Asher Ornoy

The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures.

Maternal use of antiepileptic drugs during pregnancy has been associated with an increased risk of major congenital abnormalities in the fetus. Carbamazepine (CBZ) is an antiepileptic drug that was developed and marketed mainly for the treatment of epileptic seizures. Some investigators described an increased rate of major congenital anomalies following treatment with CBZ during pregnancy while others found no such increase. In order to quantify better the risks of exposure to CBZ during pregnancy, we pooled data from prospective studies known to us. We found in prospective studies involving 1255 cases of exposure that CBZ therapy increased the rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate. CBZ may also induce a pattern of minor congenital anomalies and developmental retardation, but our study did not address these endpoints. CBZ also appears to reduce gestational age at delivery. A combination of CBZ with other antiepileptic drugs is more teratogenic than CBZ monotherapy. Children born to untreated epileptic women do not appear to have an increased rate of major birth defects. In light of these results, we recommend performing a level 2 ultrasound and fetal echocardiography in women treated with CBZ during pregnancy.

Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study

AIMS Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine. METHODS This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens. RESULTS We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of >or=10 cigarettes day(-1) and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively. CONCLUSION This study suggests a possible association between cardiovascular anomalies and first-trimester exposure to fluoxetine.

Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats

Bisphosphonates are clinically used mainly to reduce bone resorption. We studied the transplacental effects of two bisphosphonates on the fetal skeleton in rats. Pregnant rats were treated during days 11-20 of pregnancy with daily subcutaneous injections of 0.1 mg/kg of alendronate or a newly synthesized bisphosphonate, VS-b6. This period of pregnancy was chosen because the active development of bones from mesenchyme through cartilaginous models occurs during that time. Histological examination of midlongitudinal sections of the 21-day-old fetuses showed an increase in the amount of diaphyseal bone trabeculae with slight shortening of the diaphysis in the experimental fetuses, in comparison to controls. Computerized histomorphometric studies similarly showed an increase in the amount of diaphyseal bone trabeculae with a concomitant decrease in bone marrow volume, but no change in cartilage volume. In addition, chemical analysis of the fetal bones showed an increase in calcium content in the treated fetuses. 14C-alendronate was shown to pass through the rat placenta and accumulate in the fetuses, most probably in their bones. This is presumed because bisphosphonates are known to accumulate in bone, being stored there for long periods of time. It is important, in light of our results, to give careful consideration to the treatment of women with bisphosphonates at childbearing age, whenever this is needed.

The developmental outcome of children born to heroin-dependent mothers, raised at home or adopted

In the present investigation we were interested to study the possible role of in-utero exposure to heroin and of the home environmental in the etiology of long-term developmental problems in children born to heroin-dependent parents in comparison to matched controls. The children were examined at .5-6 years of age by a developmental pediatrician and a developmental psychologist using, for the children up to 2.5 years of age, the Bayley Developmental Scales, and for children aged 3-6 years the McCarthy Scales for Childrens Abilities. We examined 83 children born to heroin-dependent mothers, and compared the results to those of 76 children born to heroin-dependent fathers and to three control groups; 50 children with environmental deprivation, 50 normal children from families of moderate or high socioeconomic class, without environmental deprivation, and 80 healthy children from kindergartens in Jerusalem. There were five children (6.0%) with significant neurological damage among the children born to heroin-dependent mothers and six (7.9%) children among those born to heroin-dependent fathers. The children born to heroin-dependent mothers had a lower birth weight and a lower head circumference at examination when compared to controls. The children born to heroin-dependent parents also had a high incidence of hyperactivity, inattention, and behavioral problems. The lowest DQ or IQ among the children with cognitive levels above 70 was found in the children with environmental deprivation, next was the DQ or IQ of children born to heroin-dependent fathers, then the DQ or IQ of the children born to heroin-dependent mothers. When the children born to heroin-dependent mothers were divided to those that were adopted at a very young age and to those raised at home, the adopted children were found to function similarly to the controls while those not adopted functioned significantly lower. Our results show that the developmental delay and behavioral disorders observed among children born to drug-dependent parents raised at home may primarily result from severe environmental deprivation and the fact that one or both parents are addicted. The specific role of the in-utero heroin exposure in the determination of the developmental outcome of these children (if they do not have significant neurological damage), seems to be less important in comparison to the home environment.

