A história obstétrica de gestantes com trombofilias hereditárias / Obstetric history of pregnant women with hereditary thrombophilias

Introdução: A doença tromboembólica venosa e as complicações obstétricas resultantes do tromboembolismo placentário são as principais causas de morbidade e mortalidade materna e fetal. Pode-se dizer que a gravidez é um fator independente para o desenvolvimento de trombose, já que seu risco é de 5 a 6 vezes maior em mulheres grávidas quando comparadas a não grávidas, sendo mais elevado após o parto. Métodos: Trata-se de uma coorte histórica, onde foram estudadas pacientes atendidas no Serviço de Obstetrícia da Universidade Federal de Juiz de Fora (expostos=n=70 pacientes) e na Faculdade de Medicina de Barbacena (não expostos=n=74 pacientes). As pacientes foram divididas em dois grupos: Grupo 1 = pacientes com alguma trombofilia identificada (expostos) através das dosagens de proteína S, proteína C, homocisteína, antitrombina III, mutação da MTHFR, mutação da protrombina e do fator V de Leiden; e Grupo 2 = pacientes do serviço de baixo risco obstétrico. Resultados: Houve associação entre trombofilia e aborto prévio, bem como trombofilia e morte fetal prévia (p<0,05). O tipo de trombofilia que foi associada a abortamento prévio foi o déficit da proteína S. A mutação da MTHFR foi associada aos antecedentes de HELLP síndrome (p=0,03; x2 =4,2) e de pré-eclâmpsia (p=0,03; X2 =4,5) quando em homozigotia mutante. A homozigotia para a MTHFR foi também associada às médias de homocisteína, de forma que as homozigotas eram aquelas que apresentavam a maior dosagem de homocisteína (p=0,01; X2 =5,8; X= 27,2 ± 41,2 vs. 12,62 ± 19,0). Conclusão: As trombofilias hereditárias podem estar associadas a mau desfecho obstétrico e devem ser valorizadas na clínica obstétrica. (AU)

Introduction: Venous thromboembolic disease and obstetric complications resulting from placental thromboembolism are the main causes of maternal and fetal morbidity and mortality. Pregnancy is considered an independent factor for the development of thrombosis, as its risk is 5 to 6 times greater in pregnant women when compared to non-pregnant women, being even higher after childbirth. Methods: This historical cohort included patients seen at the Obstetrics Service of Federal University of Juiz de Fora (exposed patients, n = 70) and at the School of Medicine of Barbacena (unexposed patients, n = 74). The patients were divided into two groups: Group 1 consisted of patients with some thrombophilia identified through measurement of protein S, protein C, homocysteine, antithrombin III, MTHFR mutation, prothrombin and factor V Leiden mutations; and Group 2 consisted of patients from the low obstetric risk service. Results: There was an association between thrombophilia and previous abortion, as well as thrombophilia and previous fetal death (p < 0.05). MTHFR mutation was associated with history of HELLP syndrome (p = 0.03; x2 = 4.2) and preeclampsia (p = 0.03; x2 = 4.5) when in homozygous mutation. Homozygous MTHFR was also associated with mean homocysteine levels, so that homozygotes were those with highest homocysteine levels (p = 0.01; x2 = 5.8; x = 27.2 ± 41.2 vs. 12.62 ± 19.0). Conclusions: Hereditary thrombophilias may be associated with poor obstetric outcome and should be valued at clinical obstetrics. (AU)

Revealed versus concealed criteria for placental insufficiency in an unselected obstetric population in late pregnancy (RATIO37): randomised controlled trial study protocol.

