The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy

Successful pregnancy requires an immunological shift with T helper CD4+ bias based on disbalance Th1/Th17 versus Th2/T regulatory (Tregs) required to induce tolerance against the semi-allogeneic fetus and placenta and to support fetal growth. Considered a pregnancy-specific hypertensive disorder, pre-eclampsia is characterized by multifaceted organ involvement related to impaired maternal immune tolerance to paternal antigens triggered by hypoxic placental injury as well as excessive local and systemic anti-angiogenic and inflammatory factor synthesis. Both systemic and local Th1/Th2 shift further expands to Th17 cells and their cytokines (IL-17) complemented by suppressive Treg and Th2 cytokines (IL-10, IL-4); alterations in Th17 and Tregs cause hypertension during pregnancy throughout vasoactive factors and endothelial dysfunction, providing an explanatory link between immunological and vascular events in the pathobiology of pre-eclamptic pregnancy. Apart from immunological changes representative of normotensive pregnancy, lupus pregnancy is generally defined by higher serum pro-inflammatory cytokines, lower Th2 polarization, defective and lower number of Tregs, potential blockade of complement inhibitors by anti-phospholipid antibodies, and similar immune alterations to those seen in pre-eclampsia. The current review underpins the immune mechanisms of pre-eclampsia focusing on local (placental) and systemic (maternal) aberrant adaptive and innate immune response versus normotensive pregnancy and pregnancy in systemic autoimmune conditions, particularly lupus.

Clinical correlates of plasma antithrombin and protein C levels in patients with pre-eclampsia and eclampsia in Sokoto, Northwest Nigeria

Background: Hypertensive disorders of pregnancy complicate 17% of pregnancies in Sokoto, Nigeria with pre-eclampsia and eclampsia accounting for 6% and 4.29% respectively. Pre-eclampsia and eclampsia stand out as major causes of poor pregnancy outcomes with eclampsia contributing 46% of adolescent maternal mortality in Sokoto. These disorders increase risk of venous thromboembolism, DIC, placental abruption, IUGR, premature delivery and recurrent pregnancy loss. The roles of antithrombin and protein C in disease severity and outcomes of pregnancies in pre-eclampsia/eclampsia are subject of recent researches albeit with conflicting findings. The aim of the study was to determine the plasma antithrombin and protein C levels of pre-eclampsia and eclampsia in Sokoto with a view to assessing any relationship with clinical severity and pregnancy outcomes.Methods: Prospective comparative study involving 31 each of pregnant women with pre-eclampsia, eclampsia and normotensive pregnancy. Plasma antithrombin and protein C levels were determined via kinetic method using S4 Nortek semi-automated coagulometer. Data analysis was performed using SPSS version 21.0. Results: The mean plasma antithrombin and protein C levels for eclampsia, pre-eclampsia and normotensive pregnancy were (61.17±9.13 and 60.00±5.76) vs (71.24±13.15 and 71.06±6.16) vs (85.54±8.77 and 89.64±7.61) respectively; p=0.0001. Severe pre-eclampsia when compared with mild pre-eclampsia had lower antithrombin (70.21±13.58 vs 73.74±12.43; p=0.507) and protein C (70.52±6.27 vs 72.40±6.00; p=0.451) levels respectively, though without statistical significance. Pre-eclampsia with low plasma antithrombin levels had increased risk of preterm delivery when age, gravidity and booking status were factored (OR, 1.2, 95% CI 0.035 to 0.348, p=0.017).Conclusions: Lower plasma antithrombin and protein C levels were found with eclampsia and severe pre-eclampsia suggesting consumptive depletion of anticoagulants with disease progression. Women with pre-eclampsia and low plasma antithrombin levels were found to have increased odds of having preterm delivery when age, gravidity and booking status were considered.

Abstract P232: Pregnancy Induced Changes In Urinary Uromodulin Excretion In Normotensive And Chronic Hypertensive Rodent Models

