Cytokine mediated expansion of human umbilical cord blood CD34+ cells: comparison of the use of partially purified and pure CD34+ target cells

The study compares an occurrence rate of congenital malformations in newborn infants of mothers with insulin dependent diabetes (IDDM) and newborns of healthy mothers and mothers with pregnancy diabetes (GDM). This paper evaluates the influence of stage of advancement (a class) of diabetes in the mother and its control during early pregnancy on a rate of congenital malformations in the fetus. We have taken a group of 170 neonates of mothers with IDDM. The control group was 56 newborn infants of mothers with GDM and 26,368 newborn infants of healthy women. We found 11.2% of congenital malformations in newborn infants of mothers with IDDM, compared to 1.8% of ones in the newborn infant population of mothers with GDM and 2.2% in the population of healthy mothers. The occurrence rate of congenital malformations in offspring of diabetic mothers with IDDM was 5-times higher than in the general population of newborn infants of healthy and also mothers with GDM. A risk of major birth defect occurrence in the fetus was directly proportional to the grade of the blood glucose level control in mothers during the I trimester of pregnancy, but the presence of diabetic angiopathy (classes D-H) had a significant influence on the occurrence rate of major birth defects in the fetus only in metabolic imbalance cases.     

Blockade of the oestrogen-induced luteinizing hormone surge in ovariectomized ewes by a highly selective opioid mu-receptor agonist: evidence for site of action

OBJECTIVE: We studied the course of pregnancy in women with epilepsy to identify possible risk factors which might complicate the epilepsies and pregnancy outcomes. MATERIAL AND METHODS: Data were collected retrospectively from the records of 151 pregnancies in 124 women with epilepsy from 1978-1992. Epilepsy variables were compared with that of non-pregnant women with epilepsy matched for age. Obstetric and neonatal variables were compared with those of all deliveries in the same unit from 1979-1992 (n=38,983). RESULTS: Pregnancy among patients with epilepsy was more likely to occur in women with relatively mild epilepsy. In 12% of the pregnancies, the women were untreated while 71% were on monotherapy. Twenty-one percent had increased seizure frequency during the pregnancy. Perinatal deaths among newborns of epileptic mothers (1.3%) was more frequent but not significantly increased compared to the background population of 0.5% (95% CI 0.2-4.7). A total of 5.3% had congenital malformations compared to 1.5% in the controls (95% CI 2.3-10.3). No neural tube defects were observed. Maternal treatment with phenytoin was significantly related to the occurrence of congenital malformations, P=0.04. CONCLUSIONS: Most women with epilepsy have an uncomplicated pregnancy and normal healthy offsprings. Maternal treatment with phenytoin might be associated with congenital malformations. No other risk factors could be identified.     

The Diabetes in Early Pregnancy Study: beta-hydroxybutyrate levels in type 1 diabetic pregnancy compared with normal pregnancy. NICHD-Diabetes in Early Pregnancy Study Group (DIEP). National Institute of Child Health and Development