INTRODUCTION: Fetal growth restriction (FGR) affects 5%-10% of all pregnancies, contributing to 30%-50% of stillbirths. Unfortunately, growth restriction often is not detected antenatally. The last weeks of pregnancy are critical for preventing stillbirth among babies with FGR because there is a pronounced increase in stillbirths among growth-restricted fetuses after 37 weeks of pregnancy. Here we present a protocol (V.1, 23 May 2016) for the RATIO37 trial, which evaluates an integrated strategy for accurately selecting at-risk fetuses for delivery at term. The protocol is based on the combination of fetal biometry and cerebroplacental ratio (CPR). The primary objective is to reduce stillbirth rates. The secondary aims are to detect low birth weights and adverse perinatal outcomes. METHODS AND ANALYSIS: The study is designed as multicentre (Spain, Chile, Mexico,Czech Republic and Israel), open-label, randomised trial with parallel groups. Singleton pregnancies will be invited to participate after routine second-trimester ultrasound scan (19+0-22+6 weeks of gestation), and participants will be randomly allocated to receive revealed or concealed CPR evaluation. Then, a routine ultrasound and Doppler scan will be performed at 36+0-37+6 weeks. Sociodemographic and clinical data will be collected at enrolment. Ultrasound and Doppler variables will be recorded at 36+0-37+6 weeks of pregnancy. Perinatal outcomes will be recorded after delivery. Univariate (with estimated effect size and its 95% CI) and multivariate (mixed-effects logistic regression) comparisons between groups will be performed. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 23May 2016. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT02907242; pre-results.

Monitoring of Hemostasis and Management of Anticoagulant Thromboprophylaxis in Pregnant Women with Increased Risk of Fetal Loss.

Physiological prothrombotic changes during pregnancy and the postpartum period, along with other preexisting maternal risk factors, increase the risk of both venous thromboembolism (VTE) and adverse pregnancy outcomes. Pregnancy complications that develop due to placental insufficiency as a result of inappropriate activation of coagulation are present in more than 5% of pregnancies and can contribute to significant maternal morbidity and mortality. Therefore, anticoagulant prophylaxis in women with congenital and acquired thrombophilic conditions should be actively considered. According to the Guidelines of American College of Chest Physicians, the use of low-molecular-weight heparin is suggested for prophylaxis of VTE and pregnancy complications in high-risk pregnant women. However, personalized refinements of such thromboprophylaxis remains unspecified, despite the necessity of better targeted recommendations for life-threatening conditions. We, therefore, review the possibilities of longitudinal monitoring and comprehensive assessment of changes in hemostasis in the group of high-risk pregnant women, which can then be used for early prediction and individualization of the optimal anticoagulant thromboprophylaxis of pregnancy complications. Simultaneously, we present our single-center experience with such monitoring and our first series of results.

Broccoli sprout supplementation during pregnancy prevents brain injury in the newborn rat following placental insufficiency.

Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200mg of dried BrSp from E15 - postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p<0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p<0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency.

[Prognostic factors of perinatal short-term outcome in severe placental insufficiency using Doppler sonography to assess end-diastolic absent and reverse blood flow in umbilical arteries]. / Prognosefaktoren des perinatalen Kurzzeitergebnisses bei schwerer Plazentainsuffizienz mit dopplersonografisch enddiastolischem Null- und Rückfluss in der Art. umbilicalis.

Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high-risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications.

Decrease of the incidence of renin-angiotensin-system inhibitor induced oligohydramnios-sequence in Germany in 2011.

AIM: to assess whether the incidence of angiotensin II-receptor type 1 antagonist (AT1-antagonist)­ or ACE-inhibitor induced cases of oligohydramnios sequence (OHS) in 2011 was reduced after intensive alerts as to the causal association between AT1-antagonist /ACE-inhibitor and OHS in the German medical literature. METHOD: 3 sources of information were used: A nationwide active surveillance of OHS in German paediatric hospitals (ESPED); Embryotox, (Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy) and screening of pubmed (AT1-antagonist/ACE-inhibitor induced OHS). RESULTS: 45 cases of OHS were identified, no case due to maternal AT1-antagonist/ACE-inhibitor treatment. Causes for OHS were: premature rupture of membranes (PPROM) (n = 28), congenital anomalies of fetal kidneys and urinary tract(CAKUT (n = 15), placental insufficiency (n = 1),unknown cause (n = 1). Mortality until discharge was 37.8 % (32.1 % PPROM, 57.1 % CAKUT). Embryotox identified 3 exposures to AT1-antagonists in pregnancy, no case was associated with OHS. The pubmed search did not identify any case of OHS related to AT1-antagonist/ACE-inhibitor in pregnancy in Germany in 2011. CONCLUSION: Treatment of pregnant women with ACE inhibitors or AT1-antagonists still occurs but no cases of AT1-antagonist- or ACE-inhibitor induced OHS were reported in 2011 in Germany most likely due to repeated published alerts underlining the importance of consequent education. OHS remains a serious condition with high mortality despite modern intensive care.

