Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction.

PURPOSE: To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS: A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS: 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION: An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.

Incidence, clinical features and perinatal outcome in anomalous fetuses with late-onset growth restriction: cohort study.

OBJECTIVE: To describe the incidence, clinical features and perinatal outcome of late-onset fetal growth restriction (FGR) associated with genetic syndrome or aneuploidy, structural malformation or congenital infection. METHODS: This was a retrospective multicenter cohort study of patients who attended one of four tertiary maternity hospitals in Italy. We included consecutive singleton pregnancies between 32 + 0 and 36 + 6 weeks' gestation with either fetal abdominal circumference (AC) or estimated fetal weight < 10th percentile for gestational age or a reduction in AC of > 50 percentiles from the measurement at an ultrasound scan performed between 18 and 32 weeks. The study group consisted of pregnancies with late-onset FGR and a genetic syndrome or aneuploidy, structural malformation or congenital infection (anomalous late-onset FGR). The presence of congenital anomalies was ascertained postnatally in neonates with abnormal findings on antenatal investigation or detected after birth. The control group consisted of pregnancies with structurally and genetically normal fetuses with late-onset FGR. Composite adverse perinatal outcome was defined as the presence of at least one of stillbirth, 5-min Apgar score < 7, admission to the neonatal intensive care unit (NICU), need for respiratory support at birth, neonatal jaundice and neonatal hypoglycemia. The primary aims of the study were to assess the incidence and clinical features of anomalous late-onset FGR, and to compare the perinatal outcome of such cases with that of fetuses with non-anomalous late-onset FGR. RESULTS: Overall, 1246 pregnancies complicated by late-onset FGR were included in the study, of which 120 (9.6%) were allocated to the anomalous late-onset FGR group. Of these, 11 (9.2%) had a genetic syndrome or aneuploidy, 105 (87.5%) had an isolated structural malformation, and four (3.3%) had a congenital infection. The most frequent structural defects associated with late-onset anomalous FGR were genitourinary malformations (28/105 (26.7%)) and limb malformation (21/105 (20.0%)). Compared with the non-anomalous late-onset FGR group, fetuses with anomalous late-onset FGR had an increased incidence of composite adverse perinatal outcome (35.9% vs 58.3%; P < 0.01). Newborns with anomalous, compared to those with non-anomalous, late-onset FGR showed a higher frequency of need for respiratory support at birth (25.8% vs 9.0%; P < 0.01), intubation (10.0% vs 1.1%; P < 0.01), NICU admission (43.3% vs 22.6%; P < 0.01) and longer hospital stay (median, 24 days (range, 4-250 days) vs 11 days (range, 2-59 days); P < 0.01). CONCLUSIONS: Most pregnancies complicated by anomalous late-onset FGR have structural malformations rather than genetic abnormality or infection. Fetuses with anomalous late-onset FGR have an increased incidence of complications at birth and NICU admission and a longer hospital stay compared with fetuses with isolated late-onset FGR. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Third-trimester ultrasound for antenatal diagnosis of placenta accreta spectrum in women with placenta previa: results from the ADoPAD study.

