Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

Human Umbilical Cord Mesenchymal Stem Cell-Based in vitro Model for Neurotoxicity Testing.

Neurotoxicity (NT) testing for regulatory purposes is based on in vivo animal testing. There is general consensus, however, about the need for the development of alternative methodologies to allow researchers to more rapidly and cost effectively screen large numbers of chemicals for their potential to cause NT, or to investigate their mode of action. In vitro assays are considered an important source of information for making regulatory decisions, and human cell-based systems are recommended as one of the most relevant models in toxicity testing, to reduce uncertainty in the extrapolation of results from animal-based models. Human neuronal models range from various neuroblastoma cell lines to stem cell-derived systems, including those derived from mesenchymal stem/stromal cells (hMSC). hMSCs exhibit numerous advantages, including the fact that they can be obtained in high yield from healthy human adult tissues, can be cultured with a minimal laboratory setup and without genetic manipulations, are able of continuous and repeated self-renewal, are nontumorigenic, and can form large populations of stably differentiated cells representative of different tissues, including neuronal cells. hMSCs derived from human umbilical cord (hUC) in particular possess several prominent advantages, including a painless, non-invasive, and ethically acceptable collection procedure, simple and convenient preparation, and high proliferation capacity. In addition, hMSCs can be efficiently differentiated into neuron-like cells (hNLCs), which can then be used for the assessment of neuronal toxicity of potential neurotoxic compounds in humans. Here, we describe a step-by-step procedure to use hMSCs from the umbilical cord for in vitro neurotoxicity testing. First, we describe how to isolate, amplify, and store hMSCs derived from the umbilical cord. We then outline the steps to transdifferentiate these cells into hNLCs, and then use the hNLCs for neurotoxicity testing by employing multiple common cytotoxicity assays after treatment with test compounds. The approach follows the most updated guidance on using human cell-based systems. These protocols will allow investigators to implement an alternative system for obtaining primary NLCs of human origin, and support advancement in neurotoxicity research. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Isolation and maintenance of human mesenchymal stem/stromal cells (hMSCs) obtained from the umbilical cord lining membrane Basic Protocol 2: Transdifferentiation of hMSCs into neuron-like cells (hNLCs) and basic neurotoxicity assessment.

Is a tailored strategy using proton beam radiotherapy for reirradiation advantageous for elderly women? A case report.

BACKGROUND: The management of primary or recurrent vaginal tumours in an aging population is challenging for gynecologic and radiation oncologists. In patients unsuited for surgery and already irradiated on the pelvis, proton beam radiotherapy may be worthwhile due to its ballistic advantages. CASE REPORT: We report the case of an 80-year-old woman with a squamous cell carcinoma of the vagina after a history of pelvic radiation and vaginal brachytherapy delivered for a previous endometrial adenocarcinoma. She received proton beam radiotherapy with a complete response after 12 months and mild toxicity. CONCLUSIONS: The complexity of reirradiation management in the frail and elderly population requires attention. Efforts should be focused on maintaining autonomy and quality of life in order to improve adherence and clinical compliance to the treatment. In the era of the tailored approach, hadrontherapy can play an important role to minimize toxicity, obtain good local control, and reduce the overall treatment time.

Endometrial Cancer: When Upfront Surgery Is Not an Option.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.

In vitro toxicity screening of magnetite nanoparticles by applying mesenchymal stem cells derived from human umbilical cord lining.