Fetal venous circulation in monochorionic twin pregnancies with placental insufficiency: prediction of acidemia at birth or intrauterine fetal death.

OBJECTIVES: To investigate fetal venous Doppler measurements in monochorionic twin pregnancies complicated by placental insufficiency and the relationship between fetal venous flow and acidemia at birth or intrauterine fetal death. METHODS: This was a prospective study of 18 monochorionic twin pregnancies with placental insufficiency. Inclusion criteria were monochorionic-diamniotic twin pregnancy, abnormal umbilical artery (UA) Doppler indices, intact membranes and absence of fetal congenital abnormalities. Cases of twin-to-twin transfusion syndrome were excluded. The following Doppler measurements were studied: UA pulsatility index (PI), ductus venosus PI, middle cerebral artery PI and peak systolic velocity, intra-abdominal umbilical vein (UV) time-averaged maximum velocity (TAMXV) and left portal vein (LPV) TAMXV. Doppler parameters were transformed into Z-scores (SD values from the mean) or multiples of the median according to normative references. RESULTS: UA pH < 7.20 occurred in nine (25.0%) neonates, pH < 7.15 in four (11.1%) and intrauterine death in four (11.1%) fetuses. The UV-TAMXV and LPV-TAMXV Z-scores were significantly lower in the group with pH < 7.20 or intrauterine fetal death (-1.79 vs -1.22, P = 0.006 and -2.26 vs -1.13, P = 0.04, respectively). In cases with pH < 7.15 or intrauterine fetal death, UV pulsations were more frequent (50.0% vs 10.7%, P = 0.03) and UV-TAMXV Z-score was significantly lower (-1.89 vs -1.26, P = 0.003). Mixed effects logistic regression analysis, accounting for the paired nature of the outcomes for the two twins in each pregnancy, demonstrated that the UV-TAMXV Z-score significantly predicted UA pH at birth < 7.20 or intrauterine fetal death. The Doppler parameter that independently predicted pH < 7.15 or intrauterine fetal death was presence of pulsation in the UV. CONCLUSION: UV Doppler parameters may predict acidemia at birth or intrauterine fetal death in monochorionic twins complicated by placental insufficiency.

Dopplervelocimetria da artéria cerebral média fetal e outros parâmetros de vitalidade fetal na sobrevida neonatal em gestações com insuficiência placentária / Doppler velocimetry of the fetal middle cerebral artery and other parameters of fetal well-being in neonatal survival during pregnancies with placental insufficiency