OBJECTIVE: The objective was to assess relationships between beta-hydroxybutyrate (beta-OHB) level and pregnancy outcome in human pregnancy in light of the fact that high levels of beta-OHB cause malformations and growth retardation in in vitro studies. RESEARCH DESIGN AND METHODS: We analyzed beta-OHB in prospectively collected specimens from the National Institute of Child Health and Human Development-Diabetes in Early Pregnancy Study, in gestational weeks 6-12 in diabetic (n = 204-239) and nondiabetic (n = 316-332) pregnant women. RESULTS: Levels of beta-OHB in diabetic women were 2.5-fold higher than in nondiabetic pregnant women at 6 weeks' gestation and declined to 1.6-fold above nondiabetic women by 12 weeks' gestation (P < 0.0001 at all times). beta-OHB was positively correlated with glucose levels (P < 0.0001) in diabetic mothers, probably reflecting degree of diabetic control. beta-OHB correlated inversely with glucose (P < 0.0003) (gestational week 6 only) in nondiabetic mothers, possibly reflecting caloric intake. beta-OHB tended to be lower (not higher) in diabetic and nondiabetic mothers with malformed infants or pregnancy losses, but the difference was not statistically significant. beta-OHB in diabetic mothers at 8, 10, and 12 weeks correlated inversely with birth weight (P = 0.004-0.02), even after adjusting for maternal glucose levels. beta-OHB levels were also generally lower in diabetic mothers of macrosomic infants, and week 12 ultrasound crown-rump measurements were inversely related to beta-OHB levels. CONCLUSIONS: The lst trimester beta-OHB is significantly higher in diabetic than nondiabetic pregnant women. In both groups, beta-OHB tended to be lower, not higher, in mothers who had a malformed infant or pregnancy loss. beta-OHB was inversely related to crown-rump length and birth weight. The modest beta-OHB elevation in the 1st trimester of reasonably well-controlled diabetic pregnancy is not associated with malformations, probably because beta-OHB levels causing malformations in embryo culture models are 20- to 40-fold higher. The mechanism of the beta-OHB association with impaired fetal growth is unknown.     

Pregnancies of women with epilepsy: a population-based study in Iceland

PURPOSE: Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered to have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection. METHODS: We performed a historical population-based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19-year period in Iceland. RESULTS: In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7-fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy. CONCLUSIONS: Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring.     

Transforming growth factor-beta isoforms expressions in pulmonary adenocarcinomas as prognostic markers: an immunohistological study of one hundred and twenty patients

Congenital eye malformations were studied in a small geographical area in 212,479 consecutive births. For each of the 145 new cases studied during the period 1979 to 1994, more than 50 factors were compared in probands and in controls. The prevalence rate of congenital eye malformations was 6.8 per 10,000 for microphthalmia 1.7, anophthalmia 0.23, cataract 2.7 and coloboma 1.4 respectively. Sex ratio was 0.82. Prenatal diagnosis was performed in 18 cases and 7 cases were induced abortions. The more common types of associated malformations in the 81 affected cases (53.8%) with at least one anomaly other than an eye malformation were clubfeet, microcephaly, hydrocephaly, cleft lip/palate and facial dysmorphia. At birth infants with eye malformations and other malformations were smaller, weighted less and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with eye malformations were more often complicated by threatened abortion, oligoamnios and polyhydramnios. Mothers of children with congenital eye malformations took more often drugs during pregnancy than mothers of controls. Fathers of children with congenital eye malformations were more often exposed to occupational hazards than fathers of controls. There was a significant association between eye malformations and consanguinity of parents. The recurrence risk for first degree relatives of probands was 8.9%. First degree relatives of probands had more than three times the prevalence of non-eye malformations than controls. These results are of relevance to genetic counseling.     

Anticonvulsants and congenital malformations

Earlier studies indicated that the prevalence of congenital anomalies is greater in infants of epileptic mothers treated with anticonvulsants than in infants of mothers without epilepsy. We carried out a study of women in the General Practice Research Database who delivered liveborn infants between January 1988 and March 1993 and who were exposed to an anticonvulsant drug during the first trimester of pregnancy, and women with epilepsy not treated with anticonvulsants during pregnancy. We matched two nonexposed women without epilepsy to each exposed woman for age at delivery, date of baby's birth, and general practice. Two hundred ninety-seven women treated for epilepsy had 10 liveborn infants with major anomalies (3.4%) compared with 6 of the 594 nonexposed women (1.0%, RR = 3.3, 95% CI 1.2-9.2). We conclude that the infants of women with epilepsy who are treated with an anticonvulsant during the first trimester of pregnancy have an increased risk of major congenital anomalies.     

