics.Results. The analysis was carried out in 258 pregnant women with a high risk ofchromosomal abnormalities in the first trimester using markers: biochemical testing ofPAPP + free β-hCG from 10-14 weeks of pregnancy; measurement of the collar spacethickness and visualization or absence of the nasal bone. The pathology is increasedexponentially with the collar space from 0.2% for those fetuses whose thickness isbetween the 5th and 95th centiles, up to 65% for a thickness of 6.5 mm or more. Inthe group of fetuses with chromosomal abnormalities, about 50% have trisomies 21,25% have trisomies 18 or trisomies 13, 10% have Turner syndrome, 5% have triploidy,and 10% have other chromosomal abnormalities. The combination of collar size andPAPP-A and free ß-hCG testing results in a sensitivity of over 90% and a specificity ofover 95%. The rate of false positives is reduced from 3.0% to 2.5%.Conclusions. The thickness of the collar space in chromosomal abnormalities growsexponentially with the thickness of the collar space from 0.2% for those fetuses whosethickness is between the 5th and 95th centile, up to 65% with a collar space thicknessof 6.5 mm or more. In the group of fetuses with chromosomal abnormalities, about 50%have trisomies 21, 25% have trisomies 18 or 13, 10% have Turner's syndrome, 5% havetriploidy, and 10% have other chromosomal abnormalities. The combination of the sizeof the collar space and PAPP-A and free ß-hCG determinations showed a sensitivity ofmore than 90% and a specificity over 95%.

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.