OBJETIVO: Estudar a dopplervelocimetria da artéria cerebral média fetal em gestações complicadas pela insuficiência placentária e verificar o seu papel no prognóstico de sobrevida neonatal. MÉTODOS: Trata-se de estudo prospectivo de 93 gestantes com diagnóstico de insuficiência placentária estabelecida antes da 34ª semana. A insuficiência placentária foi caracterizada pelo Doppler de artéria umbilical (AU) alterado (> p95). Foram analisados os seguintes parâmetros: índice de pulsatilidade (IP) da artéria umbilical (AU), IP da artéria cerebral média (ACM), relação cerebroplacentária -RCP(IP-ACM/IP-AU), pico de velocidade sistólicada ACM (PVS-ACM) e IP para veias (IPV) do ducto venoso (DV). Os parâmetros foram analisados pelos valores absolutos, em escores zeta (desvios padrão a partir da média) ou múltiplos da mediana (MoM). O desfecho investigado foi o óbito neonatal no período de internação após o nascimento. RESULTADOS: Nas 93 gestações analisadas, ocorreram 25 (26,9%) óbitos neonatais. No grupo que evoluiu com óbito neonatal, quando comparado com o grupo com sobrevida, houve associação significativa com o diagnóstico de diástole zero ou reversa (88% vs. 23,6%, p < 0,001), com maior mediana do IP da AU (2,9 vs. 1,7, p < 0,001) e seu escore zeta (10,4 vs. 4,9, p < 0,001); maior valor do PVS-ACM MoM (1,4 vs. 1,1, p = 0,012); menor valor da RCP (0,4 vs. 0,7, p < 0,001); maior valor do IPV-DV (1,2 vs. 0,8, p < 0,001) e no escore zeta do DV (3,6 vs.0,6, p<0,001). Na regressão logística, as variáveis independentes para a prediçãodoóbito neonatal foram a idade gestacional no parto (OR = 0,45; IC95% 0,3 a 0,7, p < 0,001) e o escore zeta do IP-AU (OR 1,14, IC95% 1,0 a 1,3, p = 0,046). CONCLUSÃO: Apesar da associação verificada pela análise univariada entre a morte neonatal e os parâmetros da dopplervelocimetria cerebral fetal, a análise multivariada identificou a prematuridadeeograude insuficiência da circulação placentária como fatores independentes relacionados com o óbito neonatal em gestações complicadas por insuficiência placentária.

OBJECTIVE: To study the Doppler velocimetry of the fetal middle cerebral artery in pregnancies complicated by placental insufficiency, and to verify its role in the prognosis of neonatal survival. METHODS: This was a prospective study of 93 pregnant women with diagnosis of placental insufficiency detected before the 34th week of pregnancy. Placental insufficiency was characterized by abnormal umbilical artery (UA) Doppler (> 95th percentile). The following parameterswere analyzed: umbilical artery (UA) pulsatility index (PI); middle cerebral artery (MCA) PI; brain-placenta ratio - BPR (MCA-PI/UA-PI); MCA peak systolic velocity (MCA-PSV); and PI for veins (PIV) of ductus venosus (DV). The parameters were analyzed in terms of absolute values, z-scores (standard deviations from the mean), or multiples of the median (MoM). The outcome investigatedwas neonatal death during the hospitalization period after birth. RESULTS: Of the 93 pregnancies analyzed, there were 25 (26.9%) neonatal deaths. The group that died, when compared to the survival group, presented a significant association with the diagnosis of absent or reversed end-diastolic flow (88% vs. 23.6%, p < 0.001), with a higher median of UA PI (2.9 vs. 1.7, p < 0.001) and UA PI z-score (10.4 vs. 4.9, p < 0.001); higher MCAPSV MoM (1.4 vs. 1.1, p = 0.012); lower BPR (0.4 vs. 0.7, p < 0.001); higher PIV-DV (1.2 vs. 0.8, p < 0.001) and DV z-score (3.6 vs. 0.6, p < 0.001). In the logistic regression, the independent variables predictive of neonatal death were: gestational age at birth (OR = 0.45; 95% CI: 0.3 to 0.7; p < 0.001) and UA PI z-score (OR = 1.14, 95% CI: 1.0 to 1.3, p = 0.046). CONCLUSION: Despite the association verified by the univariate analysis between neonatal death and the parameters of fetal cerebral Doppler velocimetry, the multivariate analysis identified prematurity and degree of insufficiency of placental circulation as independent factors related to neonatal death in pregnancies complicated by placental insufficiency.

Doppler velocimetry of the fetal middle cerebral artery and other parameters of fetal well-being in neonatal survival during pregnancies with placental insufficiency.

