S. De Carolis

Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β2‐glycoprotein I

OBJECTIVE To investigate the in vitro ability of antiphospholipid antibodies (aPL) to bind human trophoblast cells and to affect gonadotropin secretion and invasiveness. METHODS Antiphospholipid antibody IgG from women with recurrent miscarriages, beta2-glycoprotein I (beta2GPI)-independent IgG aPL human monoclonal antibody (mAb) (519), and IgM anti-beta2GPI human mAb (TMIG2) were investigated for their binding to trophoblasts cultured for various amounts of time, their ability to affect invasiveness of Matrigel-coated filters, and their release of human chorionic gonadotropin (hCG). RESULTS Polyclonal IgG aPL, as well as mAb 519 and TMIG2, bound to trophoblasts, the highest binding being found when cells displayed the greatest amount of syncytium formation. TM1G2 binding was found to be betaGPI dependent. Both polyclonal and monoclonal aPL, but not the controls, significantly reduced hCG release and Matrigel invasiveness. CONCLUSION These findings suggest that aPL recognition of both anionic PL and adhered beta2GPI on trophoblast cell structures might represent a potential pathogenetic mechanism for defective placentation in women with the antiphospholipid syndrome.

In vitro effect of antiphospholipid antibody-containing sera on basal and gonadotrophin releasing hormonedependent human chorionic gonadotrophin release by cultured trophoblast cells

Our objective was to evaluate whether antiphospholipid antibody-containing sera could play a regulatory role in signal transduction induced by gonadotrophin releasing hormone (GnRH) when incubated with normal human trophoblast cells. To test this hypothesis we established an in vitro placental culture system in which GnRH addition in the presence of normal human serum resulted in a significant increase in human chorionic gonadotrophin (hCG) secretion. When GnRH was added to the culture medium with antiphospholipid antibody-containing sera, the hCG increase was inhibited. These results suggest the possibility that antiphospholipid antibody-positive sera can exert their effect on GnRH-induced signal transduction. Further studies are needed to explain their exact site of action.

Complementemia and obstetric outcome in pregnancy with antiphospholipid syndrome

Objective: To investigate the predictive value of serum C3 and C4 complement component levels in relation to pregnancy outcome in patients with antiphospholipid syndrome (APS). Materials and methods: A prospective study of 47 pregnancies associated with APS was performed. Pregnancy outcome was analyzed in terms of: fetal loss, preterm delivery (≤34 gestational weeks), fetal intrauterine growth restriction (IUGR), birth weight <2500 g and preeclampsia. Week at delivery, neonatal birth weight and neonatal birth weight percentile were also investigated. Hypocomplementemia, positivity for anti-dsDNA and triple positivity for antiphospholipid antibodies (aPL) were related to pregnancy outcome. Results: Forty-three pregnancies ended in live births with a fetal loss rate of 8.5%. Fetal death, preterm delivery and birth weight <2500 g were associated with hypocomplementemia (p = 0.019, p = 0.0002, p < 0.0001 respectively). Lower neonatal birth weight, lower neonatal birth weight percentile and lower week at delivery were associated with hypocomplementemia (p < 0.0001, p = 0.0003, p < 0.0001 respectively) and with triple aPL positivity (p = 0.008, p = 0.014, p = 0.03 respectively). A poor pregnancy outcome was confirmed among primary APS (PAPS) pregnancies with hypocomplementemia. Multivariate analysis confirmed that hypocomplementemia was an independent predictor of lower neonatal birth weight (p = 0.0001) and lower week at delivery (p = 0.002). Conclusion: Hypocomplementemia could be considered a novel prognostic factor for pregnancy outcome in APS patients.

False-positive IgM for CMV in pregnant women with autoimmune disease: a novel prognostic factor for poor pregnancy outcome.

Our aims were to assess the frequency of false-positive IgM antibodies for cytomegalovirus in pregnant women with autoimmune diseases and in healthy women (controls) and to determine their relationship with pregnancy outcome. Data from 133 pregnancies in 118 patients with autoimmune diseases and from 222 pregnancies in 198 controls were assessed. When positive IgM for cytomegalovirus was detected, IgG avidity, cytomegalovirus isolation and polymerase chain reaction for CMV-DNA in maternal urine and amniotic fluid samples were performed in order to identify primary infection or false positivity. A statistically significantly higher rate of false-positive IgM was found in pregnancies with autoimmune diseases (16.5%) in comparison with controls (0.9%). A worse pregnancy outcome was observed among patients with autoimmune disease and false cytomegalovirus IgM in comparison with those without false positivity: earlier week of delivery (p = 0.017), lower neonatal birth weight (p = 0.0004) and neonatal birth weight percentile (p = 0.002), higher rate of intrauterine growth restriction (p = 0.02) and babies weighing less than 2000 g (p = 0.025) were encountered. The presence of false cytomegalovirus IgM in patients with autoimmune diseases could be used as a novel prognostic index of poor pregnancy outcome: it may reflect a non-specific activation of the immune system that could negatively affect pregnancy outcome. Lupus (2010) 19, 844—849.

