Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease.

Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn's disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.

Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine /mercaptopurine.

BACKGROUND: Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond. AIM: To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP. METHODS: A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. RESULTS: Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals. CONCLUSIONS: Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.

Impaired neutrophil chemotaxis in Crohn's disease relates to reduced production of chemokines and can be augmented by granulocyte-colony stimulating factor.

BACKGROUND: Defective neutrophil recruitment has been described as a primary pathogenic abnormality in Crohn's disease. Cantharidin-induced blisters provide a novel investigative tool to assess cellular influx and inflammatory mediator production during acute inflammation and allows the effects of therapy on these parameters to be measured. AIMS: To determine whether reduced neutrophil tissue penetration in Crohn's disease relates to impaired production of inflammatory mediators, and whether it can be reversed by granulocyte-colony stimulating factor (G-CSF). METHODS: Neutrophil and monocyte/macrophage populations and inflammatory mediators were measured in cantharidin blisters at 24 h. Neutrophil chemotaxis was assessed in vitro using blister fluid as the chemoattractant. The effect of s.c. G-CSF on blister phenotype was determined. RESULTS: Significantly fewer neutrophils migrated into blisters in Crohn's patients. The production of neutrophil chemokines, but not other inflammatory mediators, was reduced. This significantly correlated with reduced chemotaxis in vitro. Differences were unrelated to caspase-recruitment domain 15 genotype. G-CSF significantly increased blister neutrophil concentrations in control subjects and Crohn's patients. CONCLUSIONS: Reduced neutrophil migration during acute inflammation in Crohn's disease is associated with impaired production of appropriate chemoattractants. G-CSF therapy increases neutrophil tissue migration, which may partially account for its observed therapeutic effect.

A randomized trial of the effects of coached vs uncoached maternal pushing during the second stage of labor on postpartum pelvic floor structure and function.

OBJECTIVE: The purpose of this study was to determine if refraining from coached pushing during the second stage of labor affects postpartum urogynecologic measures of pelvic floor structure and function. STUDY DESIGN: Nulliparous women at term were randomized to coached (n = 67) vs uncoached (n = 61) pushing. At 3 months' postpartum women underwent urodynamic testing, pelvic organ prolapse examination (POPQ), and pelvic floor neuromuscular assessment. RESULTS: Urodynamic testing revealed decreased bladder capacity (427 mL vs 482 mL, P = .051) and decreased first urge to void (160 mL vs 202 mL, P = .025) in the coached group. Detrusor overactivity increased 2-fold in the coached group (16% vs 8%), although this difference was not statistically significant (P = .17). Urodynamic stress incontinence was diagnosed in the coached group in 11/67 (16%) vs 7/61 (12%) in the uncoached group (P = .42). CONCLUSION: Coached pushing in the second stage of labor significantly affected urodynamic indices, and was associated with a trend towards increased detrusor overactivity.

Recurrence of preterm birth in singleton and twin pregnancies.

OBJECTIVE: To assess recurrence of preterm birth and its impact on an obstetric population. METHODS: Women with consecutive births at our hospital beginning with their first pregnancy were identified (n = 15,945). The first pregnancy was categorized as delivered between 24 and 34 weeks' gestation or 35 weeks or beyond, singleton or twin, and spontaneous or induced. The risk of preterm delivery in these same women during subsequent pregnancies was then analyzed. RESULTS: Compared with women who delivered a singleton at or beyond 35 weeks' gestation in their first pregnancy, those who delivered a singleton before 35 weeks were at a significant increased risk for recurrence (odds ratio [OR] 5.6, 95% confidence interval [CI] 4.5, 7.0), whereas those who delivered twins were not (OR 1.9, 95% CI 0.46, 8.14). The OR for recurrent spontaneous preterm birth presenting with intact membranes was 7.9 (95% CI 5.6, 11.3) compared with 5.5 (95% CI 3.2, 9.4) with ruptured membranes. Of those women with a recurrent preterm birth, 49% delivered within 1 week of the gestational age of their first delivery and 70% delivered within 2 weeks. Among 15,863 nulliparous women with singleton births at their first delivery, a history of preterm birth in that pregnancy could predict only 10% of the preterm births that ultimately occurred in the entire obstetric population. CONCLUSION: In a population-based study at our hospital, women who initially delivered preterm and thus were identified to be at risk for recurrence ultimately accounted for only 10% of the prematurity problem in the cohort.