OBJECTIVE: To study the Doppler velocimetry of the fetal middle cerebral artery in pregnancies complicated by placental insufficiency, and to verify its role in the prognosis of neonatal survival. METHODS: This was a prospective study of 93 pregnant women with diagnosis of placental insufficiency detected before the 34(th) week of pregnancy. Placental insufficiency was characterized by abnormal umbilical artery (UA) Doppler (> 95(th) percentile). The following parameters were analyzed: umbilical artery (UA) pulsatility index (PI); middle cerebral artery (MCA) PI; brain-placenta ratio--BPR (MCA-PI/UA-PI); MCA peak systolic velocity (MCA-PSV); and PI for veins (PIV) of ductus venosus (DV). The parameters were analyzed in terms of absolute values, z-scores (standard deviations from the mean), or multiples of the median (MoM). The outcome investigated was neonatal death during the hospitalization period after birth. RESULTS: Of the 93 pregnancies analyzed, there were 25 (26.9%) neonatal deaths. The group that died, when compared to the survival group, presented a significant association with the diagnosis of absent or reversed end-diastolic flow (88% vs. 23.6%, p<0.001), with a higher median of UA PI (2.9 vs. 1.7, p<0.001) and UA PI z-score (10.4 vs. 4.9, p<0.001); higher MCA-PSV MoM (1.4 vs. 1.1, p=0.012); lower BPR (0.4 vs. 0.7, p<0.001); higher PIV-DV (1.2 vs. 0.8, p<0.001) and DV z-score (3.6 vs. 0.6, p<0.001). In the logistic regression, the independent variables predictive of neonatal death were: gestational age at birth (OR=0.45; 95% CI: 0.3 to 0.7; p<0.001) and UA PI z-score (OR=1.14, 95% CI: 1.0 to 1.3, p=0.046). CONCLUSION: Despite the association verified by the univariate analysis between neonatal death and the parameters of fetal cerebral Doppler velocimetry, the multivariate analysis identified prematurity and degree of insufficiency of placental circulation as independent factors related to neonatal death in pregnancies complicated by placental insufficiency.

Placental pathology and long-term neurodevelopment of very preterm infants.

OBJECTIVE: The objective of the study was to compare neonatal morbidity and long-term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN: We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS: At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P = .001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P = .12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION: Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants.

Impact of Doppler sonography on intrauterine management and neonatal outcome in preterm fetuses with intrauterine growth restriction.

OBJECTIVES: To test the hypothesis that earlier delivery may be warranted to improve neonatal outcome of fetuses with intrauterine growth restriction (IUGR) with abnormal Doppler parameters. METHODS: This was a retrospective cohort study of 110 fetuses with an antenatal diagnosis of IUGR due to placental insufficiency which had a very low birth weight (< 1500 g), delivered at the Department of Fetomaternal Medicine of the Medical University of Vienna, Austria, between January 1999 and July 2009. Doppler results before delivery were classified as follows: Group 1: abnormal umbilical artery (UA) pulsatility index (PI) more than 2 SD above the mean for normal reference data, or absent UA end-diastolic flow, both with normal middle cerebral artery (MCA) PI (mean ± 2 SD); Group 2: abnormal UA-PI > mean + 2 SD, or absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and normal ductus venosus (DV) PI (mean ± 2 SD); Group 3: absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and abnormal DV-PI (> mean + 2 SD) and/or absent or reversed end-diastolic DV flow. Pregnancy outcome was analyzed according to Doppler results. RESULTS: Due to very poor prognosis, 19 fetuses underwent expectant management and died in utero. These were excluded from further analyses. Of the remaining 91 cases, 17 were in Doppler Group 1, 44 in Group 2 and 30 in Group 3. Within 4 weeks after delivery, 0/17 (0%) infants in Group 1 died, 2/44 (4.5%) infants in Group 2 died and 7/30 (23.3%) infants in Group 3 died (P = 0.019). None of the 42 Group 2 cases that delivered at or after 28 completed gestational weeks died within 4 weeks after delivery, in contrast to 4/20 (20.0%) Group 3 cases (P = 0.009). In comparison, among infants delivered before 27 completed gestational weeks, 2/2 (100%) Group 2 cases died and 3/10 (30.0%) Group 3 cases died; P = 0.152). CONCLUSIONS: Doppler examinations are highly predictive in assessing the outcome of IUGR fetuses. From 28 completed gestational weeks, early delivery before the onset of fetal cardiac decompensation might be beneficial.

[The modern concepts of placental pathology and its role in perinatal mortality in the context of forensic medical practice].

