Alcohol abuse--a persistent preventable risk for congenital anomalies.

OBJECTIVE: To examine whether alcohol abuse (ALC) continued to be a health hazard to pregnant women in the 1990s. STUDY DESIGN: Analysis of a perinatal data base comprising 170,258 women with singleton pregnancies. Univariate cross table analysis and logistic regression were conducted to examine the association between alcohol abuse and congenital malformations coded according to the International Classification of Diseases (ICD). RESULTS: 14,727/170,258 mothers (8.6%) admitted to ALC during pregnancy and 36,705/170,258 (21.6%) to smoking. Anomaly rates for ALC (365/14,092, 4.3%) vs. Non-ALC (6187/149,344, 4.0%) differed significantly (p<0.001). The rates of specific anomalies varied between <0.1% and 1.1%. Odds ratios for 16 ICD 9 anomaly categories were >1 in 14 instances overall (Sign test, p=0.004), in 12 instances in women <30 years (p=0.08), and in 13 instances in women over 30 years (p=0.02). Congenital anomalies of the "respiratory system" (ICD9 748), of "genital organs" (ICD9 752.1), of the "integument" (ICD9 757), and "other anomalies of limbs/other musculoskeletal anomalies" (ICD 755/756) were statistically significantly associated with ALC, especially in women>30 years. CONCLUSION: ALC in pregnancy continued to be an important factor independently associated with an increased incidence of a broader range of congenital anomalies than previously recognized. Risk for anatomic anomalies was increased in offspring of ALC women over age 30, consistent with previous reports of increased risk of neurobehavioral abnormality in offspring of women over 30.

Epstein-Barr virus and post-transplant lymphoproliferative disease.

There is convincing evidence that Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD). Primary EBV infection following transplantation occurs in as many as 90% of cases of PTLD in children and pretransplant EBV seronegativity is a recognized risk factor for developing PTLD. Other risk factors include young age at the time of transplant, the type of transplant that the recipient receives and the type and intensity of immunosuppression. The clinical presentation is often nonspecific and tissue biopsy is necessary to establish the diagnosis. There appears to be a correlation between PTLD and EBV viral load measured by polymerase chain reaction (PCR) of the peripheral blood and quantitative PCR may be a useful guide in the management of PTLD. Antiviral drugs and cytomegalovirus-immunoglobulin G may have a role in preventing PTLD. Because PTLD results from functional over-immunosuppression, the initial treatment is reduction of immunosuppression. Antiviral agents, interferon, immuno-based monoclonal therapy, cell-based therapy and chemotherapy also have a potential role in treating this disorder. At the present time there is no standardized approach to the evaluation and treatment of PTLD.

Successful allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. Patients with SDS have varying degrees of marrow aplasia, which can be severe or progress to leukemic transformation. While allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for the hematologic disturbances of SDS, a recent review of the literature reveals few survivors. Poor outcome with HSCT is often related to excessive cardiac and other organ toxicity from transplant preparative therapy. We describe two young children with SDS who developed aplastic anemia and subsequently underwent successful allografting using a non-cardiotoxic conditioning regimen. Case 1 received marrow from an HLA-identical sibling while case 2 received partially matched umbilical cord blood from an unrelated donor. Both patients are presently alive and well with sustained donor engraftment and excellent hematopoietic function at 36 and 22 months post-HSCT.

Cholangiocyte biology and cystic fibrosis liver disease.

Cystic fibrosis (CF) is one of the most common inherited diseases in the white population. The disease results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). How this gene defect leads to the clinical manifestations of the disease, however, is not entirely clear. CFTR functions as a Cl(-) channel in the apical membrane of most secretory epithelia, including biliary epithelial cells, or cholangiocytes. In cholangiocytes, CFTR appears to be an important determinant of biliary secretion and bile flow. Additionally, recent evidence suggests that CFTR regulates other membrane transporters, channels, and proteins. Improving life expectancy has led to an increasing recognition of hepatobiliary complications from CF. The true prevalence of CF liver disease is unknown, but may affect up to 17-25% of CF patients. Clinical manifestations include hepatic steatosis, neonatal cholestasis, focal nodular cirrhosis, multilobular cirrhosis, and biliary tract complications. Why only a subset of CF patients develops severe liver disease and others with the same genotype do not is one of the many scientific curiosities of this disease. This review focuses on the function of CFTR in cholangiocytes with emphasis on ductular bile formation as well as the clinical consequences of abnormal CFTR, namely CF-associated liver disease. Data on the pathogenesis, prevalence, clinical course, and treatment of CF liver disease will be reviewed.

Prenatal alcohol exposure and childhood behavior at age 6 to 7 years: I. dose-response effect.

