Interleukin-6 in Amniotic Fluid: A Reliable Marker for Adverse Outcomes in Women in Preterm Labor and Intact Membranes.

INTRODUCTION: Amniotic fluid (AF) interleukin-6 (IL-6) concentration has been associated to preterm delivery and perinatal morbidity and mortality in women with preterm labor and intact membranes. Nevertheless, the clinical significance of this biomarker of intra-amniotic inflammation (IAI) is still unclear due in part to the paucity of large studies. METHODS: AF IL-6 concentrations were determined in 452 consecutive women with preterm labor and intact membranes, categorized into 3 groups: 302 without IAI (IL-6 of <2.6 ng/mL), 64 with mild IAI (IL-6 of 2.6-11.2 ng/mL), and 86 with severe IAI (IL-6 of ≥11.3 ng/mL). RESULTS: The severe IAI group had a short pregnancy duration from amniocentesis to delivery (median 3 days) than in without IAI group (median 45 days); meanwhile, the mild IAI group had a latency that was intermediate to the severe and without IAI groups (median 9.5 days). As compared to women without IAI, women with mild and severe IAI had higher rates of preterm delivery at both <34 and <37 weeks of gestation and perinatal morbidity and mortality. Furthermore, the risk of various individual adverse outcomes (short latency from amniocentesis to delivery [at ≤3 days, ≤7 days, and ≤14 days], preterm delivery at both <34 and <37 weeks of gestation, histologic chorioamnionitis, respiratory distress syndrome, and congenital sepsis) was higher in women with severe IAI (OR ≥ 2.8), compared with women without IAI. CONCLUSIONS: AF IL-6 concentrations appear to be suitable marker to assess the degree of IAI and are associated with increased risk of adverse outcomes.

Soluble Endoglin As a Marker for Preeclampsia, Its Severity, and the Occurrence of Adverse Outcomes.

Preeclampsia is characterized by an imbalance in angiogenic factors, including sEng (soluble endoglin). However, the relationship of sEng with the severity of preeclampsia, clinical, and laboratory parameters, and the occurrence of adverse outcomes are not fully elucidated. We studied 1002 women with preeclampsia. Serum concentrations of sEng were measured by ELISA. Serum sEng levels were significantly different (P<0.001) in patients with preeclampsia than in healthy pregnancy. In addition, these factors were markedly different in patients with hemolysis, elevated liver enzymes, low platelet count syndrome and eclampsia than in patients with preeclampsia with or without severe features (P<0.001) and in patients with preeclampsia with severe features than in those without severe features (P<0.001). sEng correlated positively with blood pressure, proteinuria, and levels of creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase; and inversely with gestational age, infant's birth weight, and platelets counts (P<0.001 for all). The risk of combined and specific adverse outcomes (pulmonary edema, acute renal failure, placental abruption, hepatic hematoma or rupture, maternal death, cerebral hemorrhage, thrombocytopenia, elevated liver enzymes, preterm delivery, small for gestational age infant, and need for endotracheal intubation, positive inotropic drug support, and hemodialysis) was higher in patients with sEng values in the highest quartile (odds ratio ≥3.1) compared with the lowest quartile. Patients in the highest quartile of sEng were more likely to deliver early compared with those in the lowest quartile (HR, 2.33; 95% CI, 1.91-2.84). We concluded that circulating concentrations of sEng seem to be a suitable marker to assess the severity of preeclampsia and are associated with increased risk of adverse outcomes.

Urinary IgM excretion: a reliable marker for adverse pregnancy outcomes in women with chronic kidney disease.