The modern concepts of placental pathology are considered and analysed in the context of forensic medical practice. The most promising approaches to the application of fundamental knowledge of placental pathology (including morphometric methods) for the purpose of forensic medical expertise are discussed.

Doppler vascular changes in intrauterine growth restriction.

Intrauterine growth restriction (IUGR) secondary to placental insufficiency is a major cause of perinatal morbidity and mortality in the United States. Historically, Doppler changes occurring in IUGR fetuses play an important role in the diagnosis and management of these fetuses, and now, based on these changes, we have proposed a staging system for IUGR fetuses that demonstrates prognostic value. This manuscript also summarizes a practical classification for IUGR fetuses. We believe that future studies should differentiate among the different types of IUGR fetuses.

Factores de riesgo de la muerte fetal anteparto / Risk factors for antepartum fetal death

La muerte fetal supone más de la mitad de las muertes perinatales. El grupo con mayor morbimortalidad corresponde a los recién nacidos que asocian prematuridad y bajo peso. Hay una marcada tendencia a repetir el mal resultado de la gestación anterior. Se presentan 2 casos de muerte fetal, y se realiza una revisión de las causas más frecuentes y de su influencia. El estudio de las alteraciones maternas, fetales y placentarias puede, en algunos casos, establecer la etiología de la muerte fetal (AU)

Fetal death represents more than half of perinatal deaths. Morbidity is highest in newborns who associate prematurity and low birth weight. Adverse pregnancy outcomes show a marked tendency to be repeated. We present two cases of fetal death and review the most frequent causes of this adverse outcome and their influence. Study of maternal, fetal and placental alterations can sometimes establish the etiology of fetal death (AU)

Doppler assessment of the aortic isthmus and perinatal outcome in preterm fetuses with severe intrauterine growth restriction.

OBJECTIVES: To evaluate the characteristics and association with perinatal outcome of the aortic isthmus (AoI) circulation as assessed by Doppler imaging in preterm growth-restricted fetuses with placental insufficiency. METHODS: This was a prospective cross-sectional study. Fifty-one fetuses with intrauterine growth restriction (IUGR) and either an umbilical artery (UA) pulsatility index (PI) > 95(th) centile or a cerebroplacental ratio < 5(th) centile were examined at 24-36 weeks' gestation. AoI impedance indices (PI and resistance index) and absolute velocities (peak systolic (PSV), end-diastolic and time-averaged maximum (TAMXV) velocities), were measured in all cases and compared with reference ranges by gestational age. Furthermore, fetuses were stratified into two groups according to the direction of the diastolic blood flow in the AoI: those with antegrade flow (n = 41) and those with retrograde flow (n = 10). Clinical surveillance was based on gestational age and Doppler assessment of the UA, middle cerebral artery and ductus venosus (DV). Adverse perinatal outcome was defined as stillbirth, neonatal death and severe morbidity (respiratory distress syndrome, bronchopulmonary dysplasia, Grade III/IV intraventricular hemorrhage, necrotizing enterocolitis and a neonatal intensive care unit stay > 14 days). RESULTS: Adverse perinatal outcome was significantly associated with an increased AoI-PI (area under the curve 0.77; 95% CI, 0.63-0.92; P < 0.005). A significant correlation (P < 0.001) was found between retrograde blood flow in the AoI and adverse perinatal outcome, the overall perinatal mortality being higher in the retrograde group (70% vs. 4.8%, P < 0.001). In 4/5 (80%) fetuses the reversal of flow in the AoI preceded that in the DV by 24-48 h. AoI-PSV and AoI-TAMXV were < 5(th) centile in 40/51 (78%) and 48/51 (94%) cases, respectively, whereas AoI-PI was > 95(th) centile in 21/51 (41%) cases. CONCLUSIONS: Retrograde flow in the AoI in growth-restricted fetuses correlates strongly with adverse perinatal outcome. Absolute velocities in the AoI are decreased in growth-restricted fetuses. The data suggest a potential role for Doppler imaging of the AoI in the clinical surveillance of fetuses with severe IUGR, which should be confirmed in larger prospective studies.