OBJECTIVE: To evaluate the performance of third-trimester ultrasound for the diagnosis of clinically significant placenta accreta spectrum disorder (PAS) in women with low-lying placenta or placenta previa. METHODS: This was a prospective multicenter study of pregnant women aged ≥ 18 years who were diagnosed with low-lying placenta (< 20 mm from the internal cervical os) or placenta previa (covering the internal cervical os) on ultrasound at ≥ 26 + 0 weeks' gestation, between October 2014 and January 2019. Ultrasound suspicion of PAS was raised in the presence of at least one of these signs on grayscale ultrasound: (1) obliteration of the hypoechogenic space between the uterus and the placenta; (2) interruption of the hyperechogenic interface between the uterine serosa and the bladder wall; (3) abnormal placental lacunae. Histopathological examinations were performed according to a predefined protocol, with pathologists blinded to the ultrasound findings. To assess the ability of ultrasound to detect clinically significant PAS, a composite outcome comprising the need for active management at delivery and histopathological confirmation of PAS was considered the reference standard. PAS was considered to be clinically significant if, in addition to histological confirmation, at least one of these procedures was carried out after delivery: use of hemostatic intrauterine balloon, compressive uterine suture, peripartum hysterectomy, uterine/hypogastric artery ligation or uterine artery embolization. The diagnostic performance of each ultrasound sign for clinically significant PAS was evaluated in all women and in the subgroup who had at least one previous Cesarean section and anterior placenta. Post-test probability was assessed using Fagan nomograms. RESULTS: A total of 568 women underwent transabdominal and transvaginal ultrasound examinations during the study period. Of these, 95 delivered in local hospitals, and placental pathology according to the study protocol was therefore not available. Among the 473 women for whom placental pathology was available, clinically significant PAS was diagnosed in 99 (21%), comprising 36 cases of placenta accreta, 19 of placenta increta and 44 of placenta percreta. The median gestational age at the time of ultrasound assessment was 31.4 (interquartile range, 28.6-34.4) weeks. A normal hypoechogenic space between the uterus and the placenta reduced the post-test probability of clinically significant PAS from 21% to 5% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 9% in the subgroup with previous Cesarean section and anterior placenta. The absence of placental lacunae reduced the post-test probability of clinically significant PAS from 21% to 9% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 36% in the subgroup with previous Cesarean section and anterior placenta. When abnormal placental lacunae were seen on ultrasound, the post-test probability of clinically significant PAS increased from 21% to 59% in the whole cohort and from 62% to 78% in the subgroup with previous Cesarean section and anterior placenta. An interrupted hyperechogenic interface between the uterine serosa and bladder wall increased the post-test probability for clinically significant PAS from 21% to 85% in women with low-lying placenta or placenta previa and from 62% to 88% in the subgroup with previous Cesarean section and anterior placenta. When all three sonographic markers were present, the post-test probability for clinically significant PAS increased from 21% to 89% in the whole cohort and from 62% to 92% in the subgroup with previous Cesarean section and anterior placenta. CONCLUSIONS: Grayscale ultrasound has good diagnostic performance to identify pregnancies at low risk of PAS in a high-risk population of women with low-lying placenta or placenta previa. Ultrasound may be safely used to guide management decisions and concentrate resources on patients with higher risk of clinically significant PAS. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound prediction of adverse perinatal outcome at diagnosis of late-onset fetal growth restriction.

OBJECTIVE: To evaluate the relationship between Doppler and biometric ultrasound parameters measured at diagnosis and perinatal adverse outcome in a cohort of late-onset growth-restricted (FGR) fetuses. METHODS: This was a multicenter retrospective study of data obtained between 2014 and 2019 including non-anomalous singleton pregnancies complicated by late-onset FGR (≥ 32 weeks), which was defined either as abdominal circumference (AC) or estimated fetal weight (EFW) < 10th percentile for gestational age or as reduction of the longitudinal growth of AC by over 50 percentiles compared to ultrasound scan performed between 18 and 32 weeks of gestation. We evaluated the association between sonographic findings at diagnosis of FGR and composite adverse perinatal outcome (CAPO), defined as stillbirth or at least two of the following: obstetric intervention due to intrapartum fetal distress, neonatal acidemia, birth weight < 3rd percentile and transfer to the neonatal intensive care unit (NICU). RESULTS: Overall, 468 cases with complete biometric and umbilical, fetal middle cerebral and uterine artery (UtA) Doppler data were included, of which 53 (11.3%) had CAPO. On logistic regression analysis, only EFW percentile was associated independently with CAPO (P = 0.01) and NICU admission (P < 0.01), while the mean UtA pulsatility index (PI) multiples of the median (MoM) > 95th percentile at diagnosis was associated independently with obstetric intervention due to intrapartum fetal distress (P = 0.01). The model including baseline pregnancy characteristics and the EFW percentile was associated with an area under the receiver-operating-characteristics curve of 0.889 (95% CI, 0.813-0.966) for CAPO (P < 0.001). A cut-off value for EFW corresponding to the 3.95th percentile was found to discriminate between cases with and those without CAPO, yielding a sensitivity of 58.5% (95% CI, 44.1-71.9%), specificity of 69.6% (95% CI, 65.0-74.0%), positive predictive value of 19.8% (95% CI, 13.8-26.8%) and negative predictive value of 92.9% (95% CI, 89.5-95.5%). CONCLUSIONS: Retrospective data from a large cohort of late-onset FGR fetuses showed that EFW at diagnosis is the only sonographic parameter associated independently with the occurrence of CAPO, while mean UtA-PI MoM > 95th percentile at diagnosis is associated independently with intrapartum distress leading to obstetric intervention. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