OBJECTIVE: Chronic kidney disease (CKD) pregnancies are at high risk of developing adverse outcomes. In non-pregnant subjects with CKD, higher urinary IgM levels are associated with poor renal survival and higher rates of cardiovascular deaths. In this study, we assessed whether urinary IgM levels are associated with an increased risk of adverse pregnancy outcomes (APO) in CKD pregnancies. METHODS: We performed a nested case-control study within a cohort of CKD patients with singleton pregnancies attended at a tertiary care hospital. The study included 90 CKD patients who eventually developed one or more APO and 77 CKD patients who did not. Urinary IgM excretion was determined from the 24-h urine samples at enrollment by an ultrasensitive enzyme immunoassay. RESULTS: The risk for combined APO and for preeclampsia (PE) was higher among women with urinary IgM and proteinuria levels values in the highest quartile or with CKD stages 4-5 (odds ratios, OR ≥ 2.9), compared with the lowest quartile or with CKD stage 1. Urinary IgM levels were more closely associated with the risk of either combined or specific APO (PE, preterm birth, and for having a small-for-gestational-age infant; OR ≥ 5.9) than either the degree of total proteinuria or CKD stages. Among patients with CKD stage 1, the risk of combined APO, PE, and preterm birth was higher in women with urinary IgM levels values in the highest quartile (OR ≥ 4.8), compared with the three lower quartiles, independently of proteinuria. CONCLUSION: In CKD pregnancies, at the time of initial evaluation, proteinuria and CKD stage are associated with increased risk of combined APO. However, urinary IgM concentrations appear to be better predictors of an adverse outcome and may be useful for risk stratification in CKD pregnancies.

Lower circulating angiotensin II levels are related to the severity of preeclampsia and its risk as disclosed by a specific bioassay.

Preeclampsia is characterized by an increased sensitivity to angiotensin II (Ang II). We herein assessed whether serum Ang II levels measured by a new developed bioassay are associated with preeclampsia, its severity, and the risk for developing this disease.Using a cross-sectional design, we studied 90 pregnant women (30 healthy pregnant and 60 with preeclampsia [30 with- and 30 without severe features]). We also used a nested case-control study with 30 women who eventually developed preeclampsia and 31 normotensive controls. Serum samples were collected at diagnosis of preeclampsia or at 4-week intervals (from weeks 12th to 36th). Ang II was measured using a bioassay.At diagnosis of preeclampsia, serum Ang II concentrations were significantly lower in preeclampsia without and with severe features (P = .001 and P < .001, respectively) than in healthy pregnancy. In addition, Ang II was different in preeclampsia with severe features than in those without severe features (P = .048). Women who subsequently developed preeclampsia had lower Ang II levels than women with normal pregnancies, and these changes became significant at 24 weeks onward. The risk to developing preeclampsia was higher among women with Ang II concentration values in the lowest quartile of the control distribution from 12 weeks onward (odds ratio ranging from 3.8 [95% CI 1.3-11.1] to 6.5 [95% CI 1.6-26.9]).We concluded that concentrations of Ang II are markedly diminished at diagnosis of preeclampsia and are closely associated with the severity of disease. Changes in circulating levels of Ang II precede the clinical presentation of preeclampsia.

Circulating angiogenic factors are related to the severity of gestational hypertension and preeclampsia, and their adverse outcomes.

Gestational hypertension (GH) and preeclampsia (PE) are characterized by an imbalance in angiogenic factors. However, the relationship among these factors with the severity of hypertensive disorders of pregnancy (HDP) and adverse outcomes are not fully elucidated. We examined whether these biomarkers are related with the severity of HDP and adverse outcomes.Using a cross-sectional design, serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin were determined in 764 pregnant women: 75 healthy pregnant, 83 with mild GH (mGH), 105 with severe GH (sGH), 122 with mild PE (mPE), and 379 with severe PE (sPE).All angiogenic factors' concentrations were significantly different (P ≤ 0.041) in HDP than in healthy pregnancy. In addition, these factors were markedly different in sPE than in mPE, sGH, or mGH (P ≤ 0.027) and in patients with sGH that in those with mPE or mGH (P < 0.05). As compared to mGH and mPE, patients with sGH and sPE had higher rates of both preterm delivery at <34 weeks of gestation and small-for-gestational age infants. Moreover, patients with sPE had higher rates of adverse maternal outcomes (P < 0.001) when compared to patients with mGH, sGH, or mPE. In all cases, levels of sFlt-1/PlGF ratio were significantly higher in patients with sGH and sPE who had adverse perinatal and maternal outcomes than in those with sGH and sPE who did not (P ≤ 0.016).Circulating concentrations of angiogenic factors appear to be suitable markers to assess the severity of GH and PE, and adverse outcomes.

Circulating Angiogenic Factors and the Risk of Preeclampsia in Systemic Lupus Erythematosus Pregnancies.