Prenatal vitamin supplementation and pediatric brain tumors: huge international variation in use and possible reduction in risk

An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976-1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and for 1919 controls in eight geographic areas of North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor [odds ratio (OR)=0.7; 95% confidence interval (CI)=0.5-0.9], with a trend toward less risk with longer duration of use (P trend= 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR=0.5; CI=0.3- 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the US, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously, from 3% in Israel and in France through 21% in Italy, 33% in Canada, 52% in Spain to 86-92% at the three US centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 up to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU and folate from 0 to 2000 mg. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.     

Risk factors in congenital anal atresias

Congenital anal atresias were studied in a small geographical area in 225,752 consecutive births. For each of the 108 new cases studied during the period 1979 to 1995, more than 50 factors were compared in probands and in controls. The prevalence rate of congenital anal atresias was 4.8 per 10,000 births. Sex ratio was 0.96. Prenatal diagnosis was performed in 14 cases and 11 cases were induced abortions. The more common types of associated malformations in the 45 non syndromic affected cases with at least one major anomaly other than anal atresia were renal agenesia, genital anomalies and ventricular septal defect. At births infants with anal atresia and other malformations were smaller, weighted less and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with anal atresia were more often complicated by threatened abortion, oligoamnios and polyhydramnios. Mothers of children with congenital anal atresia took more often drugs during pregnancy than mothers of controls. Fathers of children with anal atresia were more often exposed to occupational hazards than fathers of controls. There was a significant association between anal atresia and consanguinity of parents (p < 0.05). The recurrence risk for first degree relatives of probands was 3.7%. First degree relatives of probands had more than twice the prevalence of non-anal atresia malformations than controls.     

Cold pressor pain: comparing responses of juvenile arthritis patients and their parents

Neuroblastoma is one of the most common cancers of childhood. Some studies have shown an excess of congenital abnormalities in children who have been diagnosed with neuroblastoma. In this study we examined the medical records of all children with neuroblastoma seen at St. Justine Children's Hospital between the years 1977 and 1993. A total of 141 children (131 of French-Canadian ancestry) were included in this study. Twelve children (8.5%) had 21 defined congenital abnormalities (1,490 per 10,000 children). This compared with a rate of 444.3 children with abnormalities per 10,000 live births (4.44%) for all congenital abnormalities in the British Columbia Health Surveillance Registry, 1979-1988 (relative risk = 1.91, P = 0.03). Six of the 12 children had cardiovascular malformations. These and previous results suggest that there may be a common developmental origin to neuroblastoma and to some congenital malformations. Genes that control development may be worthy of further study in these children.     

Comparison of the barium test meal and the gamma camera scanning technic in measuring gastric emptying

In 21 patients with nonresected stomachs and symptoms of delayed gastric emptying, obstruction was excluded by upper gastrointestinal series and upper endoscopy; all had abnormal results of barium test meal (BTM) study. Each had repeat BTM after the administration of 10 mg of metoclopramide. Each patient also had two gamma camera studies after a technetium Tc 99m sulfur colloid labeled meal; normal saline or metoclopramide was administered before each test in a blinded and random manner. Half-time (T1/2) and percentage of isotope remaining at six hours (GC6) were recorded. Ten asymptomatic controls had a gamma camera scanning study, and seven of these had a BTM. Nine of 19 patients had a T1/2 in the normal range, and in 12 of 19 patients the GC6 was in the normal range. The magnitude of retention of barium at six hours on the BTM did not correlate with the T1/2 (r = 0.076) or the GC6 (r= 0.296). Thus, these tests were not comparable in this study. By regression analysis, a significant reduction was shown in the amount of retained food and barium (P less than .01), the T1/2 (P less than .01), and the GC6 (P less than .01) after intramuscular administration of metoclopramide, indicating that both tests were able to evaluate the effects of this drug.     