Despite the growing interest in nanoparticles (NPs), their toxicity has not yet been defined and the development of new strategies and predictive models are required. Human stem cells (SCs) offer a promising and innovative cell-based model. Among SCs, mesenchymal SCs (MSCs) derived from cord lining membrane (CL) may represent a new species-specific tool for establishing efficient platforms for primary screening and toxicity/safety testing of NPs. Superparamagnetic iron oxide NPs, including magnetite (Fe3 O4 NPs), have aroused great public health and scientific concerns despite their extensive uses. In this study, CL-MSCs were characterized and applied for in vitro toxicity screening of Fe3 O4 NPs. Cytotoxicity, internalization/uptake, differentiation and proliferative capacity were evaluated after exposure to different Fe3 O4 NP concentrations. Data were compared with those obtained from bone marrow (BM)-MSCs. We observed, at early passages (P3), that: (1) cytotoxicity occurred at 10 µg/mL in CL-MSCs and 100 µg/mL in BM-MSCs (no differences in toxicity, between CL- and BM-MSCs, were observed at higher dosage, 100-300 µg/mL); (2) cell density decrease and monolayer features loss were affected at ≥50 µg/mL in CL-MSCs only; and (3) NP uptake was concentration-dependent in both MSCs. After 100 µg/mL Fe3 O4 NP exposures, the capacity of proliferation was decreased (P5-P9) in CL-MSCs without morphology alteration. Moreover, a progressive decrease of intracellular Fe3 O4 NPs was observed over culture time. Antigen surface expression and multilineage differentiation were not influenced. These findings suggest that CL-MSCs could be used as a reliable cell-based model for Fe3 O4 NP toxicity screening evaluation and support the use of this approach for improving the confidence degree on the safety of NPs to predict health outcomes.

Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure.

Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 astrocyte- and SH-SY5Y neuronal-like cells, and optimized in combination with standard assays (viability readout and cell morphology) to test neurotoxic effects caused by Fe3O4NPs, as NP-model, after short- (24­48 h; 1­100µg/ml) and long-term repeated exposure (30days; 0.1­25µg/ml). Short-term exposure of 3D-spheroids to Fe3O4NP induced cytotoxicity at 10 µg/mL in astrocytes and 25 µg/mL neurons. After long-term repeated dose regimen, spheroids showed concentration- and time-dependent cell mortality at 10 µg/mL for D384 and 0.5 µg/mL for SH-SY5Y, indicating a higher susceptibility of neurons than astrocytes. Both spheroid types displayed cell disaggregation after the first week of treatment at ≥0.1 µg/mL and becoming considerably evident at higher concentrations and over time. Recreating the 3D-spatial environment of the CNS allows cells to behave in vitro more closely to the in vivo situations, therefore providing a model that can be used as a stand-alone test or as a part of integrated testing strategies. These models could drive an improvement in the species-relevant predictivity of toxicity testing.

Conditioned medium from human amniotic mesenchymal stromal cells limits infarct size and enhances angiogenesis.

The paracrine properties of human amniotic membrane-derived mesenchymal stromal cells (hAMCs) have not been fully elucidated. The goal of the present study was to elucidate whether hAMCs can exert beneficial paracrine effects on infarcted rat hearts, in particular through cardioprotection and angiogenesis. Moreover, we aimed to identify the putative active paracrine mediators. hAMCs were isolated, expanded, and characterized. In vitro, conditioned medium from hAMC (hAMC-CM) exhibited cytoprotective and proangiogenic properties. In vivo, injection of hAMC-CM into infarcted rat hearts limited the infarct size, reduced cardiomyocyte apoptosis and ventricular remodeling, and strongly promoted capillary formation at the infarct border zone. Gene array analysis led to the identification of 32 genes encoding for the secreted factors overexpressed by hAMCs. Among these, midkine and secreted protein acidic and rich in cysteine were also upregulated at the protein level. Furthermore, high amounts of several proangiogenic factors were detected in hAMC-CM by cytokine array. Our results strongly support the concept that the administration of hAMC-CM favors the repair process after acute myocardial infarction.

Multiple human papillomavirus infection with or without type 16 and risk of cervical intraepithelial neoplasia among women with cervical cytological abnormalities.