Antenatal dexamethasone and decreased birth weight.

OBJECTIVE: To test the hypothesis that antenatal dexamethasone treatment to promote fetal lung maturation results in decreased birth weight corrected for gestational age. METHODS: The birth weights of all dexamethasone-treated, singleton, live-born infants delivered at our hospital were compared with our overall obstetric population; a group of untreated infants frequency matched approximately 3:1 according to maternal race, infant sex, and gestational age at delivery; and an historical cohort of infants with an indication for dexamethasone but delivered in the 12 months before the introduction of corticosteroid therapy at our hospital. RESULTS: Dexamethasone-treated infants (n = 961), when compared with either the overall population (n = 122,629) or matched controls (n = 2808), had significantly lower birth weights after adjustment for week of gestation (P <.001). Compared with the historical cohort of infants, the average birth weight of dexamethasone-treated infants was smaller by 12 g at 24-26 weeks, 63 g at 27-29 weeks, 161 g at 30-32 weeks, and 80 g at 33-34 weeks' gestation. CONCLUSION: Antenatal dexamethasone administered to promote fetal maturation is associated with diminished birth weight.

An appraisal of treatment guidelines for antepartum community-acquired pneumonia.

OBJECTIVE: The optimal strategy for the initial evaluation and management, including criteria for hospitalization, of pregnant women with pneumonia has not been defined. Our purpose was to evaluate a treatment protocol for antepartum pneumonia and to identify criteria for selection of women for potential outpatient treatment. STUDY DESIGN: A protocol based on British and American Thoracic Society guidelines was introduced and included prompt hospitalization and empiric initiation of erythromycin therapy. Maternal and neonatal outcomes were analyzed to assess the efficacy of the protocol. A second analysis involved the retrospective application of published guidelines to ascertain for which women outpatient management might have been appropriate. RESULTS: There were no maternal deaths among the 133 women studied, and in 14 (10%) women there was a misdiagnosis at admission. Erythromycin monotherapy was judged adequate in all but one of the 99 women so treated. Using a modified version of the American Thoracic Society guidelines, we project that only 25% of the women hospitalized with pneumonia could have been managed safely as outpatients. CONCLUSION: Most pregnant women with pneumonia respond well to monotherapy with erythromycin. Outpatient management may be a reasonable option for selected women.

Sexual violence: the victim.

Molestation and rape in childhood or adulthood is sexual violence. This chapter discusses issues for sexual violence victims and suggests several best practices for this population.

Treating traumatized patients and victims of violence.

This chapter presents a thorough exposition of treating traumatized patients and victims of violence, addressing many aspects of trauma and victimization critical to a vast proportion of the work that mental health professionals find themselves doing.

Pregnancy outcomes after antepartum diagnosis of oligohydramnios at or beyond 34 weeks' gestation.

OBJECTIVE: Our purpose was to assess whether antepartum oligohydramnios is associated with adverse perinatal outcomes. STUDY DESIGN: Women delivered between July 1, 1991, and September 30, 1996, who underwent ultrasonography at >/=34 weeks' gestation were analyzed. Oligohydramnios was defined as an amniotic fluid index 50 mm. RESULTS: In our analysis of 6423 pregnancies, 147 (2.3%) were complicated by oligohydramnios. This complication was associated with increased labor induction (42% vs 18%; P <.001), stillbirth (1. 4% vs 0.3%; P <.03), nonreassuring fetal heart rate (48% vs 39%; P <. 03), admission to the neonatal intensive care nursery (7% vs 2%; P <. 001), meconium aspiration syndrome (1% vs 0.1%; P <.001), and neonatal death (5% vs 0.3%; P <.001). CONCLUSION: Antepartum oligohydramnios is associated with increased perinatal morbidity and mortality.

Fetal pulse oximetry: duration of desaturation and intrapartum outcome.

