Should phenotype of previous preterm birth influence management of women with short cervix in subsequent pregnancy? Comparison of vaginal progesterone and Arabin pessary.

OBJECTIVE: To investigate whether the classification of a previous spontaneous preterm birth (sPTB) as preterm labor (PTL) with intact membranes (IM) or as preterm prelabor rupture of membranes (PPROM) impacts the efficacy of cervical pessary or vaginal progesterone for prevention of sPTB in pregnant women with short cervix on transvaginal ultrasound. METHODS: This was a retrospective cohort study of asymptomatic high-risk singleton pregnancies with a short cervix and history of sPTB, treated using Arabin pessary or vaginal progesterone for primary PTB prevention, conducted at four European hospitals. A log-rank test on Kaplan-Meier curves was used to assess the difference in performance of pessary and progesterone, according to history of PTL-IM or PPROM. Linear regression analysis was used to evaluate significant predictors of gestational age at delivery. RESULTS: Between 2008 and 2015, 170 women were treated with a pessary and 88 with vaginal progesterone. In women treated with a pessary, rate of sPTB < 34 weeks was 16% in those with a history of PTL-IM and 55% in those with a history of PPROM. In women treated with progesterone, rate of sPTB < 34 weeks was 13% in those with a history of PTL-IM and 21% in those with a history of PPROM. Treatment with a pessary resulted in earlier delivery in women with previous PPROM than in any other subgroup (P < 0.0001). Linear regression analysis showed a clear effect of PPROM history (P < 0.0001), combination of PPROM history and treatment (P = 0.0003) and cervical length (P = 0.0004) on gestational age at birth. CONCLUSIONS: Cervical pessary may be a less efficacious treatment option for women with previous PPROM; however, these results require prospective validation before change in practice is recommended. Phenotype of previous preterm birth may be an important risk predictor and treatment effect modifier; this information should be reported in future clinical trials. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Randomised Italian Sonography for occiput POSition Trial Ante vacuum (R.I.S.POS.T.A.).

OBJECTIVE: To assess whether sonographic diagnosis of fetal head position before instrumental vaginal delivery can reduce the risk of failed vacuum extraction and improve delivery outcome. METHODS: Randomised Italian Sonography for occiput POSition Trial Ante vacuum (R.I.S.POS.T.A.) is a randomized controlled trial of term (37 + 0 to 41 + 6 weeks' gestation) singleton pregnancies with cephalic presentation requiring instrumental delivery by vacuum extraction, which was conducted between April 2014 and June 2017 and involved 13 Italian maternity hospitals. Patients were randomized to assessment of fetal head position before attempted instrumental delivery by either vaginal examination (VE) alone or VE plus transabdominal sonography (TAS). Primary outcome was incidence of emergency Cesarean section due to failed vacuum extraction. A sample size of 653 women per group was planned to compare the primary outcome between the two groups. The sample size estimation was based on the hypothesis that the risk of failed vacuum delivery in the VE group would be 5% and that ultrasound assessment of fetal position prior to vacuum extraction would decrease this risk to 2%. RESULTS: On interim analysis, the trial was stopped for futility. During this period, 222 women were randomized and 221 were included in the final data analysis, of whom 132 (59.7%) were randomized to evaluation of fetal head position by VE only and 89 (40.3%) to assessment by VE plus TAS prior to vacuum extraction. No significant differences were observed between the two groups with respect to incidence of emergency Cesarean section due to failed instrumental delivery and other maternal and fetal outcomes. Women randomized to assessment by VE plus TAS showed higher incidence of non-occiput anterior position of the fetal head at randomization and lower incidence of incorrect diagnosis of occiput position compared with women undergoing assessment by VE alone. A higher rate of episiotomy was noted in the women undergoing both VE and TAS compared with those in the VE-only group. CONCLUSIONS: Our prematurely discontinued randomized controlled trial did not demonstrate any benefit in terms of reduced risk of failed instrumental delivery or maternal and fetal morbidity in women undergoing sonographic assessment of fetal head position prior to vacuum extraction. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study.

OBJECTIVE: In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals. METHODS: We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery. RESULTS: Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety-net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG-STV group, 51% of infants were delivered because of reduced STV. In the DV-p95 group, 34% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival. CONCLUSIONS: In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal study of computerized cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.

