Prediction of Cerebral Palsy or Death among Preterm Infants Who Survive the Neonatal Period.

OBJECTIVE: To assess whether neonatal morbidities evident by the time of hospital discharge are associated with subsequent cerebral palsy (CP) or death. STUDY DESIGN: This is a secondary analysis of data from a multicenter placebo-controlled trial of magnesium sulfate for the prevention of CP. The association between prespecified intermediate neonatal outcomes (n = 11) and demographic and clinical factors (n = 10) evident by the time of discharge among surviving infants (n = 1889) and the primary outcome of death or moderate/severe CP at age 2 (n = 73) was estimated, and a prediction model was created. RESULTS: Gestational age in weeks at delivery (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.67-0.83), grade III or IV intraventricular hemorrhage (IVH) (OR: 5.3, CI: 2.1-13.1), periventricular leukomalacia (PVL) (OR: 46.4, CI: 20.6-104.6), and male gender (OR: 2.5, CI: 1.4-4.5) were associated with death or moderate/severe CP by age 2. Outcomes not significantly associated with the primary outcome included respiratory distress syndrome, bronchopulmonary dysplasia, seizure, necrotizing enterocolitis, neonatal hypotension, 5-minute Apgar score, sepsis, and retinopathy of prematurity. Using all patients, the receiver operating characteristic curve for the final prediction model had an area under the curve of 0.84 (CI: 0.78-0.89). Using these data, the risk of death or developing CP by age 2 can be calculated for individual surviving infants. CONCLUSION: IVH and PVL were the only neonatal complications evident at discharge that contributed to an individual infant's risk of the long-term outcomes of death or CP by age 2. A model that includes these morbidities, gestational age at delivery, and gender is predictive of subsequent neurologic sequelae. KEY POINTS: · Factors known at hospital discharge are identified which are independently associated with death or CP by age 2.. · A model was created and validated using these findings to counsel parents.. · The risk of death or CP can be calculated at the time of hospital discharge..

Euploid First-Trimester Cystic Hygroma: A More Benign Entity than Previously Thought?

OBJECTIVE: Studies summarizing the outcome of first-trimester septated cystic hygroma are generally based on small studies or from multiple centers with limited ascertainment. We reviewed the natural history of a large cohort of such cases from a single tertiary referral center, with the aim being to establish contemporary outcome data, particularly in the setting of normal karyotype. METHODS: A retrospective cohort study from 2007 to 2017 was conducted at a single tertiary referral prenatal diagnosis center. Data were analyzed from a prospectively collated fetal anomaly database. Search terms were "increased nuchal translucency (NT)," "cystic hygroma," and "septated cystic hygroma." All cases were confirmed to have NT >3 mm with septations. Cases of simple increased NT without septations were excluded. RESULTS: During the study period, over 110,000 pregnancies were delivered at our center, resulting in 410 cases of septated cystic hygroma diagnosed prior to 14 weeks' gestation. Pregnancy outcome was obtained in 99% (405/410) of cases, with detailed pathology outcome available in 92% (378/410). A total of 87% (351/405) underwent invasive prenatal testing, and postnatal chromosome status was established in further 27 cases. A total of 61% (230/378) had abnormal chromosomal status. Of the 39% (148/378) with normal chromosomal status, only 13% (19/148) had a significant structural fetal abnormality, which included 7 cardiac and 12 noncardiac abnormalities. Overall, the perinatal loss was 62% (253/405). The total survival rate in the setting of euploid cystic hygroma without structural abnormality was 84% (108/129). CONCLUSIONS: Counseling regarding outcomes in the setting of first-trimester septated cystic hygroma initially focuses on the strong likelihood of an abnormal karyotype, which occurs in 61% of cases. However, once fetal chromosomal abnormality is excluded, our results demonstrate only a 13% incidence of major structural fetal abnormality, which appears significantly less than previously reported. Normal fetuses have a 77% survival rate. These data represent the largest single-center study of first-trimester cystic hygroma with complete outcome data and therefore will be useful for contemporary patient counseling. Such counseling can be more positive than previously expected, once chromosomal abnormality is first excluded.

