Associations between interpregnancy interval and preterm birth by previous preterm birth status in four high-income countries: a cohort study.

OBJECTIVE: To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term. DESIGN: Cohort study. SETTING: USA (California), Australia, Finland, Norway (1980-2017). POPULATION: Women who gave birth to first and second (n = 3 213 855) singleton livebirths. METHODS: Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random effects meta-analysis. OUTCOME MEASURE: PTB (gestational age <37 weeks). RESULTS: Absolute risk of PTB for each IPI was 3-6% after a previous term birth and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction ≤ 0.001). For women with a previous term birth, pooled ORs were increased for IPI <6 months (OR 1.50, 95% CI 1.43-1.58); 6-11 months (OR 1.10, 95% CI 1.04-1.16); 24-59 months (OR 1.16, 95% CI 1.13-1.18); and ≥ 60 months (OR 1.72, 95%CI 1.60-1.86), compared with 18-23 months. For previous PTB, ORs were increased for <6 months (OR 1.30, 95% CI 1.18-1.42) and ≥60 months (OR 1.29, 95% CI 1.17-1.42), but were less than ORs among women with a previous term birth (P < 0.05). CONCLUSIONS: Associations between IPI and PTB are modified by whether or not the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given the high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB. TWEETABLE ABSTRACT: Short versus long interpregnancy intervals associated with higher ORs for preterm birth (PTB) after a previous PTB.

Cheek support affects lung mechanics measurements of tidal-based spontaneous breathing.

BACKGROUND AND OBJECTIVE: Patients are required to support their cheeks during breath-occluding lung function tests. This prevents cheek expansion which would alter pressure measured at the mouth, and, consequently, lung mechanics measurements. To date, the effect of cheek support on airway resistance measurements has been assessed. However other lung mechanics have not been studied as thoroughly, and no algorithm to account for the effect of missing cheek support on lung mechanics measurements has been developed. METHODS: Lung mechanics were assessed with a breath occlusion test during light panting in healthy subjects with and without cheek support in a body plethysmograph. Average model-based airway resistance, lung elastance, and a parameter representing the viscoelastic were measured. Results were compared to quantify the effect of cheek support on these three parameters. RESULTS: In the nine healthy subjects (5 Female, 4 Male) recruited for this study, all mechanics tended to be underestimated when cheeks were unsupported. Changes in elastance, resistance, and viscoelastic parameter ranged between 1.6-66.8 %, -4.5-21.8 %, and -4.7-68.2 %, respectively, when cheek support was added. The underestimation was due to reduced mouth pressure during cheek expansion when the breath was occluded. The variance of lung mechanics parameters did not change with cheek support in all subjects. CONCLUSIONS: The error in lung mechanics measurement caused by unsupported cheeks was subject dependent. Hence, no rule-of-thumb could be identified to reconstruct missing cheek support. For correct lung mechanics measurements during breath-occluding lung tests, patients must have adequate cheek support. ABBREVIATIONS: ROCC: Occlusion resistance; COPD: Chronic Obstructive Pulmonary Disorder; SB: spontaneous breathing.

Preterm birth phenotypes in women with autoimmune rheumatic diseases: a population-based cohort study.

OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort. DESIGN: Retrospective cohort study. SETTING: California, USA. POPULATION: All live singleton births in California between 2007 and 2011 were analysed. Patients with autoimmune disease at delivery were identified by International Classification of Diseases, Ninth Revision , Clinical Modification (ICD-9-CM), codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA). METHODS: Maternally linked hospital and birth certificate records of 2 481 516 deliveries were assessed (SLE n = 2272, RA n = 1501, SSc n = 88, JIA n = 187, DM/PM n = 38). Multivariable Poisson regression models estimated the risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared with the general obstetric population, adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care. MAIN OUTCOME MEASURES: Preterm birth (PTB) was assessed overall (20-36 weeks of gestation) and by subphenotype: preterm prelabour rupture of membranes (PPROM), spontaneous birth, or medically indicated PTB. The risk of PTB overall and for each phenotype was partitioned by gestational age: early (20-31 weeks of gestation) and late (32-36 weeks of gestation). RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27, 95% CI 3.01-3.56), RA (RR 2.04, 95% CI 1.79-2.33), SSc (RR 3.74, 95% CI 2.51-5.58), JIA (RR 2.23, 95% CI 1.54-3.23), and DM/PM (RR 5.26, 95% CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well. CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counselling and close monitoring during pregnancy is crucial. TWEETABLE ABSTRACT: This study found that women with systemic autoimmune diseases have an elevated risk of preterm birth phenotypes.