OBJECTIVES: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death. METHODS: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: Two-year survival without neurological impairment occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50th percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not. CONCLUSIONS: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Accuracy of ultrasound in antenatal diagnosis of placental attachment disorders.

OBJECTIVES: To evaluate the accuracy of ultrasound in the diagnosis of placenta accreta and its variants, and to assess the impact of prenatal diagnosis in our population. METHODS: A total of 314 women with placenta previa were enrolled prospectively and underwent transabdominal and transvaginal ultrasound examinations. An ultrasound diagnosis (grayscale and color/power Doppler) of placental attachment disorder (PAD) was based on the detection of at least two of the following ('two-criteria system'): loss/irregularity of the retroplacental clear zone, thinning/interruption of the uterine serosa-bladder wall interface, turbulent placental lacunae with high velocity flow, myometrial thickness < 1 mm, increased vascularity of the uterine serosa-bladder wall interface, loss of vascular arch parallel to the basal plate and/or irregular intraplacental vascularization. Definitive diagnosis was made at delivery by Cesarean section. Maternal outcome in cases diagnosed antenatally was compared with that in cases diagnosed at delivery. RESULTS: There were 37/314 cases of PAD (29 anterior and eight posterior). The two-criteria system identified 30 cases of placenta accreta, providing a sensitivity of 81.1% and specificity of 98.9%. When anterior and posterior placentae were considered separately, the detection rates of PAD were 89.7 and 50.0%, respectIvely. Maternal outcome was better in women with prenatal diagnosis of PAD, as seen by less blood loss and shorter hospitalization. CONCLUSIONS: Our data confirmed that grayscale and color Doppler ultrasound have good performance in the diagnosis of PAD and that prenatal diagnosis improves maternal outcome. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

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.

Vegan-vegetarian diets in pregnancy: danger or panacea? A systematic narrative review.

BACKGROUND: Although vegan-vegetarian diets are increasingly popular, no recent systematic reviews on vegan-vegetarian diets in pregnancy exist. OBJECTIVES: To review the literature on vegan-vegetarian diets and pregnancy outcomes. SEARCH STRATEGY: PubMed, Embase, and the Cochrane library were searched from inception to September 2013 for pregnancy and vegan or vegetarian Medical Subject Headings (MeSH) and free-text terms. SELECTION CRITERIA: Vegan or vegetarian diets in healthy pregnant women. We excluded case reports and papers analysing vegan-vegetarian diets in poverty and malnutrition. Searching, paper selection, and data extraction were performed in duplicate. DATA COLLECTION AND ANALYSIS: The high heterogeneity of the studies led to a narrative review. MAIN RESULTS: We obtained 262 full texts from 2329 references; 22 selected papers reporting maternal-fetal outcomes (13) and dietary deficiencies (nine) met the inclusion criteria. None of the studies reported an increase in severe adverse outcomes or in major malformations, except one report of increased hypospadias in infants of vegetarian mothers. Five studies reported vegetarian mothers had lower birthweight babies, yet two studies reported higher birthweights. The duration of pregnancy was available in six studies and was similar between vegan-vegetarians and omnivores. The nine heterogeneous studies on microelements and vitamins suggest vegan-vegetarian women may be at risk of vitamin B12 and iron deficiencies. AUTHOR'S CONCLUSIONS: The evidence on vegan-vegetarian diets in pregnancy is heterogeneous and scant. The lack of randomised studies prevents us from distinguishing the effects of diet from confounding factors. Within these limits, vegan-vegetarian diets may be considered safe in pregnancy, provided that attention is paid to vitamin and trace element requirements.

Transdermal clonidine in the treatment of severe hyperemesis. A pilot randomised control trial: CLONEMESI.