Developmental outcome of school-age children born to mothers with heroin dependency: importance of environmental factors.

Development of children aged 5 to 12 years born to mothers with heroin dependency raised at home or adopted was studied in comparison with: (1) children with environmental deprivation alone (i.e. low parental socioeconomic status [SES] and evidence of neglect), (2) children born to fathers with heroin dependency fathers, and (3) control individuals of average SES. One hundred and sixty children (84 males and 76 females; average age at examination 8 years) were evaluated between 1998 and 1999. All were attending mainstream schools. All participants were examined by a paediatrician and a psychologist using standard neurological and psychological age‐appropriate tests, as well as tests and questionnaires to assess learning ability and attention span. The Conners and Achenbach questionnaires and the Pollack Taper test were used to assess possible presence of attention‐deficit‐hyperactivity disorder (ADHD). Mothers were assessed for ADHD using Wenders questionnaire. Children born to parents with heroin dependency raised at home and those of low SES exhibited intellectual impairment both on verbal and performance skills. They also had impaired reading and arithmetic skills. Children born to mothers with heroin dependency but who were adopted at a young age had normal intellectual and learning abilities, except for some reduced function on the performance Wechsler Intelligence Scale for Children‐Revised. We found a high rate of ADHD among all children born to parents with heroin dependency, including those adopted, as well as in children with low parental SES. The highest rate of ADHD was in children born to mothers with heroin dependency raised at home, being twice that observed in the other groups. Mothers of these groups of children also had a high rate of ADHD.

Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE To study potential teratogenic effects of quinolone exposure during pregnancy. STUDY DESIGN Prospective follow-up study. Subjects are pregnant women who contacted a teratology information center for risk information on quinolone treatment. A total of 549 pregnancies was collected by the European Network of Teratology Information Services between 1986 and 1994. In addition 116 prospectively documented pregnancies and 25 retrospective case reports on malformed children from other databases were analyzed. RESULTS The malformation rate among the live-born babies in the prospective ENTIS cohort was approximately 4.8%. No specific patterns of congenital abnormalities were found. The results do not suggest an elevated risk for spontaneous abortion, prematurity, intrauterine growth retardation and postnatal disorders. CONCLUSION The present study does not reveal any clear adverse reactions (fetal and neonatal toxicity, including birth defects) due to the in utero exposure to quinolones. Hence, termination of pregnancy because of such exposure is not indicated. However, considering the limitations of this study and the fact that diseases urgently requiring quinolone treatment are rare, it appears advisable to prefer penicillin, cephalosporins and erythromycin as antibiotics of choice.

Congenital cytomegalovirus infection: A long-standing problem still seeking a solution ☆ ☆☆ ★

OBJECTIVE The purpose of this study was to review the accuracy of current tests used for the diagnosis of in utero cytomegalovirus infection and to discuss the potential value of preconceptional and postconceptional screening programs for prevention of congenital infection. STUDY DESIGN A computer-assisted search was performed for relevant English language publications between 1987 and 1994. We identified 119 cases of suspected intrauterine cytomegalovirus infection in which either amniotic fluid or fetal blood had been analyzed antenatally. RESULTS Congenital cytomegalovirus infection affects 0.5% to 2.5% of all newborns. The rate of transmission to the fetus after primary infection during pregnancy ranges from 15% to 50%. Of the fetuses infected in utero, 10% exhibit congenital cytomegalovirus syndrome. Evaluation of 119 cases of suspected infection has shown that polymerase chain reaction and cultures of amniotic fluid are the most reliable tests for prenatally determining the presence of viral particles. However, efficacy of routine antenatal screening in reducing the rate of fetal disease is limited. CONCLUSION It is concluded that at present the accuracy of tests used for the diagnosis of in utero cytomegalovirus infection is undetermined. Serologic screening of all pregnant women is of limited value and at present is not recommended.

