Tiziana Frusca

In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1)

BACKGROUND X-linked severe combined immunodeficiency (SCIDXI) is an inherited immune defect which leads to death in infancy from severe infections. The defect is caused by mutations of the IL-2RG gene that encodes for the common gamma chain shared by several cytokine receptors. The disease is characterised by lack of T and NK cells with normal numbers of B cells. SCIDXI can be cured by bone marrow transplantation (BMT) or prevented by abortion after prenatal diagnosis. METHODS A male fetus was diagnosed as having SCIDXI by molecular, immunophenotypic, and functional analyses. The fetus was injected intraperitoneally under ultrasound guidance with CD34 haematopoietic progenitor cells purified from paternal bone marrow and T-cell depleted by E rosetting. Chimerism analysis was by HLA-DQ alpha typing and gamma-chain staining on cord blood. FINDINGS A healthy 3.6 kg boy was delivered by caesarean section at 38 weeks of gestation with no clinical or laboratory signs of graft-versus-host disease. Engraftment of donor-derived CD2 cells was found at birth. At 3.5 months of age the infant is well and his T-cell counts and function are normal. INTERPRETATION In-utero transplantation of haematopoietic progenitor cells allowed immune reconstitution of a fetus with SCIDXI and may be an alternative to elective abortion. Our report should encourage applications of this method to other inherited disorders curable by BMT.

Perinatal morbidity and mortality in early‐onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)

Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early‐onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early‐onset fetal growth restriction based on time of antenatal diagnosis and delivery.

Absent end-diastolic velocity in umbilical artery: Risk of neonatal morbidity and brain damage

OBJECTIVE We conducted a cohort study in growth-retarded fetuses to establish if absent or reverse end-diastolic flow in the umbilical artery was associated with increased perinatal mortality and morbidity and neurologic damage at long-term follow-up. STUDY DESIGN Thirty-one fetuses with intrauterine growth retardation and absent or reverse end-diastolic flow in the umbilical artery (study group) and 40 growth-retarded fetuses with detectable diastolic flow in the umbilical artery, divided into two control groups, were followed up with serial nonstress tests, Doppler flow studies, and biophysical profiles. Twenty newborns from the study group survived the perinatal period and were observed for a mean of 18 months (range 12 to 24 months). Their neurologic outcomes were compared with those of 26 neonates from the two control groups. RESULTS Study group fetuses had a higher incidence of abnormal karyotype (9.7% vs 0%) and corrected perinatal mortality (26% vs 6% and 4%) and a greater risk of permanent neurologic sequelae (35% vs 0% and 12%) compared with the fetuses from the two control groups. CONCLUSIONS Growth-retarded fetuses with absent or reverse end-diastolic flow in the umbilical artery not only have an increased fetal and neonatal mortality but also a higher incidence of long-term permanent neurologic damage when compared with growth-retarded fetuses with diastolic flow in the umbilical circulation.

Thrombophilia Is Significantly Associated With Severe Preeclampsia Results of a Large-Scale, Case-Controlled Study

The role of thrombophilia in the pathogenesis of preeclampsia is controversial. The aim of this case-controlled study was to determine whether thrombophilia increases the risk of preeclampsia or interferes with its clinical course. A total of 808 white patients who developed preeclampsia (cases) and 808 women with previous uneventful pregnancies (controls) matched for age and parity were evaluated for inherited and acquired thrombophilia (factor V Leiden; factor II G20210A; methylenetetrahydrofolate reductase C677T; protein S, protein C, and antithrombin III deficiency; anticardiolipin antibodies; lupus anticoagulant; and hyperhomocysteinemia). Odds ratios (ORs) with 95% confidence intervals (CIs) for risk of being carriers of thrombophilia in cases compared with controls and for risk of maternal life-threatening complications and adverse perinatal outcomes in preeclamptic patients with or without thrombophilia were calculated. Women with severe preeclampsia (406 cases) had a higher risk (OR, 4.9; 95% CI, 3.5 to 6.9) of being carriers of either an inherited or acquired thrombophilic factor, except for protein S, protein C, and antithrombin deficiency. In women with mild preeclampsia (402 cases), only prothrombin and homozygous methylenetetrahydrofolate reductase gene mutations were significantly more prevalent than in the controls. Thrombophilic patients with severe preeclampsia are at increased risk of acute renal failure (OR, 1.8; 95% CI, 1.5 to 2.2), disseminated intravascular coagulation (OR, 2.7; 95% CI, 1.1 to 6.4), abruptio placentae (OR, 2.6; 95% CI, 1.2 to 6.0) and perinatal mortality (OR, 1.7; 95% CI, 1.5 to 2.2) compared with nonthrombophilic preeclamptic patients. Our study demonstrates a significant association between maternal thrombophilia and severe preeclampsia in white women. Thrombophilia also augments the risk of life-threatening maternal complications and adverse perinatal outcomes in preeclamptic patients.