OBJECTIVE: To study the efficacy of transdermal clonidine in the treatment of severe refractory hyperemesis gravidarum (HG), the most severe illness of pregnancy. DESIGN: The study had a randomised, double -blind, placebo-controlled, cross-over design (RCT). SETTING: Single tertiary referral hospital after admission of patients. SAMPLE: Twelve women of gestational age 6-12 weeks and a major grade of HG clinical severity who were unresponsive to standard antiemetic treatment. METHODS: The patients were randomly treated with and without the active drug (5 mg patch) for two consecutive periods of 5 days. The patients were allocated to a random list to receive first placebo and then active drug or the other way round. Other antiemetic drugs were administered on a scheduled or as-needed basis. All patients received intravenous hydration and thiamine supplementation. MAIN OUTCOME MEASURES: Pregnancy Unique Quantification of Emesis (PUQE) and visual analog scale (VAS) clinical scores, positive morning urine ketonuria, number of doses of standard antiemetic drugs required, and number of days off intravenous therapy were compared in the two periods. RESULTS: Transdermal clonidine led to a significantly greater improvement compared with placebo of the primary (PUQE score P = 0.026 CI 0.43-3.24; VAS score P = 0.010 CI 2.17-12.83) and secondary outcome measures. A reduction of blood pressure was reported for systolic 6 mmHg P = 0.01 and diastolic 3 mmHg P = 0.055. CONCLUSIONS: This preliminary RCT demonstrates the efficacy of transdermal clonidine in the treatment of severe HG, leading to a significant reduction of symptoms and reducing the need for other supportive measures and medications.

Ultrasound methodology used to construct the fetal growth standards in the INTERGROWTH-21st Project.

A unified protocol is essential to ensure that fetal ultrasound measurements taken in multicentre research studies are accurate and reproducible. This paper describes the methodology used to take two-dimensional, ultrasound measurements in the longitudinal, fetal growth component of the INTERGROWTH-21(st) Project. These standardised methods should minimise the systematic errors associated with pooling data from different study sites. They represent a model for carrying out similar research studies in the future.

Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review.

BACKGROUND: Kidney diseases, which have a prevalence of 3% in women of childbearing age, are increasingly encountered in pregnancy. Glomerulonephritis may develop or flare up in pregnancy, and a differential diagnosis with pre-eclampsia may be impossible on clinical grounds. Use of kidney biopsy is controversial, but a systematic review has not been carried out to date. OBJECTIVES: To review the literature on kidney biopsy in pregnancy, with a focus on indications, risks and timing. SEARCH STRATEGY: Medline, Embase, CHINAL and the Cochrane Library were searched in September 2012, with 'pregnancy' and 'kidney biopsy' used as MESH and free terms, for the period 1980-2012. Results were filtered for 'human' if this option was available. SELECTION CRITERIA: Biopsies during pregnancy and within 2 months after delivery. Case reports (fewer than five cases) and kidney grafts were excluded. Paper selection was performed in duplicate. DATA COLLECTION AND ANALYSIS: Data were extracted in duplicate. The high heterogeneity in study design necessitated that the review be narrative, except for data on adverse events, which were analysed with regard to the timing of kidney biopsy. MAIN RESULTS: Of 949 references, 39 were selected, providing data on 243 biopsies in pregnancy and 1236 after delivery (timing was unclear in 106 women). The main aims of the studies were to define morphology in pre-eclampsia (23 studies), to carry out a risk-benefit analysis of kidney biopsy (11 studies), and to investigate pregnancy-related acute kidney injury (five studies). Four cases of major bleeding complications occurred at 23-26 weeks of gestation. Relevant complications were observed in 7% of women during pregnancy and 1% after delivery (P = 0.001). Kidney biopsy performed for the diagnosis of glomerulonephritis or pre-eclampsia led to therapeutic changes in 66% of cases. AUTHORS' CONCLUSIONS: The evidence on kidney biopsy in pregnancy is heterogeneous, but a significantly higher risk of complications (relative to postpartum biopsy) was found, with a possible peak at around 25 gestational weeks.

Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011.