PURPOSE: To evaluate the impact of multiple human papillomavirus (HPV) infections on the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in subjects with cervical cytological abnormalities. METHODS: A cross-sectional study of 3,842 women attending a colposcopy service was carried out. Genotyping of 18 high-risk, seven low-risk, and two undefined-risk HPVs was carried out by the INNO-LiPA genotyping system. RESULTS: The final colposcopic/pathological diagnoses were as follows: 1,933 (50.3 %) subjects were negative; 1,041 (27.1 %) CIN1; 280 (7.3 %) CIN2; 520 (13.5 %) CIN3; and 68 (1.8 %) invasive cervical cancer. The prevalence of HPV infection was 75.8 % (2,911/3,842), whereas multiple HPVs were detected in 34.5 % of HPV-positive subjects (2,255/3,842). The adjusted risks of CIN3+ in the group with multiple compared to the group with single infection were 2.31 (95 % CI = 1.54-3.47), among HPV16-positive women, and 3.25 (95 % CI = 2.29-4.61, p = 0.21 compared with HPV16-positive subjects), in HPV16-negative subjects. Out of a total of 1,285 subjects with mild lesions, followed up for a median of 16.1 months (interquartile range = 8.9-36.8), the rate of progression to CIN2-3 was 0.6 % (5/541) among subjects negative or with low-risk HPVs, 1.7 % (8/463) among those with single high-risk HPV, and 5 % (14/281, p < 0.001 compared with HPV-negative/low-risk HPV and p = 0.038 compared with single high-risk HPV) among those with multiple high-risk HPVs. CONCLUSIONS: Among women with cervical cytological abnormalities, infection by multiple high-risk HPVs increased the risk of CIN3+ in both HPV16-positive and HPV16-negative subjects. These findings suggest a potential synergistic interaction between high-risk HPVs, favoring the progression of CIN lesions.

Untypable human papillomavirus infection and risk of cervical intraepithelial neoplasia among women with abnormal cervical cytology.

The risk of cervical intraepithelial neoplasia and/or invasive cervical cancer associated with untypable human papillomavirus (HPV) infections has been not investigated fully. HPV infection caused by 18 high-risk and 7 low-risk genotypes as detected by the INNO-LIPA genotyping system, was investigated in 4,258 women with abnormal Pap smear referred to a colposcopic service. The prevalence of HPV infection was 76.1%. Rates of cervical intraepithelial neoplasia grade 3+ were 0.88% (9/1,017) in HPV-negative subjects, 1.8% (7/380) in subjects with untypable HPV infection, 3.2% (11/343) in subjects with single/multiple low-risk types, 28.3% (201/709) in subjects with multiple low and high-risk types, 15.2% (162/1,069) in subjects with single high-risk types, and 31.2% (229/733) in those with multiple high-risk types. Compared to women without any HPV infection, the odds ratios of cervical intraepithelial neoplasia grade 2+ or grade 3+ in subjects with untypable or low-risk HPV genotypes were 5.73 (95% CI = 2.79-11.78) and 12.4 (95% CI = 6.31-24.5, P = 0.014 compared to untypable) and 3.1 (95% CI = 1.11-8.16) and 7.1 (95% CI = 2.9-17.2, P = 0.07 compared to untypable), respectively. In the subgroup of subjects with cervical intraepithelial neoplasia grade 1 or negative colposcopy/biopsy, the progression to cervical intraepithelial neoplasia grade 2+ at follow-up (median 25 months, range 6-70) was 2% (14/684), 3.4% (7/205), and 5.6% (11/195, P = 0.04 compared to negative) among negative, untypable, and low-risk HPV infection, respectively. The risk of cervical intraepithelial neoplasia associated with untypable HPV infection was higher than that recorded among uninfected women, but lower than the risk associated with low- or high-risk HPV genotypes.

HIV shedding in cervico-vaginal secretions in pregnant women.

