Maternal serum fructosamine levels and stillbirth: a case-control study of the Stillbirth Collaborative Research Network.

OBJECTIVE: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth. DESIGN: Secondary analysis of a case-control study. SETTING: Multicentre study of five geographic catchment areas in the USA. POPULATION: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls. MAIN OUTCOME MEASURES: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth. RESULTS: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 µmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 µmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 µmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes. CONCLUSIONS: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth. TWEETABLE ABSTRACT: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes.

Stillbirth and fetal anomalies: secondary analysis of a case-control study.

OBJECTIVE: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth. DESIGN: Secondary analysis of a prospective, case-control study. SETTING: Multicentre, 59 hospitals in five regional catchment areas in the USA. POPULATION OR SAMPLE: All stillbirths and representative live birth controls. METHODS: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births. MAIN OUTCOME MEASURES: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent. RESULTS: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems. CONCLUSIONS: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race. TWEETABLE ABSTRACT: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.

Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.

OBJECTIVE: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). DESIGN: Case-control. SETTING: Three tertiary-care centres across the USA. POPULATION: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. METHODS: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). MAIN OUTCOME MEASURES: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). CONCLUSION: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. TWEETABLE ABSTRACT: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

Concerted transfer of multiple protons in acid-water clusters: [(HCl)(H2O)]2 and [(HF)(H2O)]4.

Molecular dynamics simulations using directly ab initio potentials are carried out for the ionically bonded clusters [(Cl-)(H3O+)]2 and [(F-)(H3O+)]4 to explore their transitions to the hydrogen-bonded [(HCl)(H2O)]2 and [(HF)(H2O)]4 structures during the first picosecond of simulation. Both the ionic and the H-bonded structures that are formed are highly symmetric. It is found that proton transfers are concerted in all trajectories for [(Cl-)(H3O+)]2. For [(F-)(H3O+)]4, the fully concerted mechanism is dominant but partially concerted transfers of two or three protons at the same time also occur. The concerted mechanism also holds for the reverse process of ionization of neutral acid molecules. It is suggested that the high symmetry of the ionic and the H-bonded structures plays a role in the preference for concerted transfers. Possible implications of the results for proton transfers in other systems are discussed.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Risk factors associated with preterm birth after a prior term delivery.

OBJECTIVE: The objective of this study was to assess the presence of newly acquired preterm birth (PTB) risk factors among primiparous women with no prior history of PTB. DESIGN: Case-control study. SETTING: Deliveries occurring within a large healthcare system from 2002 to 2012. POPULATION: Women with their first two consecutive pregnancies carried to ≥20(0/7)  weeks' gestation. METHODS: Those delivering the first pregnancy at term and the second preterm ≥20(0/7) and <37(0/7)  weeks (term-preterm cases) were compared with women with a term birth in their first two pregnancies (term-term controls). Social factors with the potential to change between the first and second pregnancies and intrapartum labour characteristics in the first pregnancy were compared between cases and controls. MAIN OUTCOME MEASURES: Risk factors for term-preterm sequence. RESULTS: About 38 215 women met inclusion criteria; 1353 (3.8%) were term-preterm cases. Cases and controls were similar with regard to race/ethnicity and maternal age at the time of the first and second deliveries. Cases delivered their second pregnancy approximately 3 weeks earlier (35.7 versus 39.1, P < 0.001). In multivariable models accounting for known PTB risk factors, women with a caesarean delivery in the first pregnancy [adjusted odds ratio (aOR) = 2.20; 95% confidence interval (CI) 1.57-3.08], new tobacco use (aOR = 2.33; 95% CI 1.61-3.38), and an interpregnancy interval <18 months (aOR = 1.37; 95% CI 1.21-1.55) were at increased risk of term-preterm sequence. CONCLUSION: Caesarean delivery in the first pregnancy, new tobacco use, and short interpregnancy interval <18 months are significant risk factors for term-preterm sequence. Women should receive postpartum counselling regarding appropriate interpregnancy interval and cessation of tobacco use. TWEETABLE ABSTRACT: Caesarean delivery in the 1st pregnancy is a significant risk factor for preterm birth following a term delivery.

Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth.

OBJECTIVE: To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis. DESIGN: A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo. SETTING: Multicentre randomised controlled trial. POPULATION: Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation. METHODS: All data were analysed by intention to treat. Univariate and multivariate analyses were performed. MAIN OUTCOME MEASURES: Primary outcome was a composite of stillbirth, death by the age of 1 year, or moderate or severe CP by the age of 2 years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2 years. Subgroup analysis assessed these outcomes in children born at <28 weeks of gestation. RESULTS: A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.] CONCLUSIONS: Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study. TWEETABLE ABSTRACT: MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis.