OBJECTIVE: We used data from a national study of pregnant women with HIV to evaluate the prevalence of congenital abnormalities in newborns from women with HIV infection. DESIGN: Observational study. SETTING: University and hospital clinics. POPULATION: Pregnant women with HIV exposed to antiretroviral treatment at any time during pregnancy. METHODS: The total prevalence of birth defects was assessed on live births, stillbirths, and elective terminations for fetal anomaly. The associations between potentially predictive variables and the occurrence of birth defects were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs) for exposed versus unexposed cases, calculated in univariate and multivariate logistic regression analyses. MAIN OUTCOME MEASURES: Birth defects, defined according to the Antiretroviral Pregnancy Registry criteria. RESULTS: A total of 1257 pregnancies with exposure at any time to antiretroviral therapy were evaluated. Forty-two cases with major defects were observed. The total prevalence was 3.2% (95% CI 1.9-4.5) for exposure to any antiretroviral drug during the first trimester (23 cases with defects) and 3.4% (95% CI 1.9-4.9) for no antiretroviral exposure during the first trimester (19 cases). No associations were found between major birth defects and first-trimester exposure to any antiretroviral treatment (OR 0.94, 95% CI 0.51-1.75), main drug classes (nucleoside reverse transcriptase inhibitors, OR 0.95, 95% CI 0.51-1.76; non-nucleoside reverse transcriptase inhibitors, OR 1.20, 95% CI 0.56-2.55; protease inhibitors, OR 0.92, 95% CI 0.43-1.95), and individual drugs, including efavirenz (prevalence for efavirenz, 2.5%). CONCLUSIONS: This study adds further support to the assumption that first-trimester exposure to antiretroviral treatment does not increase the risk of congenital abnormalities.

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

OBJECTIVES: 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. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.

NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.

Congenital diseases are increasingly being recognised in adults because of clinical mimicry, variable clinical picture or rarity of the disease; pregnancy is a valuable diagnostic occasion. The present case is the first report of an association report between NEMO syndrome (an acronym of the mutated, non-functioning gene, NF-kB essential modulator), a rare X-linked disease, characterised by developmental anomalies, immunodepression and skin lesions, and systemic lupus erythematosus (SLE). A 35-year-old patient affected by SLE sought clinical advice in the 8th week of gestation. The diagnosis of SLE dated back to the age of 24, when multisystemic manifestations (pleuropericarditis, weight loss, alopecia, skin involvement, joint pain, kidney involvement) were observed. She had been treated with steroids since 1999; immunosuppressive drugs had been added for short periods. Developmental anomalies were present, including oligodontia, retinal problems, anomalies of the corpus callosum and pes planovalgus. Family history included multiple miscarriages, dental malformations and oligodontia and skin blistering in the first months of life. On these bases, incontinentia pigmenti (IP; or NEMO syndrome) was diagnosed and confirmed by genetic testing. The NEMO gene is implicated in immune deficiencies as well as in autoimmune diseases. This report may suggest a role for NF-kB essential modulator in the pathogenesis of SLE, in the context of the complex immunologic deficiencies increasingly associated with autoimmune diseases.

Expression patterns of two serine protease HtrA1 forms in human placentas complicated by preeclampsia with and without intrauterine growth restriction.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that have in common abnormal placental implantation, a marked proliferation of villous cytotrophoblastic cells and focal necrosis of the syncytiotrophoblast. Several studies show an ischemic placenta with a high-resistance vasculature, which cannot deliver an adequate blood supply to the feto-placental unit. The cause of PE is a matter of debate, but recently studies in mice suggest that the primary feto-placental lesions are sufficient to initiate the disease. HtrA1, a member of the family of HtrA proteins, is a secreted multidomain protein with serine protease activity. It is expressed in first and third trimester of gestation. In specimens from the first trimester of gestation, immunostaining for HtrA1 is generally found in both layers of villous trophoblast, syncytiotrophoblast and cytotrophoblast. Cytoplasm of extravillous trophoblast and extracellular matrix of cell islands and cell columns are labeled for HtrA1. Specimens from third trimester of gestation show a more intense positivity for HtrA1 in the syncytiotrophoblast than in cytotrophoblast. The extravillous trophoblast and the decidual cells, is positive for HtrA1. The purpose of this study is to investigate the expression pattern of HtrA1 in placentas from PE without IUGR (maternal PE) and with IUGR (fetal PE) by quantitative western blotting and immunohistochemistry. By quantitative western blotting analysis we observed a significant upregulation of approximately 30 kDa HtrA1 form in PE. Differently, we detected a significant total HtrA1 down-regulation in PE-IUGR. Moreover, immunostaining for HtrA1 was positive in the villous trophoblast, in the syncytial knots and irregularly in the fetal vessel walls in PE placentas while immunostaining for HtrA1was present particularly in the syncytial knots in PE-IUGR placentas. In conclusion, we suggest that the approximately 30 kDa HtrA1 form can be correlated to maternal PE while that the significant down-regulation of total HtrA1 can be correlated to placental PE. These HtrA1 alterations could be considered as possible markers to discriminate placental PE from maternal PE.