What is the role of glycemic control in the development of preeclampsia among women with type 1 diabetes?

OBJECTIVE: To investigate the role of glycemic control in development of preeclampsia (PE) in women with type 1 diabetes mellitus (T1DM). METHODS: An observational case-control study comparing 244 women with type 1 diabetes and 488 controls was conducted. Among women with T1DM HbA1c, average daily glucose values, fasting, preprandial, 1-hour and 2-hour postprandial glucose levels, and daily 3 meals postprandial glucose areas were evaluated. Uterine artery pulsatility indices (PI) at 16, 20, 24 weeks' gestation were obtained. Data analysis included rates of PE in both groups, and association between glycemic control, uterine artery PI and development of PE among women with T1DM. RESULTS: PE developed in 13.1% of diabetic women and in 3.5% of women in the control group (odds ratio 4.2; 95% CI 2.2-8.1). In multivariate logistic regression analysis, HbA1c in the 1st trimester, mean daily glucose level in the 1st and 2nd trimester, daily 3 meal postprandial glucose area in the 1st and 2nd trimester, and the uterine arteries PI at 24 weeks' gestation were found to be associated with development of PE. The uterine arteries PI showed a significant positive correlation with the 3 meal postprandial glucose area at 16, 20, 24 weeks. CONCLUSION: In women with T1DM, poor glycemic control early in pregnancy is associated with an increased risk of subsequent PE. An association between poor placentation, as indicated by the increased PI of uterine arteries, and a maternal metabolic factor, that is the 3 meal post-prandial glucose area, has been shown, supporting the increased rate of PE among women with T1DM.

Fetal Growth Restriction: Does an Integrated Maternal Hemodynamic-Placental Model Fit Better?

In recent years, a growing interest has arisen regarding the possible relationship between adverse pregnancy outcomes (APOs) and inadequate maternal hemodynamic adaptations to the pregnancy. A possible association between "placental syndromes," such as preeclampsia (PE) and fetal growth restriction (FGR), and subsequent maternal cardiovascular diseases (CVD) later in life has been reported. The two subtypes of FGR show different pathogenetic and clinical features. Defective placentation, due to a poor trophoblastic invasion of the maternal spiral arteries, is believed to play a central role in the pathogenesis of early-onset PE and FGR. Since placental functioning is dependent on the maternal cardiovascular system, a pre-existent or subsequent cardiovascular impairment may play a key role in the pathogenesis of early-onset FGR. Late FGR does not seem to be determined by a primary abnormal placentation in the first trimester. The pathological pathway of late-onset FGR may be due to a primary maternal cardiovascular maladaptation: CV system shows a flat profile and remains similar to those of non-pregnant women. Since the second trimester, when the placenta is already developed and increases its functional request, a hypovolemic state could lead to placental hypoperfusion and to an altered maturation of the placental villous tree and therefore to an altered fetal growth. Thus, this review focalizes on the possible relationship between maternal cardiac function and placentation in the development of both early and late-onset FGR. A better understanding of maternal hemodynamics in pregnancies complicated by FGR could bring various benefits in clinical practice, improving screening and therapeutic tools.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Analysis of the main risk factors for gestational diabetes diagnosed with International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria in multiple pregnancies.