Predictors of neonatal outcome in early-onset placental dysfunction.

OBJECTIVE: To identify specific estimates and predictors of neonatal morbidity and mortality in early onset fetal growth restriction due to placental dysfunction. METHODS: Prospective multicenter study of prenatally diagnosed growth-restricted liveborn neonates of less than 33 weeks of gestational age. Relationships between perinatal variables (arterial and venous Dopplers, gestational age, birth weight, acid-base status, and Apgar scores) and major neonatal complications, neonatal death, and intact survival were analyzed by logistic regression. Predictive cutoffs were determined by receiver operating characteristic curves. RESULTS: Major morbidity occurred in 35.9% of 604 neonates: bronchopulmonary dysplasia in 23.2% (n=140), intraventricular hemorrhage in 15.2% (n=92), and necrotizing enterocolitis in 12.4% (n=75). Total mortality was 21.5 % (n=130), and 58.3% survived without complication (n=352). From 24 to 32 weeks, major morbidity declined (56.6% to 10.5%), coinciding with survival that exceeded 50% after 26 weeks. Gestational age was the most significant determinant (P<.005) of total survival until 26(6/7) weeks (r(2)=0.27), and intact survival until 29(2/7) weeks (r(2)=0.42). Beyond these gestational-age cutoffs, and above birth weight of 600 g, ductus venosus Doppler and cord artery pH predicted neonatal mortality (P<.001, r(2)=0.38), and ductus venosus Doppler alone predicted intact survival (P<.001, r(2)=0.34). CONCLUSION: This study provides neonatal outcomes specific for early-onset placenta-based fetal growth restriction quantifying the impact of gestational age, birth weight, and fetal cardiovascular parameters. Early gestational age and birth weight are the primary quantifying parameters. Beyond these thresholds, ductus venosus Doppler parameters emerge as the primary cardiovascular factor in predicting neonatal outcome. LEVEL OF EVIDENCE: II.

[Reverse flow in fetal vessels and perinatal events]. / Reverse Flow in den fetalen Gefässen - Klinische Bedeutung und perinatale Auffälligkeiten.

UNLABELLED: BACKGROUND/PATIENTS: A reverse flow in the umbilical artery and/or fetal aorta is associated with a higher perinatal and neonatal mortality. 30 fetuses showed a reverse flow using pulsed wave Doppler sonography (group I). A matched-pair control group including 30 fetuses with the same gestational age as well as a normal Doppler flow pattern in the umbilical artery and/or fetal aorta was taken for comparison (group II). RESULTS: In the group with reverse flow the rates of pregnancies with pre-eclampsia (n = 19/30, p < 0.0001), intrauterine growth retardation (n = 25/30, p < 0.0001), oligohydramnios (n = 21/30, p < 0.0001) and nicotine abuse (n = 15/30, p < 0.01) were significantly higher compared to the control group. Postnatal data showed significantly lower pH values in group I (p < 0.01). 40 % of the fetuses with reverse flow died in utero whereas in 67 % the reverse flow was accompanied by an insufficiency of the placenta (IUGR, oligohydramnios, histopathological abnormalities of the placenta). None of the fetuses in the control group died in utero. The incidence of IUGR (< 5ht percentile) was 83 % in group I but only 3 % in group II. The perinatal and overall mortality (including neonatal mortality 7 - 28 days after birth) amounted to 27 % and 53 % in group I, respectively, compared to 3 % and 0 % in the control group (p < 0.001). In addition cerebral anomalies could be found by ultrasound in 50 % of the neonates who presented a reverse flow prenatally. In 28 % of the surviving newborns an intracerebral hemorrhage (ICH) could be detected. None of the newborns of group II developed an ICH. CONCLUSIONS: Pregnancies with a reverse flow in the umbilical artery and/or fetal aorta have to be considered as a high risk group with a poor prognosis. The reverse flow is mainly caused by chronic placental insufficiency with IUGR. With respect to the further neuromotor development the incidence and severity of cerebral lesions in affected fetuses should be considered when discussing the perinatal situation with the parents.