Adverse effects on offspring of maternal alcohol abuse during pregnancy

To evaluate the risk of offspring of heavy drinking during pregnancy, we administered a questionnaire to 633 women at the first prenatal visit. Nutritional status, smoking, drug and alcohol use were determined. Women were classified into three groups: abstinent and rare drinkers; moderate drinkers; and heavy drinkers. After delivery, detailed pediatric, neurologic and developmental examinations were administered by a physician without prior knowledge of any history. Infants born to heavy drinkers had twice the risk of abnormality of those born to abstinent or moderate drinkers (P less than 0.001). Thirty-two per cent of infants born to heavy drinkers demonstrated congenital anomalies, as compared to 9 per cent in the abstinent and 14 per cent in the moderate group (P less than 0.001). Microcephaly and multiple congenital anomalies were much more frequent in this group (P less than 0.001). Heavy drinking during pregnancy increases the risk to offspring.     

Parenting stress and social support of mothers who physically abuse their children in Hong Kong

Thirty-seven identified abusive mothers were matched on demographic and socioeconomic parameters with a known nonabusive comparison sample in order to examine the role of parenting stress and maternal social support. The mothers were assessed using a personal (demographic) questionnaire, the Parenting Stress Index (PSI), and the Maternal Support Index (MSSI). Demographic data showed that the two groups were comparable on all variables except abusive mothers had significantly more children (p = .01). Abusive mothers showed significantly more stress on total PSI scores (p = .005), as well as in all three of the subjects: Child Domain (p = .007) Parent Domain (p = .02), and Life Stress (p = .016). Abusive mothers scored lower in all seven items on the MSSI. The difference was significant on the MSSI as a whole (p = .007) and on four subsets: number of people to count on in time of need (p = .02), perceived neighborhood support (p = .04), satisfaction with spousal relationship (p = .01), and degree of community involvement (p = .03). The greatest percentage (74.32%) of correct predictions of child abuse was achieved by combining the number of children, the Life Stress Scale and the MSSI. Implications for future research are discussed.     

A second-generation study of 427 probands with congenital heart defects and their 837 children

OBJECTIVES: This study attempted to answer the question, Do mothers with congenital cardiovascular defects have more affected children than fathers with cardiac anomalies? BACKGROUND: In the 1950s to 1960s, concern was expressed about the safety of pregnancy in women with cardiac anomalies and the possibility of inheritance. METHODS: In a prospective study over 25 years, 236 women with cardiac defects were followed through pregnancy, and their 418 offspring were examined during their 1st 3 years. A high incidence of congenital cardiac malformations was noted. Then, a retrospective study of 191 men from the same clinic group and their total family (419 children) was performed to compare the incidence of affected children between the maternal study and this subsequent paternal study. RESULTS: Of 837 live children of these 427 probands, 14.1% (118) had a congenital heart defect (13.4% in the maternal study, 14.8% in the paternal study). There was no correlation with the surgical status of the proband. Concordance was somewhat greater among the children of affected mothers compared with those of affected fathers. Included in these studies were 31 high risk probands, 10 with genetic syndromes and 21 who had an affected sibling. Respectively, 53% and 41% of their children had cardiac anomalies, with a concordance > 50%; three fourths of these children had moderate to severe anomalies. CONCLUSIONS: The incidence of congenital heart defects in the children was not statistically different between the maternal and paternal studies. With removal of the high risk probands from the total study group, the risk of one affected parent having a child with a cardiac anomaly was 10.7%. Of the entire 837 children, only 7.5% had moderate or severe defects.     

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all articles written in English from 1966 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. RESULTS: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate that first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drug use during pregnancy and for psychiatrically ill women who wish to conceive.     

Congenital varicella. Problems with prenatal diagnosis after an early, primary maternal infection

Chickenpox rarely occurs as a primary infection during pregnancy. There is a risk of foetal malformation only if the mother is infected before 20 weeks of gestation. The two main problems encountered for antenatal diagnosis of congenital varicella are the rare incidence of morphology anomalies (less than 35%) and the difficulty of establishing a functional prognosis. Echography is used to detect foetal malformations. In suspected cases the proof of viral infection can be based on results of foetal serology, viral culture or polymerase chain reactions. According to the literature, echographically detected malformations in cases with certain foetal infection have a poor outcome although conflicting cases have been reported.     