Disease burden in offspring is associated with changing paternal demographics in the United States.

BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease. OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States. METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States. RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16 years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5 years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40 years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21 years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17 years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30 years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25 years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort. CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.

Inspiratory respiratory mechanics estimation by using expiratory data for reverse-triggered breathing cycles.

BACKGROUND AND OBJECTIVE: Model-based lung mechanics monitoring can provide clinically useful information for guiding mechanical ventilator treatment in intensive care. However, many methods of measuring lung mechanics are not appropriate for both fully and partially sedated patients, and are unable provide lung mechanics metrics in real-time. This study proposes a novel method of using lung mechanics identified during passive expiration to estimate inspiratory lung mechanics for spontaneously breathing patients. METHODS: Relationships between inspiratory and expiratory modeled lung mechanics were identified from clinical data from 4 fully sedated patients. The validity of these relationships were assessed using data from a further 4 spontaneously breathing patients. RESULTS: For the fully sedated patients, a linear relationship was identified between inspiratory and expiratory elastance, with slope 1.04 and intercept 1.66. The r value of this correlation was 0.94. No cohort-wide relationship was determined for airway resistance. Expiratory elastance measurements in spontaneously breathing patients were able to produce reasonable estimates of inspiratory elastance after adjusting for the identified difference between them. CONCLUSIONS: This study shows that when conventional methods fail, typically ignored expiratory data may be able to provide clinicians with the information needed about patient condition to guide MV therapy.

A virtual patient model for mechanical ventilation.

BACKGROUND AND OBJECTIVES: Mechanical ventilation (MV) is a primary therapy for patients with acute respiratory failure. However, poorly selected ventilator settings can cause further lung damage due to heterogeneity of healthy and damaged alveoli. Varying positive-end-expiratory-pressure (PEEP) to a point of minimum elastance is a lung protective ventilator strategy. However, even low levels of PEEP can lead to ventilator induced lung injury for individuals with highly inflamed pulmonary tissue. Hence, models that could accurately predict peak inspiratory pressures after changes to PEEP could improve clinician confidence in attempting potentially beneficial treatment strategies. METHODS: This study develops and validates a physiologically relevant respiratory model that captures elastance and resistance via basis functions within a well-validated single compartment lung model. The model can be personalised using information available at a low PEEP to predict lung mechanics at a higher PEEP. Proof of concept validation is undertaken with data from four patients and eight recruitment manoeuvre arms. RESULTS: Results show low error when predicting upwards over the clinically relevant pressure range, with the model able to predict peak inspiratory pressure with less than 10% error over 90% of the range of PEEP changes up to 12 cmH2O. CONCLUSIONS: The results provide an in-silico model-based means of predicting clinically relevant responses to changes in MV therapy, which is the foundation of a first virtual patient for MV.

Out-of-hospital births in California 1991-2011.

OBJECTIVE: We investigated the frequencies and characteristics of out-of-hospital births in a 20-year period in California, where 1 of every 7 births in the United States occurs. STUDY DESIGN: Birth certificate records of deliveries in California between 1991 and 2011 were analyzed. Out-of-hospital births were assessed by year, parity, gestational age and maternal race/ethnicity. RESULTS: In the 20-year period there were 10 593,904 deliveries, of which 46 243 occurred out of hospital (0.44%). Out-of-hospital births decreased from 0.54 to 0.38% per year between 1991 and 2004, and increased from 0.41% in 2005 to 0.61% in 2011. In contrast, preterm out-of-hospital births declined from 7.2% in 2006 to 5.0% in 2011. The frequency of vaginal birth after cesarean in the out-of-hospital birth cohort increased from 1.2% (n=19) in 1996 to 4.2% (n=82) in 2011. CONCLUSION: California birth records from a 20-year period show an increase in out-of-hospital births from years 2005 to 2011, following a period of decline from 1991 to 2004.

'The obesity paradox': a reconsideration of obesity and the risk of preterm birth.