Análisis de la mortalidad perinatal (1993-1997): I mortalidad fetal / Analisis of perinatal mortality (1993-1997): I fetal mortality

Conocer la incidencia de la mortalidad fetal, las características maternas, condiciones obstétricas y factores relacionados. Estudio descriptivo análitico de 421 muertes fetales sucedidas entre 1993-1997. Hospital "Dr. Adolfo Prince Lara", Puerto Cabello, Estado Carabobo, Venezuela. La mortalidad perinatal para el período fue de 45,46 por mil nacidos vivos, y la fetal 22,28. Las muertes predominaron en edades de 24 años y menos (47,27 por ciento), con antecedentes familiares hipertensión arterial y diabetes (52,49 por ciento), antecedentes personales hipertensional arterial y diabetes (24,9 por ciento), la patología de ingreso determinante fue la hipertensión arterial 25,41 por ciento seguida de la hemorrágica placentaria 13,06 por ciento. No realizaron control prenatal el 48,22 por ciento, hubo III-VII gestantes (62,47 por ciento), la edad de gestación menor a 37 semanas 62,9 por ciento. El 77,43 por ciento fueron partos vaginales. Predominó el sexo masculino 50,36 por ciento con peso menor de 2500 g. (65,09 por ciento) y talla menor de 50 cm. (65,32 por ciento). El factor de muerte directo conocido en 265 casos fue la insuficiencia placentaria 45,28 por ciento, desencadenada especialmente por hipertensión arterial, seguida por patología hemorrágica placentaria 38,87 por ciento. Los resultados señalan hacer un mejor manejo de las patalogías hipertensivas, diabetes y hemorrágicas placentaria a fin de disminuir la mortalidad fetal

Morbidity and mortality of discordant twins up to 34 weeks of gestational age.

UNLABELLED: The combination of weight discordance and prematurity implies a high perinatal morbidity and mortality for the affected twins. Several pathomechanisms may be responsible for the weight difference in twins including a different genetic growth potential in dizygotic twins, placenta insufficiency in one twin, and chronic feto-fetal transfusion (CFFT). Little is known about neonatal morbidity and mortality of discordant twins. Therefore, a retrospective, case-controlled study on preterm discordant twins up to 34 weeks gestation was carried out. Twenty-seven (27,3%) of 99 twin pairs born in our clinic had a birth weight difference of more than 20%. The control group consisted of 27 non-discordant twins matched for gestational age. Discordant twins showed a significantly higher mortality (19%) than the control twins (2%). Severe intracranial haemorrhage (ICH) and persistent ductus arteriosus Botalli (PDA) were found more often in discordant twins than in the control group. The increased mortality and morbidity of discordant twins compared with concordant twins matched for gestational age indicates that the increased morbidity and mortality of preterm weight discordant twins is not only due to prematurity, but is also related to the discordance itself. Thirteen (48.1%) of the weight discordant twin pairs fulfilled the criteria for CFFT. Twins with CFFT differed significantly from controls with respect to the incidence of mortality and the rate of severe ICH, PDA, and the necessity of postnatal cardiopulmonary resuscitation. By contrast, no significant differences were found between discordant twins without CFFT and controls. Thus, CFFT appears to be a major contributing factor for increased mortality and morbidity of weight discordant twins. Intra-twin pair analysis revealed a higher rate of postnatal hypoglycaemia in the smaller twins only, probably caused by insufficient glycogen storage due to intra-uterine malnutrition. Mortality was the same for both the larger and the smaller twins. It may be concluded that neonatal outcome of smaller twins who have survived intra-uterine malnutrition is the same as in larger twins. Intra-twin pair analysis in twins with CFFT revealed no significant differences except for a higher rate of ICH grade 2-4 in the larger twins which might be explained by hypervolaemia of the recipient. CONCLUSION: Morbidity and mortality of weight discordant twins are increased. CFFT appears to be a major contributing factor for the increased mortality and morbidity. Postnatal mortality was the same in acceptor and donor; however, the acceptor had a higher postnatal morbidity.