OBJECTIVE: To analyze labor outcomes in relation to masked fetal arterial oxyhemoglobin saturation values above or below 30%. METHODS: Consenting gravidas with uncomplicated pregnancies at or beyond 36 weeks' gestation underwent continuous fetal pulse oximetry. Pregnancy outcomes were compared between two groups: women with fetuses with at least one epoch of arterial oxyhemoglobin saturation below 30% (10 seconds or longer) and women with fetuses without such an episode. We also attempted to ascertain whether duration of saturation below 30% correlated with fetal compromise. RESULTS: We measured arterial oxyhemoglobin saturation in 129 fetuses, 69 (53%) of whom had at least one epoch of saturation below 30%. There were no statistically significant differences in labor and delivery outcomes between the high-saturation and low-saturation groups (eg, cesarean delivery: 13 versus 9%, P = .41; umbilical artery [UA] pH less than 7.20: 10 versus 9%, P > .999). However, as duration of fetal arterial oxyhemoglobin saturation below 30% increased from 10 seconds to longer than 9 consecutive minutes, the incidence of fetal compromise (considered present when at least one of the following criteria was met: cesarean delivery for nonreassuring fetal heart rate pattern, UA pH less than 7.20, admission to the special care nursery, or 5-minute Apgar score not more than 3) increased significantly (P = .002). The threshold duration of fetal arterial oxyhemoglobin saturation below 30% associated with increased fetal compromise was 2 minutes. CONCLUSION: Transient fetal arterial oxyhemoglobin saturation values below 30% are common during normal labor and did not predict fetal compromise. Fetal arterial oxyhemoglobin saturation values less than 30% for 2 minutes or longer might be associated with fetal compromise.

Severe preeclampsia and the very low birth weight infant: is induction of labor harmful?

OBJECTIVE: To compare the effects of labor induction with the effects of cesarean delivery without labor on neonatal outcome in pregnancies complicated by severe preeclampsia and delivery of very low birth weight infants. METHODS: This was a retrospective study of 278 singleton, live-born infants who weighed 750-1500 g and were delivered because of severe preeclampsia between 1988 and 1997. Outcomes of infants delivered by cesarean without labor were compared with those of infants exposed to labor induction. Statistical analysis was performed using Student t test, Mann-Whitney U test, chi2 analysis, and Fisher exact test, where appropriate. Multiple logistic regression analysis was used to adjust for outcomes of interest. RESULTS: One hundred forty-five (52%) of the 278 women with severe preeclampsia who delivered infants weighing between 750 and 1500 g had labor induced and 133 (48%) delivered by cesarean without labor. Vaginal delivery was accomplished by 50 (34%) women in the induced group. Apgar scores of 3 or less at 5 minutes were more likely in the induced-labor group (6 versus 2%, P = .04), but other neonatal outcomes, including respiratory distress syndrome, grade 3 or 4 intraventricular hemorrhage, sepsis, seizures, and neonatal death, were similar in the two groups. Adjustment for birth weight and gestational age did not affect those results. Analysis of data from the induced-labor group did not reveal an effect by route of delivery on neonatal outcome. CONCLUSION: Induction of labor in cases of severe preeclampsia is not harmful to very low birth weight infants.

Pitfalls in ultrasonic cervical length measurement for predicting preterm birth.

OBJECTIVE: To describe the anatomic and technical difficulties encountered with transvaginal ultrasound imaging of the cervix in a consecutive series of women at risk for preterm delivery. METHODS: Three groups of women had cervical ultrasound examinations: those with histories of preterm birth, those with incompetent cervices, and those admitted for preterm labor that did not progress. Standardized ultrasound examinations of the cervix involved measuring the length of the endocervical canal, funneling length, and internal os dilation with and without fundal pressure. RESULTS: Sixty consecutive women had transvaginal ultrasound examinations for assessment of the cervix. Forty-six had histories of preterm birth, five had incompetent cervices, and nine had arrested preterm labor. Six types of problems arose, which can be divided into anatomic or technical considerations, with an overall frequency of 27% (95% confidence interval 16%, 40%). Anatomic pitfalls that hampered identification of the internal os included an undeveloped lower uterine segment (n = 5), a focal myometrial contraction (n = 1), rapid and spontaneous cervical change (n = 1), and an endocervical polyp (n = 1). Technical pitfalls included incorrect interpretation of internal os dilation because of vaginal probe orientation (n = 7) and artificial lengthening of the endocervical canal because of distortion of the cervix by the transducer (n = 1). CONCLUSION: We caution those who perform cervical length examinations to be wary of falsely reassuring findings due to potential anatomic and technical pitfalls.