INTRODUCTION: The aim is to investigate the proportion of multiple pregnancies with gestational diabetes mellitus (GDM) diagnosed using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and to identify the impact of age, body mass index (BMI), and mode of conception on incidence of GDM. MATERIALS AND METHODS: This is a single center, retrospective cohort study on 656 multiple pregnancies screened for GDM with 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation, between January 2010 and January 2016. The diagnosis of gestational diabetes mellitus (GDM) was reached through the IADPSG. RESULTS: The incidence of GDM in our population was 15.1%. When patients who conceived through heterologous assisted reproduction technology were compared with those who conceived spontaneously, there was a significant difference for GDM (31.1 vs 13.6%, p < 0.001, OR 2.86). A similar finding was also observed comparing egg donation IVF/ICSI patients with homologous IVF/ICSI patients (31.1 vs 14.8%, p = 0.006, OR 2.59). Incidence of GDM was significantly higher in obese than in non-obese patients (42.5 vs 14.8%, p < 0.001, OR 4.88) and in women over 35 compared to younger patients (18.4 vs 11.1%, p = 0.01, OR 1.81). Logistic regression comparing the diabetes onset with conception mode gave a p = 0.07. The calculation of the Chi-square and odds ratio for single mode of conception showed that homologous vs conceived spontaneously p = 0.90, OR 0.97, heterologous vs homologous p = 0.01 with OR 2.46, and heterologous vs conceived spontaneously p = 0.01 with OR 2.39. Logistic regression showed that age and BMI are risk factors for developing GDM, respectively, p = 0.03 with OR 1.4 and p < 0.01 and OR 1.09. DISCUSSION: The contribution our study can make is improved counseling about GDM risks for couples with multiple pregnancies. Our data support the role of age, BMI, and mode of conception as risk factors for GDM in multiple pregnancies.

Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the hypothesis that fetal abdominal circumference (AC) and uterine artery (UtA) Doppler pulsatility index (PI) could be used to select two homogeneous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without intrauterine growth restriction (IUGR). METHODS: This was a multicenter retrospective study of cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to fetomaternal medicine units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design composite indicators of risk factors for maternal metabolic syndrome and of severity for maternal functional organ damage. RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP cases with appropriate-for-gestational-age (AGA) fetuses (HDP-AGA), diagnosed by normal fetal AC and UtA-PI (n = 205), and a group of HDP cases with IUGR fetuses (HDP-IUGR), diagnosed by fetal AC < 5(th) centile and UtA-PI > 95(th) centile (n = 124). Curves fitted to the birth weights of these two groups were significantly different, but gestational age at admission for HDP (< 34 or ≥ 34 weeks) did not show an independent association with birth weight. When birth weight was expressed as a Z-score with respect to local reference charts, the average corresponded to the 6(th) and 48(th) centiles, respectively. The occurrence of HDP-AGA (as compared with HDP-IUGR) was significantly associated with risk factors for maternal metabolic syndrome (odds ratio, 2.79 (95% CI, 1.57-4.97)), independent of gestational age. The same risk factors yielded non-significant odds ratios for the development of late-onset (vs early-onset) HDP. Women with HDP-IUGR had worse clinical outcomes. CONCLUSIONS: This study provides new information based on simple prenatal bedside examinations that might help to differentiate HDP-IUGR from HDP-AGA fetuses. These groups are associated with different fetal growth patterns and risk factors, independent of gestational age at onset of the disease. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Autophagy in placentas from acidotic newborns: an immunohistochemical study of LC3 expression.

Autophagy is an inducible catabolic process activated during compromised conditions, such as hypoxia. Neonatal encephalopathy (NE) is a syndrome of disturbed neurological function. No absolute prognostic indicators are available at birth to identify neonates at high risk to develop NE. Immunohistochemical staining with LC3 antibody was performed on 40 placentas from uneventful term singleton pregnancies with umbilical artery pH ≤ 7.00 at birth; semi-quantitative analysis was carried-out to estimate autophagy level. 6/40 (15%) neonates developed NE. Placentas from newborns with NE exhibited a higher LC3 expression. Autophagy protein expression in placentas with severe acidosis is a potential marker for poor outcome.

Stillbirth and fetal growth restriction.

