Beatrice Landi

Preeclampsia: No longer solely a pregnancy disease

Preeclampsia, the leading cause of maternal and perinatal morbidity and mortality, has been recently considered not only a pregnancy disease but also a risk factor for developing diseases later in life. Preeclampsia is becoming a disease of interest to internists and not just obstetricians. Women who have had preeclampsia seem to be at higher risk of premature death, mortality from ischemic heart disease, cardiovascular diseases including ischemic heart disease and hypertension, fatal and non-fatal stroke, venous thromboembolism, renal failure, type 2 diabetes mellitus, hypothyroidism, and cognitive defects, although they appear surprisingly protected from cancer. Furthermore, having had preeclampsia is a problem not only for the mothers future health, but it also affects the offsprings adult health. Children born from preeclamptic pregnancies are more prone to hypertension, insulin resistance and diabetes mellitus, neurological problems, stroke, and mental disorders along their life. Whether preeclampsia is a risk factor for disease later in life or it creates long-term organ damage is an intriguing question. This review analyzes recent epidemiological evidence of the long-term outcomes of preeclampsia and the background mechanisms of this phenomenon. Understanding the etiological background may provide guidance for the prevention and follow-up of women who experience preeclampsia.

The origin of pre-eclampsia: From decidual “hyperoxia” to late hypoxia

Normal gestation implants on a relatively hypoxic deciduas so that trophoblast deeply invades endometrium and angiogenesis seeks for oxygen supply. If implantation occurs before those hypoxic conditions occur, trophoblast invasion is defective, due to the relatively high oxygen tension in the decidual environment, laying the foundations for subsequent pre-eclampsia.

The involvement of inflammatory cytokines in the pathogenesis of recurrent miscarriage.

OBJECTIVE To investigate the inflammatory cytokine expression pattern in trophoblastic tissue from women with unexplained recurrent miscarriage (RM). STUDY DESIGN Trophoblasts were obtained during uterine evacuation from 11 women with RM and from 20 healthy pregnant women undergoing elective termination of pregnancy, who served as controls. The array was performed using GEArray Q Series Human Inflammatory Cytokines & Receptors Gene Array HS-015 membranes. Data were confirmed by quantitative real-time PCR. The Mann-Whitney U test was performed for statistical analysis. RESULTS Microarray analysis identified three genes that were differentially expressed between RM patients and controls. We observed significant downregulation of Transforming Growth Factor beta 3 (TGF-β3) and Interleukin 25 (IL-25) (5-fold reduction and 2.5-fold reduction, respectively) and significant upregulation of CD-25, also known as Interleukin 2 receptor alpha (IL-2RA) (7-fold increase) in women with RM compared with controls. The median ΔC(t) of TGF-β3 was 8.2 (interquartile range, 7.67-8.9) in RM patients vs. 5.85 (interquartile range, 5.3-6.09) in controls; the median ΔC(t) of IL-25 was 5.18 (interquartile range, 4.46-5.76) in RM patients vs. 3.85 (interquartile range, 3.6-4.51) in controls, and the median ΔC(t) of CD-25 was 9.62 (interquartile range, 7.81-12.42) in RM patients vs. 12.44 (interquartile range, 11.02-13.86) in controls. DISCUSSION Our results suggest that the immunological and inflammatory regulation mechanisms of the placental environment play a key role in recurrent miscarriage. The observed trophoblast cytokine expression pattern at the maternal-fetal interface confirms the immunotrophic theory, as demonstrated by a switch from a T-helper-1 (Th1) profile to a T-helper-2 (Th2) profile in women who experience recurrent miscarriages.

Alpha-hemoglobin-stabilizing protein (AHSP) in hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome, intrauterine growth restriction (IUGR) and fetal death.