The Warburg Effect Occurs Rapidly in Stimulated Human Adult but Not Umbilical Cord Blood Derived Macrophages.

The Warburg effect, defined as increased glycolysis and decreased oxidative phosphorylation, occurs in murine macrophages following LPS stimulation and is required for activation. There are differences between human and murine macrophage metabolic responses to stimulation, with peak metabolite concentrations occurring earlier in humans than mice. Complex changes occur in the human immune system with age, resulting in the very young and the very old being more susceptible to infections. Anti-bacterial immune responses in umbilical cord immune cells are considered deficient but there is a paucity of data on the role that metabolism plays. We hypothesized that metabolic responses in human macrophages occur early during activation. In addition, we hypothesized that umbilical cord derived macrophages have an altered immunometabolic response compared with adult macrophages. We demonstrate that adult and cord blood monocyte derived macrophages (MDM) immediately increase glycolysis in response to stimulation with LPS or Mycobacterium tuberculosis (Mtb), however only adult MDM decrease oxidative phosphorylation. At 24 hours post stimulation, glycolysis remains elevated in both adult and cord blood MDM, oxidative phosphorylation remains unchanged in the cord blood MDM and has normalized in the adult MDM stimulated with Mtb. However, LPS stimulated adult MDM have increased oxidative phosphorylation at 24 hours, illustrating differences in metabolic responses to different stimuli, time-dependent variation in responses and differences in macrophage metabolism in adults compared with umbilical cord blood. We compared the phenotype and function of macrophages derived from adult or cord blood. Cord blood MDM secreted less TNF following Mtb stimulation and more IL-6 following LPS stimulation compared with adult MDM. Our findings demonstrate that whilst cord blood MDM exhibit an immediate increase in glycolytic flux in response to stimulation, similar to adult MDM, cord blood MDM do not concomitantly decrease oxygen consumption. This indicates that adult macrophages shift to Warburg metabolism immediately after stimulation, but cord blood macrophages do not. Understanding the differences in the metabolic profiles of macrophages over a human lifetime will enable the translation of immunometabolism into effective immuno-supportive therapies that could potentially be targeted at vulnerable populations, such as the very old and the very young.

Rare chromosomal abnormalities: Can they be identified using conventional first trimester combined screening methods?

OBJECTIVE: To evaluate the performance of first trimester combined screening for the detection of rare chromosomal abnormalities, other than Trisomies 21, 18 or 13 or 45 × . STUDY DESIGN: A database containing 36,254 pregnancies was analyzed. These patients were recruited at 15 US centers and included singleton pregnancies from 10 3/7-13 6/7 weeks. All patients had a nuchal translucency (NT) scan and those without a cystic hygroma (N = 36,120) underwent a combined first trimester screening test ('FTS' - NT, PAPP-A and fbHCG). A risk cut-off of 1:300, which was used for defining high risk for Trisomy 21, was also used to evaluate the detection rate for rare chromosomal abnormalities using the combined FTS test. RESULTS: 36,120 patients underwent combined FTS. Of these, 123 were found to have one of the following chromosomal abnormalities: Trisomy 21, Trisomy 18, Trisomy 13 or Turner syndrome. This study focuses on 40 additional patients who were found to have 'other' rare chromosomal abnormalities such as triploidy, structural chromosomal abnormalities, sex chromosome abnormalities or unusual chromosomal abnormalities (e.g. 47XX + 16), giving an incidence of 1.1 in 1000 for these rare chromosomal abnormalities. Of these 40 pregnancies, only 2 (5%) had an NT measurement of ≥3 mm. The detection rate for combined FTS, using a risk cut-off of ≥1:300, was 35 % (14 of 40 cases). Therefore, 65 % of cases of rarer fetal chromosomal abnormalities had a 'normal' combined FTS risk (<1:300) and 95 % had a 'normal' NT (<3 mm). CONCLUSION: Traditional FTS methods are unable to identify the vast majority of rare chromosomal abnormalities. Our data do not support the potential detection of rare fetal chromosomal abnormalities as a reason to favour nuchal translucency-based first trimester screening over NIPT.