Ab initio and semi-empirical Molecular Dynamics simulations of chemical reactions in isolated molecules and in clusters.

Recent progress in "on-the-fly" trajectory simulations of molecular reactions, using different electronic structure methods is discussed, with analysis of the insights that such calculations can provide and of the strengths and limitations of the algorithms available. New developments in the use of both ab initio and semi-empirical electronic structure algorithms are described. The emphasis is on: (i) calculations of electronic properties along the reactive trajectories and the unique insights this can contribute to the processes; (ii) electronic structure methods recently introduced to this topic to improve accuracy, extend applicability or enhance computational efficiency. The methods are presented with examples, including new results, of reactions of both isolated molecules and of molecules in media, mostly clusters. Possible future directions for this fast growing field are suggested.

A risk stratification model to predict adverse neonatal outcome in labor.

OBJECTIVE: The development and evaluation of a labor risk model consisting of a combination of antepartum risk factors and intrapartum fetal heart rate (FHR) characteristics that can reliably identify those infants at risk for adverse neonatal outcome in labor. STUDY DESIGN: A nested case-control study of term singleton deliveries at the nine hospitals between March 2007 and December 2009. Eligibility criteria included: gestational age ≥ 37.0 weeks; singleton pregnancy; documented continuous FHR monitoring for ≥ 2 h before delivery; assessment of FHR tracing at least every 20 min; and, available maternal and neonatal outcomes. Adverse neonatal outcome was defined as nonanomalous infants admitted to the newborn intensive care unit with either a 5 minute Apgar score <7 or an umbilical artery pH<7.1. Initial risk score was determined using data available at 1 h after admission. Patients with an initial risk score between 7 and 15 were considered high risk. Intrapartum risk scores were then created for these patients using FHR tracing data and labor characteristics. RESULT: A total of 51 244 patients were identified meeting study criteria. Of the antepartum variables evaluated (n=31), 10 were associated with an adverse outcome. The high-risk group made up 28% of the population and accounted for 59.8% of the adverse outcomes. Intrapartum characteristics were then evaluated in this high-risk group. Intrapartum evaluation identified the highest risk group with a C/S rate of 40% and adverse outcome rate of 11.3%. CONCLUSION: Incorporation of maternal and antepartum risk factors with FHR analysis can improve the ability to identify the fetus at risk in labor.

Risk factors for recurrent preterm birth in multiparous Utah women: a historical cohort study.

OBJECTIVE: To describe risk factors for recurrent preterm birth (PTB) in the second and third birth. DESIGN: Historical cohort study. SETTING: Utah, USA. POPULATION: Women who had their first three singleton live births in Utah between 1989 and 2007 and a preterm first or second birth were included. METHODS: Maternally linked birth records were used. Multivariable-adjusted risk ratios were calculated for recurrent PTB. Results were stratified by spontaneous and indicated PTB and by pattern of birth outcomes. MAIN OUTCOME MEASURES: Risk ratios and 95% confidence intervals for risk factors for recurrent PTB. RESULTS: Among women with PTB in their first or second live birth, recurrent PTB occurred in 21% of second live births (n = 1011/4805) and 22% of third live births (n = 1872/8468). Risk factors for recurrence included short inter-pregnancy interval, underweight prepregnancy body mass index, pre-existing maternal medical conditions, history of PTB at 28-32 weeks of gestation (versus 33-36 weeks), the presence of a fetal anomaly, and young maternal age. Risk factors for spontaneous, but not indicated PTB included young maternal age and less than appropriate gestational weight gain. Risk factors also varied in women experiencing a first versus second recurrence in their third birth. CONCLUSIONS: Risk factors may vary by the clinical subtype of the most recent PTB and the pattern of term and preterm outcomes across births 1-3; some of the risk factors identified in this study may be modifiable through interventions targeted at women in the inter-conception period.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Low maternal middle cerebral artery Doppler resistance indices can predict future development of pre-eclampsia.

OBJECTIVE: To determine if decreased resistance (vasodilatation) in the maternal middle cerebral artery (MCA) in the second trimester can predict third-trimester development of pre-eclampsia. METHODS: Four-hundred and five low-risk gravidas had MCA transcranial Doppler (TCD) once in the second trimester. Maternal/neonatal outcomes were evaluated after delivery. Mean blood pressure, MCA velocities, resistance index (RI), pulsatility index (PI) and cerebral perfusion pressure (CPP) were compared between normotensive and pre-eclamptic cohorts. RESULTS: Seven subjects (1.7%) developed pre-eclampsia. An RI of < 0.54 and a PI of < 0.81 were clinically useful in predicting subsequent pre-eclampsia. Areas under the receiver-operating characteristics curves for RI and PI were 0.93 and 0.93, respectively, with optimal sensitivity and specificity of 86% and 93% for both variables. Positive and negative likelihood ratios were 11.8/0.15 (RI) and 12.3/0.15 (PI). CONCLUSION: TCD indices of low maternal MCA resistance in the second trimester are predictive of the subsequent development of pre-eclampsia in a low-risk, ethnically homogeneous population.