OBJECTIVE: To confirm the role of fetal growth restriction (FGR) as a cause of stillbirth, and to compare diagnostic accuracy of customized fetal growth and population-based standards in identifying FGR within a pathological population of early and late stillbirths. METHODS: Retrospective study on a cohort of 189 stillbirths occurred in single pregnancy between January 2006 and September 2011. Unexplained stillbirths, defined by Aberdeen-Wigglesworth and ReCoDe classifications, were evaluated on the basis of fetal birthweight with both Tuscany population and Gardosi customized standards. Unexplained stillbirths have been classified as early or late depending on the gestational age of occurrence. RESULTS: Aberdeen-Wigglesworth classification, applied to the 189 cases of stillbirth, left 94 unexplained cases (49.7%), whereas the ReCoDe classification left only 40 (21%). By applying population standards to the 94 unexplained stillbirths we have identified 31 FGRs (33% of sample), while customized standards identified 54 FGRs (57%). Customised standards identified a larger number of FGRs with respect to population standards during the third trimester (i.e. 51% vs. 25% respectively) than in the second trimester (73% vs. 54% respectively) (p = 0.05). CONCLUSIONS: Customized standards have a higher diagnostic accuracy in identifying FGRs especially during the third trimester.

Relation between maternal thrombophilia and stillbirth according to causes/associated conditions of death.

OBJECTIVE: To investigate maternal thrombophilia in cases of Stillbirth (SB), also an uncertain topic because most case series were not characterised for cause/associated conditions of death. STUDY DESIGN: In a consecutive, prospective, multicentre design, maternal DNA was obtained in 171 cases of antenatal SB and 326 controls (uneventful pregnancy at term, 1:2 ratio). Diagnostic work-up of SB included obstetric history, neonatologist inspection, placenta histology, autopsy, microbiology/chromosome evaluations. Results audited in each centre were classified by two of us by using CoDAC. Cases were subdivided into explained SB where a cause of death was identified and although no defined cause was detected in the remnants, 64 cases found conditions associated with placenta-vascular disorders (including preeclampsia, growth restriction and placenta abruption - PVD). In the remnant 79 cases, no cause of death or associated condition was found. Antithrombin activity, Factor V Leiden, G20210A Prothrombin mutation (FII mutation) and acquired thrombophilia were analysed. RESULTS: Overall, the presence of a thrombophilic defect was significantly more prevalent in mothers with SBs compared to controls. In particular, SB mothers showed an increased risk of carrying Factor II mutation (OR=3.2, 95% CI: 1.3-8.3, p=0.01), namely in unexplained cases. Such mutation was significantly associated also with previous SB (OR=8.9, 95%CI 1.2-70.5). At multiple logistic regression, Factor II mutation was the only significantly associated variable with SB (adj OR=3.8, 95% CI: 1.3-13.5). CONCLUSION: These data suggest that Factor II mutation is the only condition specifically associated with unexplained SB and could represents a risk of recurrence. PVD-associated condition is unrelated to thrombophilia.

OS086. Methylation status of the HOXA13 promoter region in placental tissue of pregnancies complicated by early onset severe preeclampsia.

INTRODUCTION: Compromised placental function and morphology found in early onset preeclampsia as well as a modified phenotype of the fetus may derive from a deviation in the normal gene expression pattern. Previous studies demonstrated by experimental animal models, that the gene HOXA13 plays an essential role in the arrangement of the placental vascular net, identifying direct and indirect target functions this gene has on the endothelial component. Research in model systems and now expanding to human studies has suggested that the causes and consequences of a variety of pregnancy-related pathologies are connected to epigenetic regulation. OBJECTIVES: To evaluate the methylation status of the promoter region of HOXA13 within placental tissue and its association with specific clinical signs of severe early onset preeclampsia. METHODS: A prospective case - control study was performed to evaluate the methylation status of the promoter region of HOXA13 by pyrosequencing analysis within placental tissue and its association with specific clinical signs of severe early onset preeclampsia (EOSP). RESULTS: The group of preeclamptic patients reached a mean methylation degree of 27.06% (±8.94) and 30.56% (±8.08) on two CpG islands of HOXA13 5' promoter respectively. Conversely in the group of physiologic controls the mean degree of methylation resulted 15.12%(±3.64) (p<0.0016) and 18.25% (±3.45) (p<0.0005). CONCLUSION: This study firstly demonstrated that an hypermethylation of placental HOXA13 exists in preeclamptic placental tissues and concentrates only on the gene promoter. Additionally, the existence of a correspondence between themethylation process of the gene promoter HOXA 13 and the clinical manifestation of severe early onset preeclampsia supports the original hypothesis that this process may be at the base of the preeclamptic pathogenesis.