Birth weight in relation to morbidity and mortality among newborn infants.

BACKGROUND: At any given gestational age, infants with low birth weight have relatively high morbidity and mortality. It is not known, however, whether there is a threshold weight below which morbidity and mortality are significantly greater, or whether that threshold varies with gestational age. METHODS: We analyzed the neonatal outcomes of death, five-minute Apgar score, umbilical-artery blood pH, and morbidity due to prematurity for all singleton infants delivered at Parkland Hospital, Dallas, between January 1, 1988, and August 31, 1996. A distribution of birth weights according to week of gestation at birth was created. Infants in the 26th through 75th percentiles for weight served as the reference group. Data on preterm infants (those born at 24 to 36 weeks of gestation) were analyzed separately from data on infants delivered at term (37 or more weeks of gestation). RESULTS: A total of 122,754 women and adolescents delivered singleton live infants without malformations between 24 and 43 weeks of gestation. Among the 12,317 preterm infants who were analyzed, there was no specific birth-weight percentile at which morbidity and mortality increased. Among 82,361 infants who were born at term and whose birth weights were at or below the 75th percentile, however, the rate of neonatal death increased from 0.03 percent in the reference group (26th through 75th percentile for weight) to 0.3 percent for those with birth weights at or below the 3rd percentile (P<0.001). The incidence of five-minute Apgar scores of 3 or less and umbilical-artery blood pH values of 7.0 or less was approximately doubled for infants at or below the 3rd birth-weight percentile (P=0.003 and P<0.001, respectively). The incidence of intubation at birth, seizures during the first day of life, and sepsis was also significantly increased among term infants with birth weights at or below the 3rd percentile. These differences persisted after adjustment for the mother's race and parity and the infant's sex. CONCLUSIONS: Mortality and morbidity are increased among infants born at term whose birth weights are at or below the 3rd percentile for their gestational age.

Atherosis revisited: current concepts on the pathophysiology of implantation site disorders.

There are two distinct histological manifestations of impaired placental implantation in humans--incomplete trophoblastic vascular invasion and atherosis. Both have been described to occur in pregnancies affected by a variety of disorders such as preeclampsia, fetal growth restriction, systemic lupus erythematosus, and diabetes. Our purpose was to integrate recent developments in the understanding of implantation site disorders into a pathophysiological scenario that interrelates these placentation disorders and associated pregnancy complications. Sources were identified from a MEDLINE search of English-language articles published from 1966 to 1997. Additional sources were identified from references cited in relevant reports. We selected articles relating to the following topics: atherosis, implantation site disorders, trophoblastic invasion, preeclampsia, fetal growth restriction, implantation site development, atherosclerosis, and endothelial activation-damage. A contemporary version of normal placentation, including vascular adaptation, was reviewed with comments on normal trophoblastic differentiation and vascular invasion. Specific abnormalities of the implantation site, including atherosis and incomplete trophoblastic invasion, were discussed in the context of placental site hypoperfusion and the association with pregnancy complications. It was concluded that atherosis and incomplete trophoblastic invasion may be both a consequence and a cause of placental site hypoperfusion resulting in the development of preeclampsia and a variety of other pregnancy disorders.

Lack of effect of walking on labor and delivery.