Hypertensive disorders complicate 1-4% of pregnancies and are the leading cause of maternal death. Pregnancy involves major adaptions in renal hemodynamics, tubular and endocrine functions. Uromodulin (UMOD) is a renal protein that plays a role in renal sodium and divalent cation transport and is associated with hypertension and kidney diseases. We aimed to understand the role of blood pressure (BP) in urinary UMOD excretion during pregnancy. Pregnant Wistar Kyoto (WKY) and Stroke Prone Spontaneously Hypertensive (SHRSP) rats (n=8) were studied for 18.5 gestational days (GD). A group of pregnant SHRSP were treated with the beta-blocker propranolol (100mg/kgBW/day; n=8) and the calcium channel blocker nifedipine (25mg/kgBW/day; n=7) from GD 0.5. Systolic BP (SBP; tail cuff plethysmography), urine and plasma characteristic were monitored at baseline, GD3.5, GD12.5 and GD 18.5. UMOD concentration were measured in 24hr urine with ELISA. Pregnant SHRSP were hypertensive throughout the gestation compared to WKY (delta SBP 22.6 ± 3.6 mmHg, p<0.0001). At baseline (pre-pregnancy), urinary UMOD levels were 2-fold higher in WKY compared to SHRSP (p<0.05). During pregnancy, the urinary UMOD gradually decreased in WKY (2-fold decrease, p<0.05), whereas a 1.5-fold increase (p<0.05) was observed in hypertensive SHRSP compared to pre-pregnancy. The changes observed in urinary levels corresponded to total kidney UMOD levels at GD18.5, wherein SHRSP kidney shows 1.3-fold (p<0.01) greater expression of UMOD compared to WKY. Nifedipine reduced BP in pregnant SHRSP (delta SBP between GD18.5 and baseline: 44.3 ± 7.4 mmHg, p<0.0001) while propranolol did not affect BP. However, neither nifedipine nor propranolol changed urinary UMOD excretion in pregnant SHRSP. BP was not significantly correlated with urinary uromodulin levels in pregnant WKY (Pearson, r=-0.01, p 0.95) and SHRSP without (r=-0.16, p 0.46) or with (nifedipine r=0.26, p 0.31; propranolol r=0.17, p 0.45) antihypertensive treatment. We demonstrate differences in UMOD excretion between hypertensive and normotensive pregnancy and changes during pregnancy that are at least in part BP independent. Our data provide novel insights into molecular changes associated with hypertensive pregnancy.

sFlt-1/PlGF Ratio in Prediction of Short-Term Neonatal Outcome of Small for Gestational Age Neonates

Background: Small for gestational age is a pregnancy complication associated with a variety of adverse perinatal outcomes. The aim of the study was to investigate if sFlt-1/PlGF ratio is related to adverse short-term neonatal outcome in neonates small for gestational age in normotensive pregnancy. Methods: A prospective observational study was conducted. Serum sFlt-1/PlGF ratio was measured in women in singleton gestation diagnosed with fetus small for gestational age. Short-term neonatal outcome analyzed in the period between birth and discharge home. Results: Eighty-two women were included. Women with sFlt-1/PlGF ratio ≥33 gave birth to neonates with lower birthweight at lower gestational age. Neonates from high ratio group suffered from respiratory disorders and NEC significantly more often. They were hospitalized at NICU more often and were discharged home significantly later. sFlt-1/PlGF ratio predicted combined neonatal outcome with sensitivity of 73% and specificity of 82.2%. Conclusions: sFlt-1/PlGF ratio is a useful toll in prediction of short-term adverse neonatal outcome in SGA pregnancies.

Growth from birth to 6 months of infants with and without intrauterine preeclampsia exposure

Intrauterine preeclampsia exposure affects the lifelong cardiometabolic health of the child. Our study aimed to compare the growth (from birth to 6 months) of infants exposed to either a normotensive pregnancy or preeclampsia and explore the influence of being born small for gestational age (SGA). Participants were children of women participating in the Post-partum, Physiology, Psychology and Paediatric follow-up cohort study. Birth and 6-month weight and length z-scores were calculated for term and preterm (<37 weeks) babies, and change in weight z-score, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-score were calculated. Compared with normotensive exposed infants (n = 298), preeclampsia exposed infants (n = 84) were more likely to be born SGA (7% versus 23%; P < 0.001), but weight gain from birth to 6 months, by any measure, did not differ between groups. Infants born SGA, irrespective of pregnancy exposure, were more likely to have rapid weight gain and had greater increases in weight z-score compared with those not born SGA. Preeclampsia exposed infants born SGA may benefit from interventions designed to prevent future cardiometabolic disease.

Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study

Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children’s health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.

Hypertensive disorders of pregnancy and cognitive impairment: A prospective cohort study

Objective:To determine the association between hypertensive disorders of pregnancy (HDP) and cognitive impairment fifteen years after pregnancy, we measured cognitive performance in 115 women with a history of HDP and in 481 women with a previous normotensive pregnancy.Methods:This was a nested cohort study embedded in a population-based prospective cohort from early pregnancy onwards. Cognitive function was assessed with cognitive tests fifteen years after the index pregnancy (median 14.7 years, 90% range [13.9 to 16.1]). Cognitive performance was measured in different cognitive domains: executive function, processing speed, verbal memory, motor function, and visuospatial ability. A global cognition factor (g-factor) was derived from principal component analysis.Results:Of the women with HDP, n = 80 (69.6%) had gestational hypertension (GH) and n = 35 (30.4%) had pre-eclampsia. Women with HDP had a lower g-factor than women with a previous normotensive pregnancy (mean difference -0.22, 90% range [-2.06; 1.29)]). HDP was negatively associated with the 15-word learning test: immediate recall (-0.25, 95% CI [-0.44 to -0.06]) and delayed recall (-0.30, 95% CI [-0.50 to -0.10]). Women with GH perform significantly worse on their 15-word learning test than women with a previous normotensive pregnancy.Conclusion:A history of HDP is independently associated with poorer working memory and verbal learning, fifteen years after pregnancy. This association is mainly driven by women with GH. Clinicians and women who experienced HDP should be aware of this risk.