OBJECTIVE: The purpose of this study was to evaluate the presence of HIV-1 in cervico-vaginal secretions of pregnant as compared to non-pregnant HIV-seropositive women. PATIENTS AND METHODS: We compared 43 known HIV seropositive pregnant patients versus 241 age-matched (± 2 years) control non-pregnant HIV-seropositive subjects. In pregnant patients blood and cervico-vaginal samples were obtained during each trimester of pregnancy. In control subjects the same samples were obtained at enrolment. HIV-1 RNA was measured in plasma; proviral HIV-1 DNA, cell-associated and cell-free HIV-1 RNA in cervico-vaginal secretion by competitive polymerase chain reaction (cRT-PCR) and reverse transcriptase PCR. RESULTS: The genital shedding of HIV-DNA (22/43 as compared to 79/241, p = 0.02), and cell-free HIV-RNA detection (26/43 as compared to 72/241, p < .001) was more common in first-trimester pregnant than in non pregnant women. Pregnancy correlated with a significant positive trend in the cervico-vaginal load of HIV-DNA (Spearman Rho= 0.149, p= 0.012), and cell-free HIV-RNA (Spearman Rho= 0.253, p < .001), but not of HIV-RNA transcripts (Spearman Rho = 0.06, p= 0.31). After correction for potential confounders, first trimester pregnant women had increased rates of genital HIV- DNA (odds ratio = 1.94, 95% confidence interval = 1.01 3.78) and cell-free HIV-RNA (odds ratio = 4.07, 95% confidence interval = 1.97 8.41) detection compared to nonpregnant controls. CONCLUSION: The shedding of genital HIV was increased in pregnant compared to non pregnant subjects, even in patients with undetectable viremia. In this low-risk HIV-positive population the risks of vertical or horizontal transmissions should not be underestimated.

Low-dose combined oral contraceptive and cervicovaginal shedding of human immunodeficiency virus.

BACKGROUND: The role of low-dose oral contraceptives on HIV cervicovaginal shedding among HIV-positive women is controversial. STUDY DESIGN: We evaluated the effect of low-dose oral contraceptives on HIV cervicovaginal shedding in a cohort of 285 HIV-seropositive women followed for a median of 20 months. A sensitive, competitive polymerase chain reaction (cPCR) and a reverse transcription PCR (cRT-PCR) were applied for the quantification of HIV-associated and cell-free RNA and proviral DNA in cervicovaginal cells, as well as HIV-RNA in plasma. RESULTS: In multivariable logistic generalized estimating equations, plasma viral load >100 copies/mL (OR=1.81, 95% CI=1.3-2.53) and bacterial vaginosis (OR=1.49, 95% CI=1.1-2.02) were associated with an increased risk of HIV-1 DNA shedding, whereas current use of oral contraceptive was associated with a reduced risk (OR=0.55, 95% CI=0.33-0.92). Oral contraceptives were also associated with a reduction of risk (OR=0.38, 95% CI=0.21-0.69) of cell-associated but not cell-free HIV-1 RNA. CONCLUSIONS: In HIV-positive women with low levels of HIV viremia, low-dose oral contraceptives were associated with a modest but significant reduction of HIV-1 DNA and cell-associated HIV-1 RNA genital shedding.

Decreased mitochondrial DNA content in subcutaneous fat from HIV-infected women taking antiretroviral therapy as measured at delivery.

BACKGROUND: Increasing numbers of pregnant HIV-positive women are receiving combination antiretroviral regimens for preventing mother-to-child virus transmission or for treating the infection itself. Several studies have demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by several mechanisms, including depletion of mitochondrial DNA (mtDNA). By the quantification of mtDNA levels, we studied mitochondrial toxicity in HIV-positive women at delivery and the possible correlations with antiretroviral regimens, viroimmunological and metabolic parameters. METHODS: We analysed 68 HIV-positive women enrolled in the Italian Prospective Cohort Study on Efficacy and Toxicity of Antiretroviral in Pregnancy (TARGET Study); all were taking ≥1 NRTI. We quantified mtDNA copies per cell in subcutaneous fat samples collected during delivery. At the 3rd, 6th and 9th month of pregnancy, we collected data concerning CD4(+) T-cell count, plasma HIV RNA, total and high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and triglycerides. As a control, we analysed mtDNA levels in abdominal subcutaneous fat samples from 23 HIV-seronegative women at delivery. RESULTS: mtDNA content was significantly lower in HIV-infected women when compared with HIV-negative controls. mtDNA content varied independently from viroimmunological, lipid and glucose parameters at the different months, with the exceptions of triglycerides at the 9th month and of HDL at the 6th month of pregnancy. CONCLUSIONS: In subcutaneous tissue from women taking NRTI-based antiretroviral regimens, we observed a significant decrease of mtDNA content, compared with uninfected women not on antiviral treatment. Moreover, a significant correlation was noted between mtDNA content and HDL cholesterol and triglycerides.