OBJECTIVE: The association between obesity and spontaneous preterm births (sPTBs) has been shown to be influenced by obesity-attendant comorbidities. Our objective was to better understand the complex relationship of obesity and its attendant comorbidities with sPTBs. STUDY DESIGN: A retrospective analysis utilizing maternally linked hospital and birth certificate records of 2 049 196 singleton California deliveries from 2007 to 2011. Adjusted relative risks (aRRs) for sPTBs were estimated using multivariate Poisson regression modeling. RESULTS: Obese women had higher aRRs for sPTBs than their normal body mass index (BMI) controls. aRRs (95% confidence interval) increased with increasing BMI category: Obese I=1.10 (1.08 to 1.12); Obese II=1.15 (1.12 to 1.18); and Obese III=1.26 (1.22 to 1.30). When comparing only obese women without comorbidities to their normal BMI controls, aRRs reversed, that is, obese women had lower aRRs of sPTBs: Obese I=0.96 (0.94 to 0.98), Obese II=0.95 (0.91 to 0.98); and Obese III=0.98 (0.94 to 1.03). This same reversal of aRR direction was also observed among women with comorbidities: 0.92 (0.89 to 0.96); 0.89 (0.85 to 0.93); and 0.89 (0.85 to 0.93), respectively. Increasing BMI increased the aRRs for sPTBs among patients with gestational diabetes (P<0.05), while decreasing the risk among patients with chronic hypertension and pregnancy-related hypertensive disease (P<0.05). CONCLUSIONS: The obesity and preterm birth paradox is an example of what has been described as 'Simpson's Paradox'. Unmeasured confounding factors mediated by comorbidities may explain the observed protective effect of obesity upon conditioning on the presence or absence of comorbidities and thus resolve the paradox.

Effective sample size estimation for a mechanical ventilation trial through Monte-Carlo simulation: Length of mechanical ventilation and Ventilator Free Days.

Randomised control trials have sought to seek to improve mechanical ventilation treatment. However, few trials to date have shown clinical significance. It is hypothesised that aside from effective treatment, the outcome metrics and sample sizes of the trial also affect the significance, and thus impact trial design. In this study, a Monte-Carlo simulation method was developed and used to investigate several outcome metrics of ventilation treatment, including 1) length of mechanical ventilation (LoMV); 2) Ventilator Free Days (VFD); and 3) LoMV-28, a combination of the other metrics. As these metrics have highly skewed distributions, it also investigated the impact of imposing clinically relevant exclusion criteria on study power to enable better design for significance. Data from invasively ventilated patients from a single intensive care unit were used in this analysis to demonstrate the method. Use of LoMV as an outcome metric required 160 patients/arm to reach 80% power with a clinically expected intervention difference of 25% LoMV if clinically relevant exclusion criteria were applied to the cohort, but 400 patients/arm if they were not. However, only 130 patients/arm would be required for the same statistical significance at the same intervention difference if VFD was used. A Monte-Carlo simulation approach using local cohort data combined with objective patient selection criteria can yield better design of ventilation studies to desired power and significance, with fewer patients per arm than traditional trial design methods, which in turn reduces patient risk. Outcome metrics, such as VFD, should be used when a difference in mortality is also expected between the two cohorts. Finally, the non-parametric approach taken is readily generalisable to a range of trial types where outcome data is similarly skewed.

Interpregnancy interval after live birth or pregnancy termination and estimated risk of preterm birth: a retrospective cohort study.

OBJECTIVES: We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB). DESIGN: Multiyear birth cohort. SETTINGS: Fetal death, birth and infant death certificates in California merged with Office of Statewide Health Planning and Development. POPULATION: One million California live births (2007-10) after live birth and after pregnancy termination. METHODS: Logistic regression was used to estimate odds ratios (ORs) of PTB of 20-36 weeks of gestation and its subcategories for IPIs after a live birth and after a pregnancy termination. We used conditional logistic regression (two IPIs/mother) to investigate associations within mothers. MAIN OUTCOME MEASURE: PTB relative to gestations of ≥ 37 weeks. RESULTS: Analyses included 971 211 women with IPI after live birth, and 138 405 women with IPI after pregnancy termination with 30.6% and 74.6% having intervals of <18 months, respectively. IPIs of <6 months or 6-11 months after live birth showed increased odds of PTB adjusted ORs for PTB of 1.71 (95% CI 1.65-1.78) and 1.20 (95% CI 1.16-1.24), respectively compared with intervals of 18-23 months. An IPI >36 months (versus 18-23 months) was associated with increased odds for PTB. Short IPI after pregnancy termination showed a decreased OR of 0.87 (95% CI 0.81-0.94). The within-mother analysis showed the association of increased odds of PTB for short IPI, but not for long IPI. CONCLUSIONS: Women with IPI <1 or >3 years after a live birth were at increased odds of PTB-an important group for intervention to reduce PTB. Short IPI after pregnancy termination was associated with reduced odds for PTB and needs to be further explored. TWEETABLE ABSTRACT: Short and long IPI after live birth, but not after pregnancy termination, showed increased odds for PTB.

Women's prepregnancy underweight as a risk factor for preterm birth: a retrospective study.