PP109. Risk of preeclampsia in homologous and oocyte donation IVF pregnancies.

INTRODUCTION: Women who conceived by donor oocyte in vitro fertilization (IVF) are at high risk for placenta-related complications, because of advanced maternal age, nulliparity and maybe for an altered immune response. OBJECTIVES: The aim of this case-control study is to compare the incidence and the characteristics of preeclampsia in women who conceived by oocyte donor or by homologous IVF. METHODS: Data were collected from 65 consecutive women who conceived through oocyte donor IVF and 71 consecutive pregnancies from homologous IVF in women older than 35years (control group), who attended our institution between 2009 and 2011. Data are expressed as percentage, average and standard deviation (SD). Statistical analysis was performed by chi-square test for unpaired data and the results were considered significant with p<0.05. RESULTS: Thirteen women from the donor oocyte group were excluded because of first trimester miscarriage, ectopic pregnancy and lack of data. After the exclusion, 52 pregnancies from oocyte donation were compared to the control group. Baseline characteristics, such as maternal age, BMI, parity and prevalence of twin pregnancies were similar in the two groups. Preexisting hypertension was present only in the oocyte donor IVF group (n=6 cases). The risk of preeclampsia was significantly related to oocyte donor IVF (27% vs 5.6%, p=0.0024 OR=6.17), even when only singleton pregnancies were considered (16.7 vs 1.9%; p=0.02, OR=9). When women with preexisting hypertension were excluded, the incidence of severe preeclampsia remained significant (p=0.02). This result was not confirmed when both preexisting hypertension and twin pregnancies were excluded (p=0.09), even if the percentage of cases was higher in the oocyte donor IVF group (10.7% vs 1.85%). Three cases of life threatening severe preeclampsia occurred before the 24th week, two of which required interruption of pregnancy; one case was complicated by eclampsia. The two groups did not show significant differences in terms of prevalence of IUGR, both in multiple and singleton pregnancies, even if percentage values were higher in the donor IVF group (multiple: 21.2% vs 11.3%, p=0.21/ singleton 10% vs 5.6%, p=0.48). CONCLUSION: IVF with oocyte donation stands as an independent risk factor for preeclampsia. The risk of developing a severe and early preeclampsia may be increased when chronic hypertension occurs.

PP120. Hydatidiform mole as a cause of eclampsia in the first trimester: A case report.

INTRODUCTION: The occurrence of preeclampsia before the 20th week of gestation is rare and it has been associated with hydatidiform molar pregnancy. OBJECTIVES: We describe a case of first trimester eclampsia which occurred in a patient with hydatidiform mole. METHODS: Case report. RESULTS: A 16-year-old woman came to emergency service for abdominal pain and vaginal bleeding. She had been suffering of vomiting after meals and complaining for abdominal mass for 2months, without consulting her physician. The last reported period was 1month before; the patient told her periods were regular and the only disease she reported was chronic HBV hepatitis. Vital parameters were all normal. Urine pregnancy test resulted always negative. The gynecological exam reported an increased uterus and a little bleeding, so serum bhCG was performed because of the exam findings and resulted 110,5317UI/L. The transvaginal ultrasound showed images consistent with gestational trophoblastic disease. Computed tomography (CT) scan revealed the presence of an uterine mass and three lung nodules, reported as possibly metastatic. A few days later, the patient underwent dilation and curettage (D&C). Second grade hydatiform mole was diagnosed by histology. After D&C, the serum bhCG was 202,511UI/L. The day after, the patient presented bilateral acute blindness, followed by incoming general seizures, concurrent hypertension and tachycardia. Intravenous diazepam, levetiracetam and mannitol controlled the seizures, but the conscious state of the patient remained critical. Temperature reached 40°C, with concurrent leukocytosis. Then, a lumbar puncture was performed but it resulted negative for inflammatory/infective processes. A head CT was performed the same day and showed a posterior reversible encephalopathy syndrome (PRES). Intravenous methylprednisolone was started. Long term therapy with methylprednisolone and levetiracetam was effective and the patient's status improved and stabilized. A subsequent chemotherapy with EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine) was performed for six cycles, until serum bhCG resulted negative and the abdomen/pelvis ultrasound, head NMR and chest X-ray resulted normal. CONCLUSION: Preeclampsia and eclampsia are regarded as common causes of PRES, which is considered to be the result of vasogenic brain edema. Clinical and imaging findings are usually reversible. Early diagnosis and elimination of possible causes are important in order to avoid permanent visual or brain injury. Imaging (especially MRI) should be carried out in eclamptic patients with visual disturbance in order to exclude other causes of blindness. Molar pregnancy is a rare but important cause of eclampsia, and it has always to be considered in case of early manifestations.