Sex-Specific Genetic Susceptibility to Adverse Neurodevelopmental Outcome in Offspring of Pregnancies at Risk of Early Preterm Delivery.

OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10-4), accounted for linkage disequilibrium between markers. RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10-4) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant. CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.

Preeclampsia Prevention Using Routine Versus Screening Test-Indicated Aspirin in Low-Risk Women.

The objective was to evaluate whether routine aspirin 75 mg is more cost-effective than the Fetal Medicine Foundation screen-and-treat approach for preeclampsia prevention in low-risk nulliparous women. A health economic decision analytical model was devised to estimate the discounted net health and cost outcomes of routine aspirin versus Fetal Medicine Foundation screening test-indicated aspirin for a cohort of 100 000 low-risk nulliparous women. Both strategies were compared with no intervention. A subanalysis also compared disaggregated components of the algorithm. The analysis used data from hospital administration, literature, and a randomized controlled trial. Sensitivity analyses assessed the impact of aspirin adherence, test cost, and accuracy on study results. Presumed rates of preeclampsia were 3.75% with no intervention versus 0.45% with aspirin use. Results found that routine aspirin was the preferred strategy, in terms of greater health gains and larger cost savings. It provided 163 quality-adjusted life-years relative to no intervention, whereas the screen-and-treat policy achieved 108 quality-adjusted life-years. Routine aspirin would result in an estimated cost saving of €14.9 million annually relative to no intervention, whereas screen-and-treat approach would result in a smaller cost saving of €3.1 million. When the analysis was extended to consider alternative screen-and-treat strategies, routine aspirin remained the optimally cost-effective approach. In conclusion, routine aspirin use in low-risk nulliparous women has a greater health gain and cost saving compared with both the Fetal Medicine Foundation and other screen-and-treat approaches.

Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial.

OBJECTIVE: Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction. DESIGN: Multicentre open-label feasibility randomised controlled trial. SETTING: Two tertiary maternity hospitals in Dublin, Ireland. PARTICIPANTS: 546 low-risk nulliparous women completed the study. INTERVENTIONS: Women underwent computerised randomisation to: Group 1-routine aspirin 75 mg from 11 until 36 weeks; Group 2-no aspirin and; Group 3-aspirin based on the Fetal Medicine Foundation screening test. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses. RESULTS: 546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0-26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8). CONCLUSION: Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach. TRIAL REGISTRATION NUMBER: ISRCTN (15191778); Post-results.

First trimester serum biomarkers to predict gestational diabetes in a high-risk cohort: Striving for clinically useful thresholds.

OBJECTIVES: Screening and diagnosis of gestational diabetes (GDM) has been a source of controversy. The prevalence has increased in line with an obesity epidemic and a trend towards delayed child-bearing. Treatment of even modest glycaemic impairment in pregnancy has been shown to be beneficial in preventing its clinical sequalae. However the cumbersome nature and timing of the oral glucose tolerance test coupled with debate around universal versus risk factor based screening have been problematic. This group aimed to investigate a panel of biomarkers which have shown promise in the literature to predict GDM from the first trimester in a group of high risk women. METHODS: Serum samples were drawn on 248 women deemed at risk of GDM before 15 weeks' gestation to measure C-reactive protein, sex hormone binding globulin, adiponectin and 1,5 anhydroglucitol. Patients underwent an oral glucose tolerance test as per IADPSG criteria at 28 weeks' gestation. Multiple logistic regression was used to examine the link between incidence of GDM and early pregnancy serum biomarkers. RESULTS: Adiponectin levels in the first trimester are independently linked to the risk of GDM. Serum adiponectin <8.9 µg/ml gives an odds ratio of 3.3 for GDM.Mean 1,5 AG levels are significantly lower in those that go on to develop GDM. SHBG levels measured in the first trimester were linked to the risk of GDM. However, this was no longer statistically significant once BMI, ethnicity and family history were taken into consideration. First trimester measurement of CRP is not a useful indicator of GDM risk. CONCLUSIONS: First trimester measurement of Adiponectin and 1,5 Anhydroglucitol are potential early biomarkers for the later onset of GDM. Risk stratification using these biomarkers may facilitate early diagnosis and management of GDM to mitigate against its complications.