The association between prepregnancy obesity and screening positive for postpartum depression.

OBJECTIVE: To describe the association between reported prepregnancy body mass index (BMI) and screening positive for depression. DESIGN: Cohort study. SETTING: Four urban hospitals in Utah, USA. POPULATION: Women delivering a term, singleton, live-born infant at one of four urban hospitals in Utah in the period 2005-2007. METHODS: Women were enrolled immediately postpartum. Demographic, anthropometric, stressors, psychiatric, and medical/obstetric and family-history data were obtained. Prepregnancy height, weight, and pregnancy weight gain were self-reported. The primary exposure variable, prepregnancy BMI, was calculated. Women were stratified into the six World Health Organization BMI categories (underweight, normal weight, pre-obese, or obese class 1-3). MAIN OUTCOME MEASURE: At 6-8 weeks postpartum, women were screened for depression using the Edinburgh Postnatal Depression Scale (EPDS). The primary outcome measure was a prespecified EPDS score of > or =12. RESULTS: Among the 1053 women studied, 14.4% of normal weight women screened positive for postpartum depression. This proportion was greater in women classed as underweight (18.0%, n = 11), pre-obese (18.5%, n = 38), obese class 1 (18.8%, n = 16), obese class 2 (32.4%, n = 11), and obese class 3 (40.0%, n = 8) (P < 0.01). Controlling for demographic, psychological, and medical/obstetric factors, prepregnancy class-2 (aOR 2.87, 95% CI 1.21-6.81) and class-3 (aOR 3.94, 95% CI 1.38-11.23) obesity remained strongly associated with screening positive for postpartum depression, compared with women of normal weight. CONCLUSIONS: Self-reported prepregnancy obesity may be associated with screening positive for depression when measured postpartum.

Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery.

BACKGROUND: The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. OBJECTIVE: The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. RESULTS: By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. CONCLUSION: Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.

Maternal and neonatal outcomes of hospital vaginal deliveries in Tibet.

INTRODUCTION: To determine the outcomes of vaginal deliveries in three study hospitals in Lhasa, Tibet Autonomous Region (TAR), People's Republic of China (PRC), at high altitude (3650 m). METHODS: Prospective observational study of 1121 vaginal deliveries. RESULTS: Pre-eclampsia/gestational hypertension (PE/GH) was the most common maternal complication 18.9% (n=212), followed by postpartum hemorrhage (blood loss > or = 500 ml) 13.4%. There were no maternal deaths. Neonatal complications included: low birth weight (10.2%), small for gestational age (13.7%), pre-term delivery (4.1%) and low Apgar (3.7%). There were 11 stillbirths (9.8/1000 live births) and 19 early neonatal deaths (17/1000 live births). CONCLUSION: This is the largest study of maternal and newborn outcomes in Tibet. It provides information on the outcomes of institutional vaginal births among women delivering infants at high altitude. There was a higher incidence of PE/GH and low birth weight; rates of PPH were not increased compared to those at lower altitudes.

Placental abruption is more frequent in women with the angiotensinogen Thr235 mutation.

OBJECTIVE: Obstetrical complications such as preeclampsia, fetal growth restriction, and placental abruption are associated with inadequate placental perfusion. Previous studies have shown that the angiotensinogen (AGT) Thr235 mutation is associated with abnormal remodeling of the uterine spiral arteries and occurs at higher frequencies in preeclampsia. This study was done to evaluate whether the AGT Thr235 mutation increases the risk of placental abruption. MATERIALS AND METHODS: We compared 62 placentas from women who had placental abruption with 240 control patients of similar age and ethnicity. DNA was extracted from paraffin blocks from placentas. AGT Met235Thr mutation status was determined by single fluoresceine labeled probe real-time PCR using a LightCycler system. RESULT: AGT genotypes were divided into three groups: MM (homozygous wild), TT (homozygous mutant), and MT (heterozygous). The constituent ratio of AGT genotype in abrupted placentas (MM 14.5%, MT 43.5%, TT 41.9%) was significantly different from in control group (MM42.5%, MT 39.6%, TT 17.9%) (p<0.001). AGT mutant allele frequency in placental abruption (0.637) was significantly higher than in the control group (0.377) (p<0.001). CONCLUSION: The AGT Thr235 mutation was observed more frequently in placental abruption. AGT Thr235 mutation may be considered a risk factor for placental abruption.