OBJECTIVE: Moderate to heavy levels of prenatal alcohol exposure have been associated with alterations in child behavior, but limited data are available on adverse effects after low levels of exposure. The objective of this study was to evaluate the dose-response effect of prenatal alcohol exposure for adverse child behavior outcomes at 6 to 7 years of age. METHODS: Beginning in 1986, women attending the urban university-based maternity clinic were routinely screened at their first prenatal visit for alcohol and drug use by trained research assistants from the Fetal Alcohol Research Center. All women reporting alcohol consumption at conception of at least 0.5 oz absolute alcohol/day and a 5% random sample of lower level drinkers and abstainers were invited to participate to be able to identify the associations between alcohol intake and child development. Maternal alcohol, cigarette, and illicit drug use were prospectively assessed during pregnancy and postnatally. The independent variable in this study, prenatal alcohol exposure, was computed as the average absolute alcohol intake (oz) per day across pregnancy. At each prenatal visit, mothers were interviewed about alcohol use during the previous 2 weeks. Quantities and types of alcohol consumed were converted to fluid ounces of absolute alcohol and averaged across visits to generate a summary measure of alcohol exposure throughout pregnancy. Alcohol was initially used as a dichotomous variable comparing children with no prenatal alcohol exposure to children with any exposure. To evaluate the effects of different levels of exposure, the average absolute alcohol intake was relatively arbitrarily categorized into no, low (>0 but <0.3 fl oz of absolute alcohol/day), and moderate/heavy (>/=0.3 fl oz of absolute alcohol/day) for the purpose of this study. Six years later, 665 families were contacted. Ninety-four percent agreed to testing. Exclusions included children who missed multiple test appointments, had major congenital malformations (other than fetal alcohol syndrome), possessed an IQ >2 standard deviations from the sample mean, or had incomplete data. The Achenbach Child Behavior Checklist (CBCL) was used to assess child behavior. The CBCL is a parent questionnaire applicable to children ages 4 to 16 years. It is widely used in the clinical assessment of children's behavior problems and has been extensively used in research. Eight syndrome scales are further grouped into Externalizing or undercontrolled (Aggressive and Delinquent) behavior and Internalizing or overcontrolled (Anxious/Depressed, Somatic Complaints, and Withdrawn) behaviors. Three syndromes (Social, Thought, and Attention Problems) fit neither group. Higher scores are associated with more problem behaviors. Research assistants who were trained and blinded to exposure status independently interviewed the child and caretaker. Data were collected on a broad range of control variables known to influence childhood behavior and/or to be associated with prenatal alcohol exposure. These included perinatal factors of maternal age, education, cigarette, cocaine, and other substances of abuse and the gestational age of the baby. Postnatal factors studied included maternal psychopathology, continuing alcohol and drug use, family structure, socioeconomic status, children's whole blood lead level, and exposure to violence. Data were collected only from black women as there was inadequate representation of other racial groups. STATISTICAL ANALYSES: Statistical analyses were performed using the SPSS statistical package. Frequency distribution, cross-tabulation, odds ratio, and chi(2) tests were used for analyzing categorical data. Continuous data were analyzed using t tests, analyses of variance (ANOVAs) with posthoc tests, and regression analysis. RESULTS: Testing was available for 501 parent-children dyads. Almost one fourth of the women denied alcohol use during pregnancy. Low levels of alcohol use were reported in 63.8% and moderate/heavy use in 13% of pregnancies. Increasing prenatal alcohol exposure was associated with lower birth weight and gestational age, higher lead levels, higher maternal age, and lower education level, prenatal exposure to cocaine and smoking, custody changes, lower socioeconomic status, and paternal drinking and drug use at the time of pregnancy. Children with any prenatal alcohol exposure were more likely to have higher CBCL scores on Externalizing (Aggressive and Delinquent) and Internalizing (Anxious/Depressed and Withdrawn) syndrome scales and the Total Problem Score. The odds ratio of scoring in the clinical range for Delinquent behavior was 3.2 (1.3-7.6) in children with any prenatal exposure to alcohol compared with nonexposed controls. The threshold dose was evaluated with the 3 prenatal alcohol exposure groups. One-way ANOVA revealed a significant between group difference for Externalizing (Aggressive and Delinquent) and the Total Problem Score. (ABSTRACT TRUNCATED)

Abnormal cervicovaginal cytology in women with lupus: a retrospective cohort study.