Histological features of uteroplacental vessels in normal and hypertensive patients in relation to birthweight

Summary. Placental bed biopsies were obtained during caesarean section from normal, pre‐eclamptic and hypertensive pregnancies. Of the 14 biopsies from normal pregnancies 13 showed normal vascular physiological changes in the decidua and in the myometrium. Biopsies from 24 pregnancies complicated by pre‐eclampsia showed acute atherosis in 18 and physiological changes limited to the decidua in six; none had normal physiological changes. Biopsies from five hypertensive patients showed all three types of histological changes. The mean birthweight centile was lower in the group with atherosis than in the group with limited and the group with normal physiological changes.

Prognostic role of umbilical artery Doppler velocimetry in growth-restricted fetuses.

Objective: To correlate umbilical artery Doppler velocimetry with perinatal outcome in a group of growth-restricted fetuses. Design: The study was a retrospective analysis of 578 singleton pregnancies with diagnosis of intrauterine growth restriction (IUGR), delivered in a single obstetric unit, at the Spedali Civili, Brescia, Italy, a university and teaching hospital with 3500 deliveries a year and neonatal intensive care unit (NICU). Methods: During 1991-99 we studied 578 pregnancies with a diagnosis of IUGR referred for Doppler velocimetry. From this population, four subsets were formed: normal umbilical artery pulsatility index (NUAPI; 334 fetuses); increased pulsatility index but with telediastolic flow (abnormal umbilical artery pulsatility index AUAPI; 137 fetuses); absent end-diastolic flow (AEDF; 70 fetuses); reverse telediastolic flow (RF; 37 fetuses). Fetal biometry, amniotic fluid and fetal-maternal Doppler velocimetry were evaluated in all patients, with biophysical profile and routine non-stress test, when indicated. The following outcomes were examined: mean gestational age at delivery, number of preterm deliveries (< 34 weeks), mean neonatal weight, Apgar score at 5 min < 7, prenatal and neonatal deaths (within the first 28 days of life), admission to the NICU and number of days spent after birth in hospital. Neonatal morbidity was analyzed, including respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH, grade 2-3), necrotizing enterocolitis (NEC) and retinopathy of prematurity. Long-term neurological follow-up is still ongoing and will not be presented in this paper. Results: Out of 578 fetuses with IUGR, 547 were born alive. There were 26 neonatal deaths. The mean gestational age at delivery was 35.6 ± 4 weeks and mean birth weight 1844 ± 612 g. There were 28 intrauterine deaths and three elective terminations of pregnancy. A total of 60 cases (11%) were complicated by RDS, 13 cases (2.4%) by retinopathy of prematurity, IVH was present in nine cases (1.6%) and NEC in seven cases (1.3%). Total perinatal mortality was 9.8%; in the 26 cases of neonatal death, the mean week at delivery was 29.6 ± 4 with a mean weight of 840 ± 425 g. Patients with NUAPI had a mean week at delivery of 37 ± 3, those with AUAPI delivered at 34 ± 3.2, those with AEDF delivered at 31 ± 3 and those with RF delivered at 29 ± 2 weeks. In progressively worsening umbilical velocimetry, we observed an increase of incidence of low Apgar score. Days of admission to the NICU and incidence of perinatal mortality increased with the worsening of Doppler velocimetry. Conclusions: Our study underlines the existence of a strict correlation between umbilical Doppler velocimetry and an increased incidence of perinatal complications in IUGR fetuses.