ObjectiveAlpha hemoglobin-stabilizing protein (AHSP) inhibits the production of reactive oxygen species in various cells, including erythrocytes. Reduced AHSP can mean reduced protection from stressors. Our objective was to investigate whether AHSP is involved in the response to stress in pregnancy.Study designPlacentas were collected from normal term pregnancies (n = 10) and pregnancies complicated by HELLP (n = 10), intrauterine growth restriction (IUGR; n = 10) or fetal death (IUFD; n = 6). AHSP messenger RNA (mRNA) and protein were determined using real time quantitative polymerase chain reaction (PCR) and Western blot, respectively. All statistical analyses were performed by using the GraphPad Prism Software. Differences were considered significant at p < 0.05.ResultsPlacental AHSP mRNA level in HELLP (4.16E10−4 ± 1.77) and IUFD (4.19E10−4 ± 3.37) were significantly decreased compared with controls (28.47E10−4 ± 14.86; p < 0.01), whereas levels in the IUGR group (7.55E10−4 ± 6.4) showed a trend toward being lower but the difference did not reach statistical significance. Western blot analysis results indicate a no significant increase of ASHP protein in the HELLP syndrome group and a significant decrease in the IUFD group compared with controls. There was no significant difference between the IUGR and control groups.ConclusionASHP mRNA expression in the placenta is decreased in complicated pregnancies, and it may be involved in the pathogenic mechanisms leading to the adverse pregnancy outcome.

Placental Cytokines in the Pathogenesis of Preeclampsia and Hellp Syndrome

Preeclampsia and HELLP syndrome are placenta-dependent disorders with both local and systemic anomalies that are responsible for neonatal and maternal morbidity. The cytokines, produced by the placenta in response to local ischemia/hypoxia, may be involved in endothelial activation and dysfunction. The adaptive immune system could play a key role in the etiology of preeclampsia or HELLP by generating a pro- inflammatory Th1 type immune reaction: the current pathophysiologic hypothesis of preeclampsia is focused on maladaptation of immune responses and defective trophoblast invasion. Also human decidual NK cells recruited at the site of embryonic implantation induce a number of cytokines with potential functions not yet clearly established. We reviewed recent studies on effect of pro-inflammatory cytokines in preeclampsia, as well as on the role of regulatory cytokines and chemokines and discuss evidence that cytokines continue to be part of a paracrine/autocrine regulatory network in the placenta and membranes throughout the different stages of gestation. In addition we reviewed the experimental basis for the possible role of the immune system and proposed the hypothesis that these conditions could be a placental inflammatory response which can lead to a systemic and endothelial dysfunction, resulting in hypertension, proteinuria and pathologies in many organ systems.

PP047. Outpatient management of pregnancy complicated by mild hypertensive disorders

INTRODUCTION Antenatal day care units have been experienced as an alternative to inpatient care for women with pregnancy complications including hypertensive disorders. OBJECTIVES To assess the outcomes of outpatient management in women with gestational hypertension and mild preeclampsia and compare them to inpatient management. METHODS Perinatal records of 294 patients (OUT group) attending the obstetric outpatient clinic were reviewed and compared with records of 398 women (IN group) attending the obstetric unit of the same tertiary referral center. The patients were divided as: GH, gestational hypertension (OUT: 194; IN: 244), GH with Intrauterine Growth Restriction (OUT: 52; IN: 78) and PE, mild preeclampsia (OUT: 48; IN: 76). The groups were comparable for age, parity, body mass index and gestational age at enrollment. RESULTS When compared with patients treated in hospital, GH OUT women showed a higher gestational age at delivery (38±1.7 vs 35.5±2.3 weeks; p<0.001), longer time to delivery (62.0±4.8 vs 31.3±5.4days; p<0.001), higher birthweight (3251±389 vs 2271±759.1g; p<0.001), and a lower admission to neonatal intensive care unit (21.3% vs 0%; p<0.001) (hospitalization rate: 25%). Similarly, Mild PE women treated as out patient showed later gestational age at delivery (37±1.2 vs 34.4±1.7weeks), longer time to delivery (55.4±6.9 vs 35.3±4.5days), higher birthweight (3168±363 vs 2196±685.17g), and a lower admission to NICU (15.6% vs 35.5%) (hospitalization rate: 55.6%), than the inpatient controls. In the gestational hypertension with IUGR no significant differences were observed between out- and in-patient management. CONCLUSION Women attending day care units have better or comparable perinatal outcomes than inpatients. Ambulatory management at a day-care unit is an option for monitoring and following up women with mild gestational hypertension or preeclampsia remote from term. Hospitalization remains an absolute indication if worsening of preeclampsia is diagnosed.