Prenatal surgery for spina bifida: a therapeutic dilemma. Proceedings of the SHINE conference, Belfast.

This is a transcript of a scientific conference on the subject of prenatal surgery for spina bifida. It represents the views of three patients, an obstetrician, a postnatal neurosurgeon, a neonatologist, a paediatric neurologist, two surgeons who practice open spina bifida foetal surgery, a fetoscopic surgeon and an obstetrician experienced in randomised trials and systematic reviews. Implications for current practice and recommendations for future research are also discussed in detail.

Evaluation of normalization of cerebro-placental ratio as a potential predictor for adverse outcome in SGA fetuses.

BACKGROUND: Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort. OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome. STUDY DESIGN: In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. RESULTS: Data for cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group (P value <.001). CONCLUSION: The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks' gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome.

An open-label randomized-controlled trial of low dose aspirin with an early screening test for pre-eclampsia and growth restriction (TEST): Trial protocol.

OBJECTIVE: Pre-eclampsia remains a worldwide cause of maternal and perinatal morbidity and mortality. Low dose aspirin (LDA) can reduce the occurrence of pre-eclampsia in women with identifiable risk factors. Emerging screening tests can determine the maternal risk of developing placental disease, such as pre-eclampsia from the first trimester of pregnancy. The aim of this study is to determine if it is more beneficial in terms of efficacy and acceptability to routinely prescribe LDA to nulliparous low-risk women compared to test indicated LDA on the basis of a positive screening test for placental disease. METHODS: We propose a three armed multi-center open-labeled randomized control trial of; (i) routine LDA, (ii) no aspirin, and (iii) LDA on the basis of a positive first trimester pre-eclampsia screening test. LDA (75mg once daily) shall be given from the first trimester until 36-week gestation. The primary outcome measures include; (i) the proportion of eligible women that agree to participate (acceptability), (ii) compliance with study protocol (acceptability and feasibility), (iii) the proportion of women in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination (feasibility) and (iv) the proportion of women with a completed screening test that are issued the screening result within one week of having the test performed (feasibility). CONCLUSION: This will be the first clinical trial to determine the efficacy and acceptability in low-risk women of taking routine LDA versus no aspirin versus LDA based on a positive first trimester screening test for the prevention of placental disease.

Prenatal detection of major congenital heart disease - optimising resources to improve outcomes.

INTRODUCTION: Congenital heart disease (CHD) is the most common major structural fetal abnormality and the benefits of prenatal detection are well described. The objective of this study was to evaluate the precision of prenatal diagnosis at a single tertiary referral unit over two three year periods (2006, 2007, 2008 and 2010, 2011, 2012), before and after a prenatal screening protocol for CHD was developed to include extended cardiac views, mandatory recall for suboptimal views, and a multidisciplinary Fetal Cardiac clinic was established. There exists a single national centre for paediatric cardiothoracic surgery in Ireland, a situation which facilitates near complete case ascertainment. MATERIALS AND METHODS: Surgery records of the National Children's Cardiac Centre were interrogated for all cases of major congenital heart defects requiring surgical intervention in the first six months of life. Minor procedures such as ligation of a patent ductus arteriosus and isolated atrial septal defect repairs were excluded. Analyses of the Fetal Medicine database at the Rotunda Hospital (a stand-alone tertiary level perinatology centre with 8500 deliveries per year) and the mortality data at the Perinatal Pathology department were conducted. The Cochrane-Armitage trend test was used to determine statistical significance in prenatal detection rates over time. RESULTS: 51,822 women delivered during the study period, and the incidence of major congenital heart disease either that underwent surgical intervention or that resulted in perinatal mortality, was 238/51,822 (0.5%). Prenatal detection of major CHD increased from 31% to 91% (p<0.001). Detection of critical duct-dependant lesions rose from 19% to 100%. CONCLUSION: We attribute the dramatic improvement in prenatal detection rates to the multifaceted changes introduced during the study period. Improved prenatal detection for births that are geographically remote from the National Paediatric Cardiac Centre will require local replication of this prenatal programme.