Clustering patterns of human papillomavirus genotypes in multiple infections.

Many human papillomavirus (HPV) infections are sustained by multiple viral genotypes whose effect on the risk of cervical intraepithelial neoplasia (CIN) is unknown. The study investigated whether specific HPV types or species may affect the likelihood of multiple infections and have a clustered distribution in a consecutive series of 681 women with a histological diagnosis of CIN. HPV typing was performed by the SPF(10)-LIPA assay; associations were evaluated by loglinear analysis of multiple contingency tables after stratification by age and CIN grade. HPV prevalence was 99.4% with a 72.1% rate of coinfection. The risk of coinfection was higher for types 6, 11, 16, 18, 31, 33, 51, 52, 56. Significant interactions were found for species A7-A9-A10, A6-A9 and A7-A10. Coinfection by types 31-35-56, 16-51-52, 16-18 and 51-52 was more frequent than expected. Interactions between viral species and HPV 16-18 were maintained among CIN1, whereas interactions of 16-51-52 and 31-51-56 were significant only in CIN> or =2. Interactions between species and types were lost among women younger than 32 years. Significant clustering of HPV types and species occurs among women with CIN. This has implications for the assessment of the oncogenic potential and the prevention of HPV infections.

Infant sex, obstetric risk factors, and 2-year neurodevelopmental outcome among preterm infants.

AIM: To evaluate the effect of the interaction between fetal sex and obstetric variables on the risk of neurodevelopmental impairment among preterm infants. METHOD: A cohort study of 394 male and 360 female surviving infants born at 24 to 33 completed weeks of gestational age. Neurological examination and cognitive assessment of the infants (Bayley Scales of Infant Development) were performed at 2 years corrected age. RESULTS: Mean gestational age was 30.4 weeks (SD 2.4). Rates of mild and moderate-to-severe neurodevelopmental impairment were 14.6% (110/754) and 7% (53/754) respectively. In logistic analysis, male sex was associated with an increased risk of neurodevelopmental impairment (odds ratio 1.8, 95% confidence interval 1.21-2.68) compared with females. The excess risk of neurodevelopmental impairment associated with male sex was higher among preeclamptic than normotensive pregnancies (p for interaction=0.004), among infants who were either small for gestational age or delivered to a mother with preeclampsia (p for interaction=0.001) and in iatrogenic as opposed to spontaneous preterm birth or preterm premature rupture of membranes (p for interaction=0.035). INTERPRETATION: The excess risk of neurodevelopmental impairment associated with male sex among preterm infants is modulated by obstetric risk factors.

Cervical infections by multiple human papillomavirus (HPV) genotypes: Prevalence and impact on the risk of precancerous epithelial lesions.

A large proportion of human papillomavirus (HPV) infections is sustained by multiple genotypes. The effect of multiple infections on the risk of cervical intraepithelial neoplasia (CIN) and the potential efficacy of vaccine on these infections are controversial. We performed viral typing by SFP(10)-LIPA on a consecutive series of 1,323 women undergoing colposcopy, 69% of whom had cervical biopsy, and correlated CIN severity with the type and number of HPVs. Overall prevalence of HPV-DNA was 68.9%, 97.3% in CIN1, and 98.1% in CIN>/=2. HPV positivity correlated with younger age (35.9 vs. 37.3 years, P = 0.026) and history of CIN (P < 0.001). Multiple types were detected in 44.2% of cases, including 63.1% CIN1 and 80.8% CIN>/=2. Twenty-three different types were detected, HPV-16, 31 and 52 being the most frequent. Infections by HPV-6, 11, 16, or 18 occurred in 59.4% of CIN1 and 71.3% of CIN>/=2. Number of viral types and class of oncogenic risk were linearly correlated with CIN severity (P < 0.0001) by univariate and multivariate analyses controlling for age and history of CIN. The effect of the number of HPV types was maintained after exclusion from the model of infections by HPV-6, 11, 16, and 18. Frequency, distribution, and clinical correlates of multiple HPV infections highlight the importance of assessing individual types in the management and the prediction of outcome of women with abnormal baseline cytology and point to potential limitations in current vaccine strategies.