OBJECTIVE: To investigate the distribution of known factors for preterm birth (PTB) by severity of maternal underweight; to investigate the risk-adjusted relation between severity of underweight and PTB, and to assess whether the relation differed by gestational age. DESIGN: Retrospective cohort study. SETTING: State of California, USA. METHODS: Maternally linked hospital and birth certificate records of 950 356 California deliveries in 2007-2010 were analysed. Singleton live births of women whose prepregnancy body mass index (BMI) was underweight (<18.5 kg/m2 ) or normal (18.50-24.99 kg/m2 ) were analysed. Underweight BMI was further categorised as: severe (<16.00), moderate (16.00-16.99) or mild (17.00-18.49). PTB was grouped as 22-27, 28-31, 32-36 or <37 weeks (compared with 37-41 weeks). Adjusted multivariable Poisson regression modeling was used to estimate relative risk for PTB. MAIN OUTCOME MEASURES: Risk of PTB. RESULTS: About 72 686 (7.6%) women were underweight. Increasing severity of underweight was associated with increasing percent PTB: 7.8% (n = 4421) in mild, 9.0% (n = 1001) in moderate and 10.2% (475) in severe underweight. The adjusted relative risk of PTB also significantly increased: adjusted relative risk (aRR) = 1.22 (95% CI 1.19-1.26) in mild, aRR = 1.41 (95% CI 1.32-1.50) in moderate and aRR = 1.61 (95% CI 1.47-1.76) in severe underweight. These findings were similar in spontaneous PTB, medically indicated PTB, and the gestational age groupings. CONCLUSION: Increasing severity of maternal prepregnancy underweight BMI was associated with increasing risk-adjusted PTB at <37 weeks. This increasing risk was of similar magnitude in spontaneous and medically indicated births and in preterm delivery at 28-31 and at 32-36 weeks of gestation. TWEETABLE ABSTRACT: Increasing severity of maternal underweight BMI was associated with increasing risk of preterm birth.

Body Mass Index Change between Pregnancies and Risk of Spontaneous Preterm Birth.

Objective Studies have reported an increased risk of spontaneous preterm birth associated with elevated prepregnancy body mass index (BMI) among nulliparous but not multiparous women. We examined whether changes in BMI and weight between pregnancies contributed to risk of preterm birth among obese (BMI > 29 kg/m(2)) women. Study Design This study utilized maternally linked California birth records of sequential singleton births between 2007 and 2010. Preterm birth was defined as 20 to 31 or 32 to 36 weeks of gestation. BMI was examined as category change and by tertile of weight change. Primary analyses included women without diabetes or hypertensive disorders; these women were compared with those without prior preterm birth, women with preterm deliveries preceded by spontaneous preterm labor, and women without any exclusions (i.e., diabetes or hypertensive disorders). Results Analyses showed that obesity was not associated with increased risk of spontaneous preterm birth among multiparous women. Women whose BMI increased had a decreased risk of spontaneous preterm birth at 32 to 36 weeks. Change in BMI or weight between pregnancies did not substantively alter results. Conclusion Among multiparous women, obesity was associated with reduced risk of spontaneous preterm delivery. This observed association is complex and may be influenced by maternal age, gestational age, placental insufficiency, and altered immune response.

The effect of titrated fentanyl on suppressed cough reflex in healthy adult volunteers.

Cough suppression is part of the pharmacodynamic profile of opioids. We investigated the impact of clinical doses of fentanyl on suppressing the cough reflex. Thirteen volunteers received 2 µg.kg(-1) of fentanyl in a divided administration protocol. Three minutes after each administration and at 10 min intervals during washout, suppressed cough reflex testing with nebulised citric acid was performed and compared with fentanyl effect-site concentration. Mean (SD) citric acid concentration provoking cough increased from 0.5 (0.28) mol.l(-1) at baseline to 1.2 (0.50) mol.l(-1) after 2 µg.kg(-1) of fentanyl (p = 0.01). Mean (SD) fentanyl effect-site concentration after the final dose of fentanyl was 1.89 (0.05) ng.ml(-1) . A strong positive correlation was found between suppressed cough reflex thresholds and fentanyl effect-site concentrations during both fentanyl administration and washout phases of the study (r(2) = 0.79, p = 0.01). The mean (SD) length of time for return of suppressed cough response was 44.6 (18.8) min. Clinically relevant doses of fentanyl produced cough reflex suppression in healthy volunteers.

Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants.

OBJECTIVE: To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery. STUDY DESIGN: A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids. RESULTS: The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05. CONCLUSION: Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.

Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth.

OBJECTIVE: To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes. DESIGN: Population-based cohort. SETTING: California, United States of America. POPULATION: From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included. METHODS: Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results. MAIN OUTCOME MEASURE: PTB by subtype. RESULTS: In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2). CONCLUSIONS: Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies. TWEETABLE ABSTRACT: Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.