Severe fibrotic changes and altered expression of angiogenic factors in maternal scleroderma: placental findings.

OBJECTIVE: Pregnant women with systemic sclerosis (SSc; scleroderma) have an increased risk of premature delivery and small full-term infants. During placental development, angiogenesis and vascular remodelling are essential for a successful pregnancy outcome. An analysis was made of the pathological changes and expression of angiogenic factors in SSc placentas. METHODS: Placenta biopsies were obtained from three patients with SSc and four healthy uncomplicated pregnancies after delivery at 34-38 weeks of gestation. The sections were stained with Masson's trichrome and phosphotungstic-acid-haematoxylin and immunostained for connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and receptors VEGFR-1 and VEGFR-2. RESULTS: The pathological findings were signs of decidual vasculopathy, increased syncytiotrophoblast knotting, placental infarcts and villous hypoplasia. Severe and diffuse perivascular and stromal fibrosis of decidua and chorionic villi, and extensive deposition of fibrinoid material around decidual vessels and in intervillous spaces were observed. Strong CTGF expression in the vessel wall, decidual cells and fibroblasts and alpha-SMA+ myofibroblasts were found. VEGF and VEGFR-2 expression was stronger in SSc than in healthy placentas, while VEGFR-1 expression was similar to controls. PlGF immunopositivity was weaker in SSc. CONCLUSION: In SSc placentas, severe fibrosis and abnormal vascular remodelling were detected. This may result in reduced blood flow leading to deep sufferance of maternal placenta and possible premature delivery.

Pregnancy outcome in systemic lupus erythematosus complicated by anti-phospholipid antibodies.

OBJECTIVE: Pregnant women affected by SLE are at high risk of gestational hypertension and pre-eclampsia (32-50%). This risk is particularly elevated if aPLs are dosable. The present study was planned to evaluate maternal-fetal outcomes of different groups of SLE pregnant patients characterized by diverse risk factors: patients affected by APS treated with a combination of low-dose aspirin (LDA) and low-molecular weight heparin (LMWH), nulliparous patients with dosable aPL treated by LMWH and SLE patients with no aPL administered no treatment during pregnancy. METHODS: A retrospective description of maternal and fetal outcomes was made in a total of 62 pregnancies presenting APS in 8 cases (12.9%), aPL in 20 (32.2%) and no aPL in 34 (54.8%). RESULTS: No statistically significant difference was found comparing fetal and maternal outcomes of the three groups despite differences in SLE activity: SLE aPL-positive pregnancies were associated with a higher incidence of nephritis and chronic hypertension than pregnancies treated for APS or not presenting with the added risk factor. The incidence of pre-eclampsia is 15% in aPL positive, 12.5% in APS and 14.7% in no aPL pregnancies, respectively. CONCLUSIONS: LMWH is rather a possible option of prophylaxis for SLE aPL-positive pregnancies with potential maternal-fetal outcomes similar to aPL-negative patients or to standard treated APS.