BACKGROUND AND METHODS: Walking during labor may reduce patients' discomfort and improve outcomes. We conducted a randomized trial of walking during active labor to determine whether it altered the duration of labor or other maternal or fetal outcomes. Women with uncomplicated pregnancies between 36 and 41 weeks' gestation and in active labor were randomly assigned either to walking or to no walking (usual care). Pedometers were used to quantify walking, and the time spent walking was recorded. RESULTS: Of the 536 women assigned to the walking group, 380 actually walked. Their mean (+/-SD) walking time was 56+/-46 minutes. There were no significant differences between the women assigned to the walking group and the 531 women assigned to the usual-care group in the duration of the first stage of labor (6.1 hours in both groups, P=0.83), the need for labor augmentation with oxytocin (23 percent vs. 26 percent, P=0.25), and the use of analgesia (84 percent vs. 86 percent, P=0.59). Similarly, the percentages of women requiring delivery by forceps (4 percent vs. 3 percent, P=0.35) and cesarean section (4 percent vs. 6 percent, P=0.25) were not significantly different. These labor and delivery outcomes were unrelated to walking in both nulliparous and parous women. The infants' outcomes were also similar in the two study groups. CONCLUSIONS: Walking neither enhanced nor impaired active labor and was not harmful to the mothers or their infants.

A randomized placebo-controlled evaluation of terbutaline for external cephalic version.

OBJECTIVE: To evaluate the efficacy of subcutaneous terbutaline therapy on the success rate of external cephalic version in term gestation. METHODS: Women with singleton noncephalic gestations were assigned randomly to receive either terbutaline (0.25 mg) or placebo. Physicians were blinded to the assignment. Fifteen to 30 minutes after the study drug was administered, external cephalic version was attempted. It was discontinued after three attempts, for patient discomfort, for fetal heart rate decelerations, or when successful. Patients were discharged home after the procedure and allowed to enter spontaneous labor. Primary outcomes evaluated included initial success of version, presentation in labor, and route of delivery. RESULTS: One hundred three women were enrolled in the study between January 1994 and June 1995, of whom 52 were assigned to terbutaline and 51 to placebo. External cephalic version was successful in 27 of 52 (52%) women receiving terbutaline compared with 14 of 51 (27%) of those receiving placebo (P = .019). This comparison yielded a relative risk (RR) of 1.9 (95% confidence interval [CI] 1.3, 6.5). Four of the 27 (15%) successful versions in the terbutaline group and three of the 14 (21%) successful versions in the placebo group spontaneously reverted to breech presentation. Ultimately, in labor there were 24 (46%) cephalic presentations in the terbutaline group and 13 (25%) in the placebo group (P = .048, RR 1.84, 95% CI 1.1, 5.8). Cesarean delivery rates were 11 of 41 (27%) for women with successful versions and 58 of 62 (94%) among those with failed versions (P < .001). CONCLUSION: Terbutaline (0.25 mg) administered subcutaneously before an attempted version in women at term with noncephalic presentations significantly increased the initial success rate of version and the rate of cephalic presentations in labor while decreasing the rate of cesarean delivery.

The developmental outcome of children with antenatal mild isolated ventriculomegaly.

OBJECTIVE: To evaluate standardized developmental test performance of infants and children who as fetuses had mild isolated cerebral ventriculomegaly diagnosed by ultrasound. METHODS: Ultrasound records from 1990 to 1996 were searched for cases of mild isolated ventriculomegaly, and standardized developmental testing of the children was offered to their parents. Each consented child was matched to a normal antepartum subject with respect to sex, race, indication for ultrasound, and gestational age (+/- 2 weeks) at the time of ultrasound. Tests of cognitive, motor, and adaptive behavior were then administered by examiners blinded to the subjects' case or comparison status. RESULTS: Twenty-two cases and an equal number of matched comparison subjects completed the testing. The ventriculomegaly and comparison groups were similar with respect to parental age, maternal education, and household income. The ventriculomegaly subjects scored significantly lower than the comparison group on both the Bayley Scales of Infant Development: mental development index (88.95 versus 99.68, P = .017) and psychomotor development index (95.99 versus 103.95, P = .039). Eight of the 22 ventriculomegaly children were classified as developmentally delayed on the mental developmental index compared with one of 22 children in the comparison group (P = .021). Adaptive behavior skills, as measured by the Vineland Behavior Scales (99.64 versus 102.68), were not significantly different between the groups (P = .571). CONCLUSION: Mild isolated ventriculomegaly detected on antepartum sonographic examination is associated with a significant risk for developmental delay. Insofar as these children were judged to be completely normal at birth, our findings represent an important application of antepartum sonography for identifying infants who could be targeted for early childhood intervention.