Follow-up of babies born to mothers with antiphospholipid syndrome: Preliminary data from the European neonatal registry

In this review preliminary data on the follow-up of 141 babies born to mothers with antiphospholipid syndrome are reported. In spite of maternal treatment, the rate of both preterm delivery and low birth weight were 16 and 17%, respectively. At birth, no clinical evidence of perinatal thrombosis was observed. Placental transfer of antiphospholipid antibodies occurred in 20, 25 and 43% of cases for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies, respectively. At 24 months of follow-up, four children showed behaviour abnormalities suggesting the possible need for long-term neurological evaluation in this clinical setting.

Is there any role for the hydroxychloroquine (HCQ) in refractory obstetrical antiphospholipid syndrome (APS) treatment

The best therapy regimen for refractory obstetrical antiphospholipid syndrome remains to be determined. Additional treatments with steroids, plasma exchanges and immunoglobulins failed to show any beneficial effect. We present a case of a woman who had a better pregnancy outcome after the administration of hydroxychloroquine (HCQ) as additional treatment. Furthermore, we highlighted that HCQ was able to dramatically reduce the antiphospholipid antibodies levels.

Fondaparinux in pregnancy: Could it be a safe option? A review of the literature.

During pregnancy thrombo-prophylaxis could be required in high risk women. If a severe allergic reaction to low-molecular-weight-heparin (LMWH) or a heparin-induced-thrombocytopenia (HIT) occurs, its mandatory to stop the drug. Fondaparinux could be an effective option. In the present review, the maternal and pregnancy outcomes of 65 pregnancies in women using Fondaparinux were reported. It was well-tolerated and rate of pregnancy complications was similar to that observed in general population. Regarding congenital malformations, further studies are necessary to investigate the safety of the drug.

The relationship between TORCH complex false positivity and obstetric outcome in patients with antiphospholipid syndrome

Objective: The presence of TORCH IgM positivity is not a specific indicator of primary infection; the assessment of IgG avidity index has been shown to be useful in identifying or excluding primary infection in pregnant women with no pre-gestational TORCH serology. TORCH is an acronym for Toxoplasmosis, Others (HBV, syphilis, Varicella–Zoster virus, Epstein Barr virus, Coxsackie virus and Parvovirus), Rubella, Cytomegalovirus (CMV) and Herpes Simplex. Patients and methods: Data from 54 pregnancies in women with antiphospholipid syndrome (APS) were assessed in comparison with data from 222 healthy pregnant women as controls. Each woman in both groups was systematically screened for TORCH IgG and IgM during pre-conceptional evaluation and/or at the beginning of pregnancy. The assessment of IgG avidity was also evaluated in order to identify primary infection or false positivity. Results: A significant increase of CMV IgM false positivity in APS in comparison with controls was detected. A worse pregnancy outcome was observed among APS patients having CMV IgM false positivity in comparison with APS patients without false positivity; in particular a statistically significant lower neonatal birth weight and a lower neonatal birth weight percentile were observed. Conclusion: Our data suggest that the presence of CMV IgM false positivity could represent a novel prognostic factor for poor pregnancy outcome in APS patients.

European registry of babies born to mothers with antiphospholipid syndrome: a result update.

The registry is a prospective, European, multicentric, longitudinal study, which follows a cohort of children born to mothers with antiphospholipid syndrome (APS). It was started in 2003. In this report, we update the results obtained from the study of 110 mothers and 112 children (two twin births). Eighty per cent of the mothers (n = 86) had primary APS. Purely obstetrical, thrombotic and mixed (obstetrical and thrombotic) APS represent 65.5 %, 21.8 % and 12.7 % of the whole cohort respectively. Isolated antiphospholipid antibodies and isolated anticardiolipin antibodies positivity were present in 50 of 109 (46%) and in 34 of 109 (31%) of the pregnant women, respectively. In the babies, in spite of a high rate of prematurity (14.3%) with four (3.6%) of the premature babies born before 33 weeks of gestation and an increased number of newborns small for gestational age (17%), the large majority of the neonates were healthy. Thirty-one infants are now older than 24 months. Among them, three displayed behavioural abnormalities before 3 years of age. After completing data, there will be the possibility to evaluate the newborn status in relation to the mothers’ diseases, treatments and antibodies and to follow the neuropsychological development and immunological evolution of the babies during the next 5 years.

Placental transfer of phenobarbital: what is new?

The placental transfer of phenobarbital was investigated in 35 mother-infant pairs at birth. The drug was administered prenatally to the mothers for maternal epilepsy (group 1, n = 5), gestational hypertension and preeclampsia (group 2, n = 20) and prophylaxis of intraventricular hemorrhage in premature deliveries (group 3, n = 10). The phenobarbital levels in arterial cord blood were 100 +/- 2.8% in group 1, 89 +/- 21% in group 2 and 77 +/- 16% in group 3 with respect to the levels observed in the mothers. The most important factor influencing the transplacental passage was the duration of maternal treatment in the infant of group 1 (r = 0.80, p < 0.01), the gestational age in the infants of group 2 (r = 0.74, p < 0.01) and the arterial cord pH in the infants of group 3 (r = 0.89, p < 0.001).