Maternal serum markers, characteristics and morbidly adherent placenta in women with previa.

OBJECTIVE: To examine associations with morbidly adherent placenta (MAP) among women with placenta previa. STUDY DESIGN: Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236,714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls. RESULT: In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ⩾95th percentile (⩾2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ⩾95th percentile (⩾1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ⩾2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively). CONCLUSION: Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa.

Craniosynostosis and risk factors related to thyroid dysfunction.

Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable.

Stroke Volume estimation using aortic pressure measurements and aortic cross sectional area: Proof of concept.

Accurate Stroke Volume (SV) monitoring is essential for patient with cardiovascular dysfunction patients. However, direct SV measurements are not clinically feasible due to the highly invasive nature of measurement devices. Current devices for indirect monitoring of SV are shown to be inaccurate during sudden hemodynamic changes. This paper presents a novel SV estimation using readily available aortic pressure measurements and aortic cross sectional area, using data from a porcine experiment where medical interventions such as fluid replacement, dobutamine infusions, and recruitment maneuvers induced SV changes in a pig with circulatory shock. Measurement of left ventricular volume, proximal aortic pressure, and descending aortic pressure waveforms were made simultaneously during the experiment. From measured data, proximal aortic pressure was separated into reservoir and excess pressures. Beat-to-beat aortic characteristic impedance values were calculated using both aortic pressure measurements and an estimate of the aortic cross sectional area. SV was estimated using the calculated aortic characteristic impedance and excess component of the proximal aorta. The median difference between directly measured SV and estimated SV was -1.4ml with 95% limit of agreement +/- 6.6ml. This method demonstrates that SV can be accurately captured beat-to-beat during sudden changes in hemodynamic state. This novel SV estimation could enable improved cardiac and circulatory treatment in the critical care environment by titrating treatment to the effect on SV.

Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism.

We examined whether variants in genes related to sex hormone biosynthesis and metabolism were associated with hypospadias in humans. We examined 332 relatively common tag single-nucleotide polymorphisms (tagSNPs) in 20 genes. Analyses included 633 cases (84 mild, 322 moderate, 212 severe and 15 undetermined severity) and 855 population-based non-malformed male controls born in California from 1990 to 2003. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Several of the 332 studied SNPs had p < 0.01: one in CYP3A4, four in HSD17B3, one in HSD3B1, two in STARD3, 10 in SRD5A2 and seven in STS. In addition, haplotype analyses gave several associations with p < 0.01. For HSD17B3, 14-SNP and 5-SNP blocks had ORs of 1.5 (95% CI 1.1, 2.0, p < 0.001) and 2.8 (95% CI 1.6, 4.8, p < 0.001) respectively. For SRD5A2, 9-SNP, 3-SNP and 8-SNP blocks had ORs of 1.7 (95% CI 1.3, 2.2, p < 0.001), 1.4 (95% CI 1.1, 1.8, p = 0.008) and 1.5 (95% CI 1.2, 1.9, p = 0.002) respectively. Our study indicates that several genes that contribute to sex hormone biosynthesis and metabolism are associated with hypospadias risk.

Off-line breath acetone analysis in critical illness.

Analysis of breath acetone could be useful in the Intensive Care Unit (ICU) setting to monitor evidence of starvation and metabolic stress. The aims of this study were to examine the relationship between acetone concentrations in breath and blood in critical illness, to explore any changes in breath acetone concentration over time and correlate these with clinical features. Consecutive patients, ventilated on controlled modes in a mixed ICU, with stress hyperglycaemia requiring insulin therapy and/or new pulmonary infiltrates on chest radiograph were recruited. Once daily, triplicate end-tidal breath samples were collected and analysed off-line by selected ion flow tube mass spectrometry (SIFT-MS). Thirty-two patients were recruited (20 males), median age 61.5 years (range 26-85 years). The median breath acetone concentration of all samples was 853 ppb (range 162-11 375 ppb) collected over a median of 3 days (range 1-8). There was a trend towards a reduction in breath acetone concentration over time. Relationships were seen between breath acetone and arterial acetone (rs = 0.64, p < 0.0001) and arterial beta-hydroxybutyrate (rs = 0.52, p < 0.0001) concentrations. Changes in breath acetone concentration over time corresponded to changes in arterial acetone concentration. Some patients remained ketotic despite insulin therapy and normal arterial glucose concentrations. This is the first study to look at breath acetone concentration in ICU patients for up to 8 days. Breath acetone concentration may be used as a surrogate for arterial acetone concentration, which may in future have a role in the modulation of insulin and feeding in critical illness.