OBJECTIVE: The aim of this study was to review Pap smear reports in women with systemic lupus erythematosus and compare them to a large control population. METHODS: Pap smear results of 29 women with a diagnosis of lupus seen consecutively were compared to those of a control population of 747 women attending the gynecology clinic at the same medical center during the same year. Records of lupus patients were reviewed to obtain clinical data. Fisher's exact test and chi(2) analysis were used to determine statistical significance, as appropriate. RESULTS: Of 29 women with lupus, 1/29 had high-grade squamous intraepithelial lesions (HGSIL) and 6/29 had low-grade squamous intraepithelial lesions (LGSIL). The control population of 747 women had 9/747 with HGSIL and 63/747 with LGSIL. chi(2) and Fisher's exact tests showed that the lupus population had a statistically significant increase in Pap smear reports of dysplasia compared to the control group (P < 0.021 for HGSIL/LGSIL combined, P < 0.036 for LGSIL alone). Examination of serial Pap smear results revealed that 45% of the lupus patients had cervical dysplasia at some time. CONCLUSION: Women with lupus have an increased prevalence of cervical dysplasia. Serial observation revealed dysplastic cytologies in nearly half of the patients, suggesting that this may be a more common problem than previously reported. Serial prospective studies are needed to assess better the risk of premalignant cervical lesions in lupus.

Obstetrics and gynecology at the crossroads--again? Still!

It seems, if one can believe presidential addresses, as if our specialty is always at some crossroads or other. In this "opinion piece," uniquely, I don't complain about managed care. I do attempt to identify some of the issues that will be of import for obstetrics and gynecology in the near and not-so-near futures. With regard to research, we await breakthroughs, for example, in the early detection of ovarian cancer, so as to finally be able to improve outcomes. A problem, though, is our failure to focus enough effort on developing a cadre of clinician scientists, who can work out research findings with direct clinical application; this is an issue with which the specialty needs to come to grips. Regarding education, I believe we need to refocus from what type of practitioners we might want to produce to best meet the needs of our patients. The bottom line should be more flexibility in training and emphasis on clinical competence, so that excellent practitioners with competence across the breadth of our specialty are available to provide a full range of appropriate women's health care. The concept of "women's health" is controversial and evolving rapidly. Review of several available sources suggests that reproductive medicine will remain an important component of women's health but that our specialty must now evolve to include other areas, as the major health problems of women change. We need to shift from an organ-based paradigm to a more holistic view, reflecting the woman-centered focus for our specialty. This "paradigm shift" will need to entail continuation of first-rate surgical and obstetrics services but will be expanded to include a full range of services, probably offered by highly trained and competent individuals with specific areas of expertise, practicing in a multi-single-specialty group. Obstetrics and gynecology at the crossroads, indeed!

Proliferation to paucity: evolution of bile duct abnormalities in a case of Alagille syndrome.

Alagille syndrome is an autosomal dominant disorder characterized by abnormalities in multiple organ systems, including the liver, and is caused by mutations in JAG1. Chronic cholestasis secondary to paucity of interlobular bile ducts is traditionally both a clinical and a pathologic hallmark of this disease at diagnosis. We describe the biliary changes on serial liver biopsies in a patient who presented with jaundice and extrahepatic stigmata of Alagille syndrome. Her initial specimens at 6 and 10 months of age demonstrated interlobular bile duct proliferation and cholestasis, suggestive of distal biliary obstruction. A specimen at 2 years of age showed near-total absence of interlobular bile ducts, with the classic histologic appearance of bile duct paucity. We present this case to underscore the potential pitfalls in interpreting cholestatic liver morphology in the absence of clinical information. The progression of bile duct abnormalities is discussed in the context of the role postulated for JAG1 in postnatal liver growth and development.

Hepatoblastoma in a neonate: a hypervascular presentation mimicking hemangioendothelioma.

Congenital heart failure in the neonate supported by classic imaging findings may allow the implementation of medical therapy for presumed hemangioendothelioma without obtaining a tissue diagnosis. This case report describes a neonate with these classic clinical and radiographic findings but who underwent surgery for failing medical treatment and was diagnosed as having a hepatoblastoma by pathology. This case supports the need to obtain tissue confirmation before beginning medical therapy.

Transglutaminase antibodies in children with a genetic risk for celiac disease.

OBJECTIVES: The transglutaminase (TG) antibody test is accurate in identifying celiac disease in symptomatic children. We sought to determine the positive predictive value of this test in asymptomatic children at genetic risk for celiac disease. STUDY DESIGN: Asymptomatic children with a genetic risk for celiac disease were studied to investigate the relationships between TG antibody titer, small bowel histology, growth, and clinical features. Small bowel biopsy histology was graded by using the system of Marsh. RESULTS: Of 30 children with a positive TG antibody test result, 21 (70%) had definite (Marsh score 2 or 3) and 4 (13%) had possible (Marsh score 1) biopsy evidence of celiac disease. TG antibody titer correlated with Marsh score (r = 0.569, P <.01). There was an inverse correlation between Marsh score and height z score (r = -0.361, P =. 05). CONCLUSIONS: In this group of asymptomatic children screened because of a genetic risk, TG antibodies have a positive predictive value of 70% to 83% for biopsy evidence of celiac disease and may identify children before clinical features of celiac disease develop.