Evidence for a role of TGF-beta1 in the expression and regulation of alpha-SMA in fetal growth restricted placentae.

There is evidence that alpha-smooth muscle actin (alpha-SMA) is a protein that plays a pivotal role in the production of contractile forces and it is induced by transforming growth factor-beta1 (TGF-beta1). We have analysed the expression of alpha-SMA, TGF-beta1, its receptor RI and the activator phospho-Smad2 in (a) fetal growth restriction pre-eclamptic placentae characterised by early onset and absence of end diastolic velocities in the umbilical arteries (FGR-AED) and (b) control placentae accurately matched for gestational age. The study was performed by immunohistochemical, quantitative Western blotting, ELISA, RT-PCR and in vitro analyses. We found that TGF-beta1 stimulates alpha-SMA production in chorionic villi cultured in vitro. In addition, we observed that in vivo TGF-beta1 concentration is significantly higher in FGR-AED placental samples than in control placentae and that this growth factor could have a paracrine action on villous stroma myofibroblasts expressing TGF-beta1 receptors and phospho-Smad2. Indeed, we report that alpha-SMA undergoes a redistribution in FGR-AED placental villous tree, i.e. we show that alpha-SMA is enhanced in medium and small stem villi and significantly decreased in the peripheral villi. Our data allow us to consider TGF-beta1 and alpha-SMA as key molecules related to FGR-AED placental villous tree phenotypic changes responsible for increased impedance to blood flow observable in this pathology.

A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia.

Pre-eclampsia is a serious disorder of human pregnancy, characterized by decreased utero-placental perfusion and increased trophoblast cell death. Presently, the mechanisms regulating trophoblast cell death in pre-eclampsia are not fully elucidated. Herein, we have identified a novel Mtd/Bok splice isoform (Mtd-P) resulting from exon-II skipping. Mtd-P expression was unique to early-onset severe pre-eclamptic placentae as assessed by quantitative real-time-PCR and immunoblotting. Mtd-P overexpression in cell lines (BeWo: cytotrophoblast-derived; and CHO: ovary-derived) resulted in increased apoptotic cell death as assessed by caspase-3 cleavage, internucleosomal DNA laddering and mitochondrial depolarization. Moreover, Mtd-P expression increased under conditions of low oxygenation/oxidative stress in human villous explants. Antisense knockdown of Mtd under conditions of oxidative stress resulted in decreased caspase-3 cleavage. We conclude that under conditions of reduced oxygenation/oxidative stress, Mtd-P causes trophoblast cell death in pre-eclampsia and hence may contribute to the molecular events leading to the clinical manifestations of this disease.

Fetal midgut volvulus: report of eight cases.

OBJECTIVE: To evaluate whether prenatal diagnosis of intestinal midgut volvulus (a rare condition due to the small bowel loops twisting) can improve the prognosis of the newborns. METHODS: In our Prenatal Diagnosis Center, eight cases of intestinal volvulus observed between 2007 and 2014 were retrospectively considered. Ultrasonographic signs can be direct and specific (whirlpool sign, coffee bean sign) or indirect and non-specific (abdominal mass, dilated bowel loops, pseudocysts, ascites, polyhydramnios). RESULTS: Prenatal diagnosis was performed at 20-34 weeks of gestation. All newborns were exposed to an emergency surgery: the major complication was due to cystic fibrosis. CONCLUSIONS: An early suspicion of intestinal volvulus allows the clinician to refer the patient to a tertiary center so to confirm the diagnosis and perform an appropriate follow-up in order to identify the proper time of delivery. The prognosis of the babies with prenatal intestinal volvulus depends on the length of the segment involved, on the level of intestinal obstruction, on the presence of meconium peritonitis and on the gestational age at birth. Our experience, according with the literature, suggests that ascites and absence of abdominal peristalsis are ultrasonographic signs that, in the third trimester of pregnancy, correctly lead to an immediate delivery intervention.