Altered Platelet Function in Intrauterine Growth Restriction: A Cause or a Consequence of Uteroplacental Disease?

Objective A limited number of platelet function studies in intrauterine growth restriction (IUGR) have yielded conflicting results. We sought to evaluate platelet reactivity in IUGR using a novel platelet aggregation assay. Study Design Pregnancies with IUGR were recruited from 24 weeks' gestation (estimated fetal weight < 10th centile) and had platelet function testing performed after diagnosis. A modification of light transmission aggregometry created dose-response curves of platelet reactivity in response to multiple agonists at differing concentrations. Findings were compared with healthy third trimester controls. IUGR cases with a subsequent normal birth weight were analyzed separately. Results In this study, 33 pregnancies retained their IUGR diagnosis at birth, demonstrating significantly reduced platelet reactivity in response to all agonists (arachidonic acid, adenosine diphosphate, collagen, thrombin receptor-activating peptide, and epinephrine) when compared with 36 healthy pregnancy controls (p < 0.0001). Similar results were obtained for cases demonstrating an increasing in utero growth trajectory. When IUGR preceded preeclampsia or gestational hypertension, platelet function was significantly reduced compared with normotensive IUGR. Conclusion Using this comprehensive platelet assay, we have demonstrated a functional impairment of platelets in IUGR. This may reflect platelet-derived placental growth factor release. Further evaluation of platelet function may aid in the development of future platelet-targeted therapies for uteroplacental disease.

Antenatal Magnesium and Cerebral Palsy in Preterm Infants.

OBJECTIVE: To evaluate the relationship of maternal antenatal magnesium sulfate (MgSO4) with neonatal cranial ultrasound abnormalities and cerebral palsy (CP). STUDY DESIGN: In a randomized trial of MgSO4 or placebo in women at high risk of preterm delivery, up to 3 cranial ultrasounds were obtained in the neonatal period. Images were reviewed by at least 2 pediatric radiologists masked to treatment and other clinical conditions. Diagnoses were predefined for intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly. CP was diagnosed at 2 years of age by standardized neurologic examination. RESULTS: Intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly were all strongly associated with an increased risk of CP. MgSO4 administration did not affect the risk of cranial ultrasound abnormality observed at 35 weeks postmenstrual age or later. However, for the 82% of infants born at <32 weeks gestation, MgSO4 was associated with a reduction in risk of echolucency or echodensity. The reduction in risk for echolucency explained 21% of the effect of MgSO4 on CP (P = .04), and for echodensity explained 20% of the effect (P = .02). CONCLUSIONS: MgSO4 given prior to preterm delivery was associated with decreased risk of developing echodensities and echolucencies at <32 weeks gestation. However, this effect can only partially explain the effect of MgSO4 on CP at 2 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00014989.

Outcome following selective fetoscopic laser ablation for twin to twin transfusion syndrome: an 8 year national collaborative experience.