Growth plate chondrocytes store latent transforming growth factor (TGF)- β1 in their matrix through latent TGF-β1 binding protein-1

Osteoblasts produce a 100 kDa soluble form of latent transforming growth factor beta (TGF‐β) as well as a 290 kDa form containing latent TGF‐β binding protein‐1 (LTBP1), which targets the latent complex to the matrix for storage. The nature of the soluble and stored forms of latent TGF‐β in chondrocytes, however, is not known. In the present study, resting zone and growth zone chondrocytes from rat costochondral cartilage were cultured to fourth passage and then examined for the presence of mRNA coding for LTBP1 protein. In addition, the matrix and media were examined for LTBP1 protein and latent TGF‐β. Northern blots, RT‐PCR, and in situ hybridization showed that growth zone cells expressed higher levels of LTBP1 mRNA in vitro than resting zone cells. Immunohistochemical staining for LTBP1 revealed fine fibrillar structures around the cells and in the cell matrix. When the extracellular matrix of these cultures was digested with plasmin, LTBP1 was released, as determined by immunoprecipitation. Both active and latent TGF‐β1 were found in these digests by TGF‐β1 ELISA and Western blotting. Immunoprecipitation demonstrated that the cells also secrete LTBP1 which is not associated with latent TGF‐β, in addition to LTBP1 that is associated with the 100 kDa latent TGF‐β complex. These studies show for the first time that latent TGF‐β is present in the matrix of costochondral chondrocytes and that LTBP1 is responsible for storage of this complex in the matrix. The data suggest that chondrocytes are able to regulate both the temporal and spatial activation of latent TGF‐β, even at sites distant from the cell, in a relatively avascular environment. J. Cell. Physiol. 177:343–354, 1998.

Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies

The Israeli Teratogen Information Service prospectively followed up 210 pregnancies with first trimester carbamazepine exposure. Pregnancy outcome was compared with that of two overlapping controls, matched and general (n = 629), exposed to nonteratogenic agents. Our study suggests a twofold increase in the rate of major congenital anomalies (12/160 [carbamazepine] versus 18/560 [general control]; relative risk 2.24; 95% CI 1.1–4.56) and a birth weight reduction of approximately 250 g after in utero exposure to carbamazepine.

Isolation and hormonal responsiveness of primary cultures of human bone-derived cells: gender and age differences

We present a model for isolating human cell culture derived from biopsies obtained during orthopedic surgery. Four donor groups were defined by gender and age: pre- and postmenopausal women (<50 and >55 years, respectively), and younger (30-55 years) and older (>60 years) men. Bone-derived cells were identified as osteoblasts by major osteoblastic characteristics; that is, high alkaline phosphatase (ALP) activity, dose-dependent increase of ALP by 1,25(OH)2D3, high levels of parathyroid hormone (PTH)-induced cyclic AMP, and 1,25-(OH)2D3-induced osteocalcin. In all cells, levels of osteocalcin were significantly elevated (p < 0.05 and 0.01). In cells derived from men, no significant age differences were found in ALP and osteocalcin values of basal activity and in fold stimulation 1,25(OH)2D3. Cells from postmenopausal women showed a nonsignificant lower basal ALP activity than premenopausal cells. In postmenopausal cells, ALP responded less to 1,25(OH)2D3 (33% increase, p < 0.05) than the premenopausal cells (100% increase, p < 0.05). In cells from either age group, ALP did not respond to the gonadal steroids 17beta-estradiol (E2) and dihydrotestosterone (DHT) or progesterone. Basal levels of osteocalcin were higher in cells of premenopausal origin as compared with postmenopausal cells (p = 0.05), but response to 1,25(OH)2D3 was the same. PTH significantly stimulated cAMP (p = 0.001) in all age and gender groups analyzed. In all groups, no differences were found in either basal activity or in PTH response. Unlike men, cells derived from the bone of women were more susceptible to age changes. We postulate that the postmenopausal cell population had a decreased number of osteoblasts, or cells in a lower differentiation stage. These results extend our knowledge of bone biology found in animal models and reveal that human osteoblasts from men do not show the same age-dependent differences observed in women.