Placenta-associated biomarkers and pregnancy outcome in HPA-1a alloimmunization: A prospective cohort study.

INTRODUCTION: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from parental incompatibility in human platelet antigens (HPA) and subsequent maternal sensitization. The HPA-1a epitope is also expressed on placental tissue. Chronic placental inflammation and lower birth weight is observed more often in HPA-1a alloimmunized pregnancies, suggesting a placental component in the pathophysiology of FNAIT. Today, prediction of FNAIT severity is limited. The aim of the study was to investigate whether dysregulated maternal angiogenic proteins are associated with neonatal outcome in HPA-1a alloimmunized pregnancies. MATERIAL AND METHODS: Eighty-seven HPA-1a negative pregnant women were identified from a large prospective screening study in Poland (PREVFNAIT) including 43 HPA-1a immunized and 44 non-immunized controls. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in maternal plasma from 2nd and 3rd trimester by enzyme-linked immunosorbent assay and levels/ratios were compared between study groups, using uni- and multivariable analyses. Main outcome measures were either classic FNAIT-related (severe thrombocytopenia, petechia, intracranial hemorrhage), placenta-related (small for gestational age) or a composite variable combining them all. RESULTS: There were no significant differences in plasma concentrations of sFlt-1, PlGF, sEng nor sFlt-1/PlGF ratio when comparing immunized and non-immunized pregnancies. Among HPA-1a alloimmunized pregnancies, increasing levels of the sFlt-1 protein in 3rd trimester were significantly associated with lower neonatal platelet count (multivariable linear regression, p = 0.024). Increased sFlt-1 and sFlt-1/PlGF ratio in 3rd trimester were significantly associated with higher odds of a composite adverse neonatal outcome in alloimmunized pregnancies (multivariable logistic regression, p = 0.029 and p = 0.019, respectively). CONCLUSION: An anti-angiogenic profile in HPA-1a alloimmunized mothers is associated with a composite adverse neonatal outcome. This suggests that sFlt-1 and the sFlt-1/PlGF ratio may assist in predelivery risk stratification and clinical management decisions for FNAIT.

What's with the boys? Lower birth weight in boys from HPA-1a alloimmunized pregnancies - New insights from a large prospective screening study in Poland.

Fetomaternal incompatibility in human platelet antigens (HPAs) can cause maternal alloimmunization, which in turn may lead to thrombocytopenia with or without intracranial hemorrhage (ICH) in the fetus or newborn. Retrospective studies suggest that boys from alloimmunized mothers may have higher risk of ICH and lower birth weight than girls. The objective of this study was to assess how maternal HPA-1a alloimmunization, sex of the neonate and birth weight relates in a large prospective cohort. Through a national screening study in Poland (PREVFNAIT) involving HPA-1 typing of 24,259 pregnant women during 2013-2017, 606 HPA-1a negative pregnant women and their offspring were identified and included. Various multivariate models were used to assess if and how maternal HPA-1a alloimmunization status was associated with birth weight and risk of having a small for gestational age (SGA) neonate, and if and how sex of the neonate mattered. Most immunized pregnancies had male fetuses (69 %). Women carrying a male fetus had increased likelihood of having an SGA newborn if they were HPA-1a alloimmunized compared to non-immunized mothers. Increasing maternal anti-HPA-1a antibody levels were significantly associated with reduced birth weight and SGA risk among male-fetus pregnancies, but not if the fetus was female. In conclusion, anti-HPA-1a antibodies in a male fetus pregnancy is associated with increased risk of SGA and lower birth weight, especially if the antibody level is high. Sex of the fetus may therefore be considered as a new clinical predictor of more severe FNAIT neonatal outcome.

Non-genomic cell growth inhibition by progesterone. cell cycle retardation and induction of cell death.

BACKGROUND: Non-genomic mechanisms have been proposed to play a role in progesterone-dependent cell growth inhibition. MATERIALS AND METHODS: The human cell line C-4I, derived from a squamous carcinoma of the uterine cervix, was progesterone receptor-negative. The culture medium contained 10% (v/v) fetal calf serum and the cells, growing in monolayer, were exposed to various progesterone concentrations. Flow cytometry and morphometry were employed to assess the effects. RESULTS: Progesterone caused a concentration-dependent growth inhibition with an IC50 value of 2.06 +/- 0.46 microM (mean value +/- SEM, n = 4). At 320 microM no viable and attached cells were left. Two mechanisms appeared to be responsible for the effect. Firstly, the cells accumulated in the G1/G0-phase indicating a cell cycle-specific arrest. Secondly, progesterone induced cell death with apoptosis and necrosis. Morphometric analysis showed that progesterone caused a marked reduction in the nuclear size, compatible with apoptosis. CONCLUSION: The present results show that progesterone exerts non-genomic effect(s) by reducing the input of and accelerating the exit of cells from the C-4I cell population.