Fatal cold anti-i autoimmune haemolytic anaemia complicating hairy cell leukaemia.

Hairy cell leukaemia (HCL) is a rare lymphoproliferative disorder associated with pancytopenia, splenomegaly and the presence of typical hairy B lymphocytes in the bone marrow and/or peripheral blood. The most significant complication relates to opportunistic infections that arise as a consequence of neutropenia and monocytopenia. HCL is occasionally associated with systemic autoimmune disorders including polyarteritis nodosa and rheumatoid disease. Secondary autoimmune haemolytic anaemia (AIHA) appears to be rare. We report on two cases of HCL complicated by fatal cold anti-i AIHA. Fulminant haemolysis causing death is rare in cold AIHA and only a few individual cases have been reported, none having anti-i specificity.

Glutathione status of isolated rat hepatocytes affects bile acid-induced cellular necrosis but not apoptosis.

An accumulation of hydrophobic bile acids is implicated in the pathogenesis of cholestatic liver diseases. In the present study, we determined if hydrophobic bile acid-induced cellular injury compromised hepatocyte glutathione (GSH) status, and if modulating intracellular GSH levels prevented or facilitated bile acid-induced cellular cytotoxicities. Freshly isolated rat hepatocytes incubated with >/=125 microM of the hydrophobic bile acid, glycochenodeoxycholic acid (GCDC), underwent a time- and dose-dependent decrease of intracellular GSH levels by 4-h incubation. This loss of intracellular GSH was not associated with an increase of intracellular GSH disulfide (GSSG). Rather, GCDC stimulated the dose-dependent accumulation of extracellular GSSG. The mechanism for extracellular GSSG accumulation by GCDC was through increased efflux of reduced GSH from hepatocytes into the media, where it subsequently oxidized to GSSG. Treatment of hepatocytes with GCDC (0-750 microM) did not directly alter GSH-dependent enzyme activities. The reduction of intracellular GSH with 125 microM GCDC correlated with extensive apoptosis at this concentration as determined by fluorescence microscopy of DAPI (4, 6-diamindino-2-phenylindole hydrochloride)-stained nuclei. Higher concentrations of GCDC (>/=500 microM) favored cellular necrosis and lipid peroxidation. Depleting GSH by treating hepatocytes with 1-bromoheptane increased their sensitivity toward GCDC-induced cellular necrosis, but not apoptosis. However, enhancing the hepatocyte GSH content by supplementation with GSH-ethylester (GSH-EE) failed to protect hepatocytes against either mode of cellular death. In conclusion, while GCDC-induced cytotoxicities were associated with an increased efflux of GSH from rat hepatocytes, GSH status modulated GCDC-induced necrosis, but not apoptosis.

Effects of gestational alcohol exposure on the fatty acid composition of umbilical cord serum in humans.

This study examined the effects of maternal periconceptional alcohol intake on polyunsaturated fatty acid (PUFA) concentrations in human neonates. The area percentage of each fatty acid in cord blood serum from 12 infants born to control women (who consumed <2 mL absolute ethanol/d) was compared with that of 9 infants born to women whose periconceptional alcohol intake averaged > or = 30mL absolute ethanol/d. Periconceptional alcohol use was associated with a 30% increase in the proportion of docosahexaenoic acid (22:6n-3) in cord blood (3.0% of total lipid in control infants compared with 3.9% in alcohol-exposed infants; P < 0.01). The rise in the proportion of 22:6n-3 was responsible for increases in the ratio of n-3 to n-6 fatty acids and the ratio of long-chain n-3 to n-6 fatty acids (P < 0.055). Examination of the lipid-class fatty acid profile indicated that serum lipid alterations were localized to the cholesterol esters; 22:6n-3 in the cholesterol esters of alcohol-exposed infants increased 54% (P < 0.011) and arachidonic acid increased 55% (P < 0. 005). The relative fatty acyl composition of maternal serum showed a significant increase in 18:0 fatty acids in the alcohol-exposed group (25%, P < 0.005) but there were no changes in the other fatty acids. The increase in the proportion of 22:6n-3 was unexpected but is consistent with the hypothesis that this essential lipid may be conserved selectively. These results imply that the lifelong neurobehavioral and sensory dysfunction in fetal alcohol syndrome and other alcohol-related neurodevelopmental disorders may be due in part to PUFA dysregulation.