OBJECTIVE: With the recognition of the role of fetoscopic laser ablation for twin to twin transfusion syndrome (TTTS), there is a requirement for auditable standards for this technically challenging and specialized treatment. The purpose of this study is to report on the perinatal and medium-term neurodevelopmental outcomes following an 8-year national single center experience in the management of TTTS using the selective fetoscopic laser ablation technique. STUDY DESIGN: An audit of all cases of TTTS treated with selective laser ablation by a single national fetal medicine team was performed. Overall perinatal survival and medium-term neurodevelopmental outcomes were reported and correlated with gestational age at diagnosis, placental location, volume of amnio-reduction, Quintero staging and percentage inter-twin growth discordance. Procedure-related complications were recorded. RESULTS: The overall fetal survival for the first 105 consecutive cases of TTTS was 61% (128/210 fetuses). Dual survival occurred in 47% (49/105) of cases, and with a single survival rate of 28% (30/105), perinatal survival of least one infant was achieved in 75% (79/105) of cases. No correlation was found between any clinical or sonographic marker and perinatal outcome, although dual survival was noted to be significantly decreased with increasing Quintero stage (p=0.041). Currently, 86% of survivors have been reported to have a normal medium-term neurological outcome. CONCLUSION: Fetoscopic laser ablation is the established optimal treatment for severe twin to twin transfusion syndrome (TTTS). We report comparable short and medium-term outcomes following the selective fetoscopic technique comparing results from our national program with internationally published single-center outcomes, supporting the efficacy and safety of this treatment at our center.

Platelet function in patients with a history of unexplained recurrent miscarriage who subsequently miscarry again.

OBJECTIVE: This study was designed to evaluate platelet aggregation in pregnant women with a history of unexplained recurrent miscarriage (RM) and to compare platelet function in such patients who go on to have either another subsequent miscarriage or a successful pregnancy. STUDY DESIGN: A prospective longitudinal study was performed to evaluate platelet function in a cohort of patients with a history of unexplained RM. Platelet reactivity testing was performed at 4-7 weeks gestation, to compare platelet aggregation between those with a subsequent miscarriage and those who had successful live birth outcomes. Platelet aggregation was calculated using a modified assay of light transmission aggregometry with multiple agonists at different concentrations. RESULTS: In a cohort of 39 patients with a history of RM, 30 had a successful pregnancy outcome while nine had a subsequent miscarriage again. Women with subsequent miscarriage had reduced platelet aggregation in response to adenosine diphosphate (P value 0.0012) and thrombin receptor activating peptide (P value 0.0334) when compared to those with successful pregnancies. Women with subsequent miscarriages also had a trend towards reduced platelet aggregation in response to epinephrine (P value 0.0568). CONCLUSION: Patients with a background history of unexplained RM demonstrate reduced platelet function if they have a subsequent miscarriage compared to those who go on to have a successful pregnancy.

Length of latency with preterm premature rupture of membranes before 32 weeks' gestation.

OBJECTIVE: The objective of the article is to describe latency for patients with preterm premature membrane rupture (PPROM) between 24(0/7) and 31(6/7) weeks' gestation. STUDY DESIGN: Secondary analysis of data collected prospectively in a multicenter clinical trial of magnesium sulfate for cerebral palsy prevention. Women with PPROM and fewer than six contractions per hour at enrollment who were candidates for expectant management (n = 1,377) were included in this analysis. Length of latency was calculated in days by subtracting the time of delivery from the time of membrane rupture. RESULTS: At each week of gestation, median latency between 24 and 28 weeks was similar at approximately 9 days, but it was significantly shorter with PPROM at 29, 30, and 31 weeks (p < 0.001). In addition, the percentage of patients remaining undelivered at 7 days and 14 days was similar for PPROM between 24 and 28 weeks, but it decreased significantly after that. For each gestational age, the proportion of patients remaining pregnant declined in a fashion similar to an exponential pattern. CONCLUSION: Median latency after PPROM is similar from 24 to 28 weeks' gestation, but it shortens with PPROM at and after 29 weeks.

Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage.