OBJECTIVE: To investigate whether angiogenic factors are associated with risk of developing preeclampsia in pregnant women with systemic lupus erythematosus (SLE). METHODS: We performed a nested case-control study within a cohort of SLE women with singleton pregnancies. The study included 42 patients with SLE who eventually developed preeclampsia and 75 normal SLE pregnancies. Serum samples were collected at 4-week intervals (from weeks 12 to 36). Serum samples were analyzed for soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). RESULTS: Women destined to develop preeclampsia had lower PlGF levels and higher sFlt-1 and sEng levels, and a higher sFlt-1/PlGF ratio than normal pregnancies. These changes became significant at 12 weeks in patients destined to develop either early onset (< 34 weeks, p ≤ 0.003) or late-onset preeclampsia (≥ 34 weeks, p ≤ 0.02). The risk to develop preeclampsia was higher among patients with PlGF concentration values in the lowest quartile or with sFlt-1 and sEng levels, and sFlt-1/PlGF ratio, in the highest quartile of the normal SLE pregnancies distribution. The OR were higher and appeared earlier in patients destined to develop early onset preeclampsia (OR ≥ 16.2, from Week 12 onward) than in patients who presented preeclampsia later (OR ≥ 8.9, from Week 24 onward). CONCLUSION: Changes in circulating concentrations of sFlt-1, PlGF, sEng, and the sFlt-1/PlGF ratio precede the onset of preeclampsia in SLE pregnancies. The risk profile of circulating angiogenic factors for developing preeclampsia distinctly evolves depending on whether this condition is manifested earlier or later.

Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia.

Preeclampsia is characterized by an imbalance in angiogenic factors. Urinary prolactin (PRL) levels and its antiangiogenic PRL fragments have been associated with disease severity. In this study, we assessed whether these biomarkers are associated with an increased risk of adverse maternal and perinatal outcomes in preeclamptic women. We studied 501 women with preeclampsia attended at a tertiary care hospital. Serum concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng), as well as urinary PRL levels, were measured by enzymed-linked immunosorbent assay. Antiangiogenic PRL fragments were determined by immunoblotting. The risk for any adverse maternal outcome and for having a small-for-gestational-age infant was higher among women with sFlt-1/PlGF ratios, sEng, and urinary PRL level values in the highest quartile (odds ratios ≥ 2.7), compared with the lowest quartile. Both urinary PRL levels and the presence of antiangiogenic PRL fragments were more closely associated with the risk of specific adverse maternal outcomes (placental abruption, hepatic hematoma or rupture, acute renal failure, pulmonary edema, maternal death, and need for endotracheal intubation, positive inotropic drug support, and hemodialysis; odds ratios ≥ 5.7 and ≥ 4.7, respectively) than either sFlt-1/PlGF ratio or sEng alone. We concluded that in preeclamptic women at the time of initial evaluation, sFlt-1/PlGF ratio and sEng are associated with increased risk of combined adverse maternal outcomes. However, urinary PRL concentrations and its antiangiogenic fragments appear to be better predictors of an adverse maternal outcome and may be useful for risk stratification in preeclampsia.

Frequency of Macroprolactinemia in Hyperprolactinemic Women Presenting with Menstrual Irregularities, Galactorrhea, and/or Infertility: Etiology and Clinical Manifestations.

Aim. To determine the frequency of macroprolactinemia, its etiology, and the clinical manifestations in patients with hyperprolactinemia presenting with menstrual irregularities, galactorrhea, and/or infertility who were attended by the gynecology-endocrinology service. Methods. In a cross-sectional study, 326 hyperprolactinemic women were tested for serum prolactin (PRL) concentrations before and after chromatographic separation (gel filtration and affinity with protein G) and extraction of free PRL with polyethylene glycol (PEG). Results. Sera from 57 patients (17.5%) were found to have macroprolactinemia. The presence of macroprolactinemia was attributable to anti-PRL autoantibodies in 54 (94.7%) patients. The median serum PRL levels were similar in patients with or without macroprolactinemia (42.0 versus 38.1 ng/mL). In contrast, patients with macroprolactinemia had lower serum-free PRL levels (median 9.2 versus 31.7 ng/mL, P < 0.001). Patients without macroprolactinemia had a higher frequency of galactorrhea and abnormal pituitary imagine findings (P < 0.002). Conclusions. We can conclude that macroprolactinemia should be considered as a benign variant, and it must be ruled out in women presenting with menstrual irregularities, galactorrhea, and/or infertility in order to investigate other causes different than hyperprolactinemia. Serum PRL precipitated with PEG is a convenient and simple procedure to screen for the presence of macroprolactinemia.