Maternal assessment of infant development: associations with alcohol and drug use in pregnancy

Surveillance by parental concern has been advocated to assess whether formal child developmental testing is needed. To determine whether alcohol intake or illicit drug use in pregnancy is associated with differences in maternal perception of infant development, mothers with acknowledge alcohol and drug habits during pregnancy (N = 120) were interviewed at 11 months' postpartum, within 1 month before infant testing by use of the Bayley Scales of Infant Development. Women with heavy alcohol intake during pregnancy (> 3.5 oz absolute alcohol per week) were 15-fold more likely to overestimate their infant's mental development (P < 0.05), whereas mothers using illicit drugs were 4-fold more likely to overestimate their infant's physical development (P = 0.02). Given the frequent denial of substance abuse, we suggest that health care providers be cautious in accepting a lack of parental concern about a child's development and rely more heavily on formal testing, particularly in high-risk populations.     

Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation

PURPOSE: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. PATIENTS AND METHODS: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutropenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. RESULTS: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) for epirubicin correlated with prothrombin index (P < .01), antipyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, some of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. CONCLUSION: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.     

Differences in late fetal death rates in association with determinants of small for gestational age fetuses: population based cohort study

OBJECTIVE: To examine differences in late fetal death rates in association with determinants of small for gestational age fetuses. DESIGN: Population based cohort study. SUBJECTS: 1 026 249 pregnancies without congenital malformations. SETTING: Sweden 1983-92. MAIN OUTCOME MEASURE: Late fetal death rate. RESULTS: Depending on underlying determinants late fetal death rates were greatly increased in extremely small for gestational age fetuses (range 16 to 45 per 1000) compared with non-small for gestational age fetuses (1.4 to 4.6). In extremely small for gestational age fetuses late fetal death rates were increased from 31 per 1000 in mothers aged less than 35 years to 45 per 1000 in older mothers, and from 22 per 1000 in women <155 cm in height to 33 per 1000 in women >=175 cm tall. Late fetal death rates were also higher in extremely small for gestational age fetuses in singleton compared with twin pregnancies and in non-hypertensive pregnancies compared with pregnancies complicated by severe pre-eclampsia or other hypertensive disorders. Slightly higher late fetal death rates were observed in nulliparous compared with parous women and in non-smokers compared with smokers. CONCLUSIONS: Although the risk of late fetal death is greatly increased in fetuses that are extremely small for gestational age the risk is strongly modified by underlying determinants-for example, there is a lower risk of late fetal death in a small for gestational age fetus if the mother is of short stature, has a twin pregnancy, or has hypertension.     

Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules

BACKGROUND: Little information is available about the safety of high doses of mesalazine during pregnancy. AIM: To study the fate of pregnancy and foetal outcome in women taking 1-4 g/day of mesalazine microgranules for inflammatory bowel disease. PATIENTS AND METHODS: Case reports were collected from the Pharmacovigilance Department of Ferring SA, France, from a survey conducted in three gastroenterology units, and from a teratology information service. The evolution of pregnancy and foetal outcome were assessed by questionnaire. RESULTS: The study covered a total of 123 pregnancies (126 foetuses). Ninety-six women took mesalazine during the first trimester, 85 during the second and 83 during the third. The mean daily dose was 2.1+/-0.8 g; 86 women received <3 g/day (low-dose group), 37 women received > or =3 g/day (high-dose group). The following abnormalities were observed in the low-dose and high-dose groups, respectively: ectopic pregnancy (1/0), spontaneous abortions (1/1), foetal death (0/1), premature deliveries (3/5, P < 0.05), congenital malformations (3/1) and one case of lethal oxalosis. Abnormalities were not considered to be related to mesalazine. CONCLUSIONS: The use of oral mesalazine microgranules during pregnancy is safe at doses < or =2 g/day, and probably also at a dose of 3 g/day.