OBJECTIVE: We sought to determine subsequent pregnancy outcomes in a cohort of women with a history of unexplained recurrent miscarriage (RM) who were not receiving medical treatment. STUDY DESIGN: This was a prospective cohort study, of women with a history of three unexplained consecutive first trimester losses, who were recruited and followed in their subsequent pregnancy. Control patients were healthy pregnant patients with no previous adverse perinatal outcome. RESULTS: A total of 42 patients with a history of unexplained RM were recruited to the study. About nine (21.4%) experienced a further first trimester miscarriage, one case of ectopic and one case of partial molar pregnancy. About 74% (23/31) of the RM cohort had a vaginal delivery. There was one case of severe pre-eclampsia. The RM group delivered at a mean gestational age of 38 + 2 weeks and with a mean birthweight of 3.23 kg. None of the neonates were under the 10th centile for gestational age. Overall, there was no significant difference in pregnancy outcomes between the two cohorts. CONCLUSION: Our study confirms the reassuring prognosis for achieving a live birth in the unexplained RM population with a very low incidence of adverse events with the majority delivering appropriately grown fetuses at term.

The association of cord serum cytokines with neurodevelopmental outcomes.

OBJECTIVE: To test whether elevated umbilical cord serum inflammatory cytokine levels predicted subsequent cerebral palsy (CP) or neurodevelopmental delay (NDD). STUDY DESIGN: Nested case-control analysis within a clinical trial of antenatal magnesium sulfate (MgSO4) before anticipated preterm birth (PTB) for prevention of CP, with evaluation of surviving children at the age of 2. NDD was defined as a Bayley psychomotor developmental index (PDI) and/or mental developmental index (MDI) < 70. Controls, defined as surviving children without CP and with Bayley PDI and MDI ≥ 85, were matched by race and gestational age. Cord serum was analyzed for interleukin-8 (IL-8) interleukin-1 beta (IL-1ß), and tumor necrosis factor-α (TNF-α) levels. Elevated cytokine levels were defined as ≥ 75th percentile in placebo-exposed controls. Analyses compared case/control cytokine levels, adjusting for MgSO4 exposure, gestational age, race/ethnicity, and sociodemographic differences. RESULTS: Logistic regression analysis with 339 cases and 276 controls showed that elevated IL-8 and IL-1ß were more common in cord blood serum from infants with subsequent low MDI as compared with controls. After adjusting for additional confounders, the significant differences were no longer evident. Cytokine levels (IL-8, IL-1ß, and TNF-α) were not elevated with CP or low PDI. CONCLUSION: Cord serum IL-8, IL-1ß, and TNF-α levels in preterm infants are not associated with subsequent CP or NDD.

Defining the residual risk of adverse perinatal outcome in growth-restricted fetuses with normal umbilical artery blood flow.

OBJECTIVE: We sought to determine the cause of adverse perinatal outcome in fetal growth restriction (FGR) where umbilical artery (UA) Doppler was normal, as identified from the Prospective Observational Trial to Optimize Pediatric Health (PORTO). We compared cases of adverse outcome where UA Doppler was normal and abnormal. STUDY DESIGN: The PORTO study was a national multicenter study of >1100 ultrasound-dated singleton pregnancies with an estimated fetal weight <10th centile. Each pregnancy underwent intensive ultrasound, including multivessel Doppler. UA Doppler was considered abnormal when the pulsatility index was >95th centile or end-diastolic flow was absent/reversed. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death. RESULTS: In all, 57 (5.0%) of the 1116 fetuses had an adverse perinatal outcome. Nine (1.3%) of 698 fetuses with normal UA Doppler had an adverse outcome, compared with 48 (11.5%) of 418 with abnormal UA Doppler (P < .0001). There were 2 perinatal deaths in the normal group and 6 in the abnormal group (P = .01). The perinatal deaths in the normal group were 1 case of pulmonary hypoplasia after prolonged preterm rupture of the membranes from 12 weeks' gestation and a case of placental abruption. Gestation at delivery was 33 ± 3 vs 31 ± 4 weeks (P = .05) and mean birthweight was 1830 ± 737 vs 1146 ± 508 g (P = .001) in the respective groups. Neonatal sepsis was the commonest adverse outcome in both groups: 0.1% and 0.4%, respectively (P = .01). CONCLUSION: Adverse perinatal outcome is uncommon in FGR with normal UA Doppler. The cases we identified were associated with heterogenous pathologies. FGR with normal UA blood flow is a largely benign condition.