Expressive language development of children exposed to cocaine prenatally: literature review and report of a prospective cohort study.

It was hypothesized that prenatal exposure to cocaine and other substances would be related to delayed expressive language development. Speech and language data were available for 458 6-year olds (204 were exposed to cocaine). No significant univariate or multivariate differences by cocaine exposure group were observed. Classification and regression tree modeling was then used to identify language variable composites predictive of cocaine exposure status. Meaningful cut points for two language measures were identified and validated. Children with a type token ratio of less than 0.42 and with fewer than 97 word types were classified into a low language group. Low language children (n = 57) were more likely to be cocaine exposed (63.1%), with cocaine-exposed children 2.4 times more likely to be in the low language group compared with control children after adjustment for covariates. Prenatal cigarette, but not alcohol exposure, was also significantly related to expressive language delays.

Cold haemagglutinin disease: clinical significance of serum haemolysins.

Two hundred and twenty-one patients with cold haemagglutinins of thermal amplitude > or = 30 degrees C (considered to be a reasonable indicator of clinical significance) were classified by in vitro haemolysin activity into three groups. Group 1 contained 116 individuals in whom haemolysins were never detected; the 74 patients in Group 2 had monophasic haemolysins alone; whereas both monophasic and biphasic haemolysins were detected in the 31 Group 3 patients. There was a significantly higher proportion of patients in Groups 2 and 3 with haptoglobin levels < 0.1 g/l compared with Groups 1 and 2, respectively (P < 0.005 and P < 0.001). Direct antiglobulin test results showed that the autoimmune response became more complex and IgM predominant through Groups 1-3, resulting in an increasing ability to activate complement which was reflected in increasing haemolysin activity and number of patients with active haemolysis. The 31 patients in Group 3 were mostly elderly (median age 71 years at presentation) and the majority had chronic cold haemagglutinin disease (CHAD), several in association with lymphoid neoplasms or carcinomas; only four had acute CHAD. The natural history of idiopathic chronic CHAD was of mild, well compensated haemolysis, punctuated by severe acute episodes necessitating intensive therapy. The condition often remained active for long periods and did not appear to affect natural lifespan. In some cases, no treatment (or just warmth) was needed; in others continuous or intermittent prednisolone and/or chlorambucil were effective; yet others required a greater variety and more intense therapy, or treatment of associated conditions. Blood transfusion support was frequently required when haemolysis was severe.

Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen.

OBJECTIVE: To prospectively evaluate the biochemical status of vitamins A, D, and E in children with cystic fibrosis (CF). SUBJECTS: A total of 127 infants identified by the Colorado CF newborn screening program. DESIGN: Vitamin status (serum retinol, 25-hydroxy vitamin D, ratio of alpha-tocopherol/total lipids) and serum albumin were assessed at diagnosis (4 to 8 weeks), ages 6 months, 12 months, and yearly thereafter, to age 10 years. RESULTS: Deficiency of 1 or more vitamins was present in 44 (45.8%) of 96 patients at age 4 to 8 weeks as follows: vitamin A 29.0%, vitamin D 22.5%, and vitamin E 22.8%. Of these patients with initial deficiency, the percent that was deficient at 1 or more subsequent time points, despite supplementation, was vitamin A 11.1%, vitamin D 12.5%, and vitamin E 57.1%. Of the initial patients with vitamin sufficiency, the percent who became deficient at any time during the 10-year period was as follows: vitamin A 4.5%, vitamin D 14.4%, and vitamin E 11.8%. The percent of patients deficient for 1 or more vitamins ranged from 4% to 45% for any given year. CONCLUSIONS: Despite supplementation with standard multivitamins and pancreatic enzymes, the sporadic occurrence of fat-soluble vitamin deficiency and persistent deficiency is relatively common. Frequent and serial monitoring of the serum concentrations of these vitamins is therefore essential in children with CF.

Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma.

Paroxysmal cold haemoglobinuria is an autoimmune haemolytic anaemia characterized by a biphasic polyclonal IgG autoantibody, the Donath-Landsteiner (D-L) antibody. Although classically described in association with chronic syphilis, it is most commonly seen after acute viral infections in children. We describe a case of high-grade B-cell non-Hodgkin's lymphoma which presented with paroxysmal cold haemoglobinuria. The lymphoma responded promptly to combination chemotherapy whilst, at the same time, the haemolytic process rapidly resolved. Subsequent investigations showed that the D-L antibody originated from the lymphoma cells.