Maternal thrombophilia and the risk of recurrence of preeclampsia

OBJECTIVE The aim of this prospective study was to determine the impact of thrombophilia on the recurrence of preeclampsia. STUDY DESIGN In a multicenter, observational, cohort design, 172 white patients with a previous pregnancy complicated by preeclampsia were observed in the next pregnancy. They were evaluated for heritable thrombophilia (factor V Leiden and factor II G20210A mutations, protein S, protein C, and antithrombin deficiency), hyperhomocystinemia, lupus anticoagulant, and anticardiolipin antibodies. Development of preeclampsia and maternal complications and both gestational age at delivery and birthweight were recorded. RESULTS Sixty women (34.9%) showed the presence of a thrombophilic defect. They had a higher risk for the recurrence of preeclampsia (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.2-5.1), compared to patients without thrombophilia. Similar findings were observed considering only heritable thrombophilia. Thrombophilic patients were at increased risk for the occurrence of very early preterm delivery (< 32 weeks; OR, 11.6; 95% CI, 3.4-43.2). CONCLUSION When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management.

Evidence against a pathogenetic role for endothelin in pre‐eclampsia

Objective To assess whether increased placental or systemic endothelin synthesis has a pathogenic role in pre‐eclampsia (gestational proteinuric hypertension).

Mid- and long-term outcome of extremely low birth weight (ELBW) infants: an analysis of prognostic factors.

Objective. To evaluate morbidity and long-term neurological outcome in a group of extremely low birth weight infants (ELBW; <1000 g) and to correlate the neurological outcome in a small group of intrauterine growth retarded (IUGR) infants with Doppler indices in the umbilical artery. Methods. One hundred and eighty-three live births with birth weight <1000 g and gestational age ≤34 weeks were included in the study. Neonatal mortality and morbidity were evaluated. At 24 months of corrected age an evaluation of the neurological development of the children was made by pediatric neuropsychiatrists. The children were classified as: normal, with minor neurological sequelae, and with major neurological sequelae. The evaluation of umbilical artery velocimetry was applied to 84 fetuses presenting with IUGR and the velocimetric patterns were correlated with neurological outcome. Results. In the 183 infants discharged from the Department of Neonatology, respiratory distress syndrome (RDS) was the most frequent pathology (76.6%); less frequent were bronchopulmonary dysplasia (BPD; 19.5%), patent ductus arteriosus (PDA; 29.7%) and necrotizing enterocolitis (NEC; 5.5%). Retinopathy of prematurity (ROP) affected 34 children (26.6%), and 14.8% of the children developed intraventricular hemorrhage (IVH) and 14.1% periventricular leukomalacia (PVL). Out of the 183 infants included in the study, 107 had a neurological assessment at two years: 22 (20.6%) suffered from severe neurological sequelae, 20 (18.7%) from minor neurological sequelae, and 65 (60.7%) had a normal neurological development. In 84 IUGR fetuses a Doppler evaluation of the umbilical artery was performed: the incidence of neurologically normal children was 67% in the group with normal umbilical velocimetry, 93% in the group with increased umbilical resistances, and 59% in those with absent or reversed end-diastolic velocity (ARED). Conclusions. This study, confirms that an extremely low birth weight implies a high risk of perinatal mortality and neonatal morbidity, but that the most significant variable that can be correlated to the long-term neurological outcome is the gestational age.

Doppler velocimetry of the uterine arteries in nulliparous women

The aim of this study was to evaluate the role of uterine artery Doppler velocimetry performed at 20 and 24 weeks gestation in predicting gestational hypertension and small-for-gestational age babies in a population of nulliparous women. Four hundred and fifty-six patients without risk factors for pregnancy complications and with fetuses free from structural abnormalities at ultrasonographic examination at 20 weeks gestation were considered in the study. During the routine 20 weeks ultrasound a continuous-wave Doppler examination of the uterine arteries was performed. The patients with abnormal uterine Resistance Index (RI) repeated the Doppler evaluation at 24 weeks by means of Colour Doppler equipment. Among the 419 women who completed the study an abnormal Doppler uterine arteries velocimetry was found in 8.6% of the patients. Pregnancy complications (gestational hypertension and/or small-for-gestational age babies) were observed in 56% of the patients presenting high uteroplacental RI versus 10% of those with normal uterine artery velocimetry (P = 0.0001). In the group of patients with an abnormal RI value, the presence of a diastolic notch in one or both of the uterine arteries identified a population of pregnant women at higher risk for pregnancy complications when compared with patients without notch (78% vs. 33%, P = 0.007). The knowledge of the uteroplacental resistance can help in identifying a subgroup of patients at higher risk of hypertensive disorders and small-for-gestational age babies that could benefit from prophylaxis with low dose aspirin.