Multiple human papillomavirus infection and high grade cervical intraepithelial neoplasia among women with cytological diagnosis of atypical squamous cells of undetermined significance or low grade squamous intraepithelial lesions.

OBJECTIVE: To evaluate the effect of multiple human papillomavirus (HPV) infection on the prevalence of cervical intraepithelial neoplasia (CIN) among women undergoing colposcopy following a cytological diagnosis of atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesions (LSIL). METHODS: HPV type-specific sequences of 15 high-risk and 10 low risk types were detected by the line probe, INNO-LiPA HPV genotyping assay before colposcopic examination and targeted biopsies. Multinomial logistic regression was used to evaluate the effect of multiple infection on pathologic outcome adjusting for confounders. RESULTS: The prevalence of HPV infection in the 1218 women enrolled was 69.9% (851/1218). HPV 16 (37.4%), 31 (26.1%), 51 (17.4%), 52 (15.7%) and 18 (14%) were the commonest viral types identified. Overall, the rates of multiple infection were 22.5% (153/680) among subjects with negative colposcopy/biopsy, 63.6% (218/343) and 79.5% (155/195) among those with CIN 1 and CIN>or=2, respectively (p for trend <.001). The corresponding rates among subjects uninfected by HPV 16 or 18 were 13.5% (77/572), 57.4% (112/195) and 62% (48/77), respectively (p for trend <.001). In multinomial logistic regression, the odds ratio of CIN>or=2 in multiple high risk as compared to single high risk HPV infection was 4.33 (95% confidence intervals=2.32-7.14) in the overall population and 2.76 (95% confidence intervals=1.36-5.59) among women uninfected by HPV 16 or 18. CONCLUSIONS: Multiple HPV infection is a significant risk factor for CIN>or=2 among women undergoing colposcopy because of ASCUS/LSIL.

Prognostic significance of the interaction between abnormal umbilical and middle cerebral artery Doppler velocimetry in pregnancies complicated by fetal growth restriction.

OBJECTIVE: To evaluate the prognostic significance of the interaction between umbilical artery (UA) and middle cerebral artery (MCA) Doppler measurements in pregnancies complicated by fetal growth restriction (FGR). DESIGN: Cohort study. SETTING: Third-level Perinatology Center in Northern Italy. POPULATION: A study of 184 singleton pregnancies at 24-35 weeks' gestational age complicated by FGR and abnormal UA Doppler measurements. METHODS: FGR was diagnosed by serial ultrasonograms. Neonatal brain damage was defined as the presence of cystic leukomalacia or grade III-IV intraventricular hemorrhage. MAIN OUTCOME MEASURES: Perinatal death and neonatal brain damage. RESULTS: The prevalence of fetal/neonatal death or brain damage was 18.2% (16/88) in pregnancies with UA absent/reversed diastolic flow and 4.2% (4/96) in those with increased UA Doppler pulsatility. Stepwise logistic regression identified decreasing gestational age (OR=1.75, 95% confidence interval, CI=1.35-2.22) and absent/reversed UA blood flow (OR=3.34, 95% CI=1.1-10.9) as predictors of fetal/neonatal death or brain damage. A MCA pulsatility index below the 10th percentile was a risk factor for fetal/neonatal death or brain damage among women with absent/reversed UA diastolic flow (14/53 as compared to 2/35; OR=5.9, CI =1.4-40.3) but not in pregnancies with forward velocity (1/33 as compared to 3/63; OR=0.63, 95% CI=0.02-6.13, Synergy index=27.7, p=0.007). CONCLUSIONS: In pregnancies complicated by FGR and absent/reversed UA end diastolic flow, vasodilatation of the MCA is a risk factor for neonatal death or brain damage.