Benjamin Bar-Oz

Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors

BACKGROUND Antidepressants have been commonly used by women of childbearing age. Recent studies suggest that paroxetine, a selective serotonin reuptake inhibitor (SSRI), might specifically increase teratogenic risk. OBJECTIVES The purpose of this study was to quantify first-trimester exposure to paroxetine and birth defects and examine potential sources of bias in the in utero or postnatal detection of more congenital malformations among women with depression. We also sought to examine whether paroxetine was used for the same indications as other SSRIs among pregnant women. METHODS This meta-analysis was designed to quantify malformation rates associated with the use of paroxetine. A search of the literature from 1985 to 2006 (English language) found in MEDLINE, EMBASE, REPROTOX, Scopus, and Biological Abstracts was conducted using the following terms: pregnancy outcome, congenital or fetal AND anomalies, malformations, cardiac/heart defects, AND selective serotonin reuptake inhibitors, paroxetine, and Paxil. Administrative databases of medication and medical services use in the Province of Quebec, Canada, were used to calculate the rates of ultrasound and echocardiogram in pregnancy and infancy in women/infants exposed to SSRIs and to compare the indications for general SSRI use versus paroxetine use. RESULTS Based on the studies analyzed, first-trimester paroxetine exposure was associated with a significant increase in the risk for cardiac malformation (odds ratio [OR], 1.72; 95% CI, 1.22-2.42). Women using antidepressants in pregnancy had a 30% higher rate of utilization of ultrasound in pregnancy. Infants of women who received SSRIs underwent approximately twice as many echocardiograms in the first year of life compared with children of women who used nothing. Significantly more women receiving paroxetine used the drug for anxiety or panic than women receiving other SSRIs (OR, 4.11; 95% CI, 2.39-7.08). CONCLUSIONS Based on the results of this metaanalysis, first-trimester exposure to paroxetine appears to be associated with a significant increase in the risk for cardiac malformation. However, a detection bias cannot be ruled out as contributing to the apparent increased detection of cardiovascular malformation of children exposed in utero to paroxetine. A significantly greater number of women were using paroxetine for anxiety or panic when compared with women using other SSRIs.

Maternal Hyperthermia and the Risk for Neural Tube Defects in Offspring: Systematic Review and Meta-Analysis

Background: In animals, excessive core body temperatures have been documented to cause malformations; neural tube defects (NTDs) are among the most frequently reported. In humans, data are inconclusive and often conflicting. The objective of our report is to determine the risk for neural tube defects associated with maternal hyperthermia in early pregnancy Methods: We conducted a systematic review and meta-analysis to evaluate available evidence on this topic in humans. MEDLINE, EMBASE, references from published reports, and biologic abstracts from meetings were searched for relevant studies. Reviewers evaluated all the retrieved articles and extracted the relevant data. Individual and summary odds ratios and relative risks were calculated using the Mantel–Haenszel method. Results: Fifteen studies, reporting on 1,719 cases and 37,898 noncases, were included in the meta-analysis. The overall odds ratio for neural tube defects associated with maternal hyperthermia was 1.92 (95% confidence interval = 1.61–2.29). When analyzed separately, the 9 case-control studies had an odds ratio of 1.93 (1.53–2.42). The summary relative risk for the 6 cohort studies was 1.95 (1.30–2.92). Conclusions: Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen.

Enterobacter sakazakii infection in the newborn.

Enterobacter sakazakii, a Gram‐negative bacillus, previously known as “yellow pigmented Enterobacter cloacae,” is a rare cause of neonatal infection. We describe the detailed clinical presentation of two cases in whom E. sakazakii was isolated in our neonatal service during the course of 1 mo. These include one case of sepsis and meningitis complicated by cerebral infarction, and one case of sepsis. In addition, three cases of intestinal colonization were identified. The source of the organism was thoroughly sought and was found to be a blender in the milk kitchen that was used for preparation of the reconstituted powdered milk formula.

Cluster of Neonatal Infections in Jerusalem due to Unusual Biochemical Variant of Enterobacter sakazakii

Abstract.Reported here is a cluster of infections due to a nitrate-negative variant of Enterobacter sakazakii, which occurred among premature neonates at the Hadassah Hospital, Mount Scopus, Jerusalem, in December 1999–January 2000. Pulsed-field gel electrophoresis showed cluster isolates to be identical but unrelated to previous systemic isolates recovered in 1993 and 1998. The organism was not isolated from infant formula powder, but it was recovered from prepared formula and from a kitchen blender. Elimination of the environmental focus, a change to factory-prepared infant formula, and isolation of affected infants terminated the event. Faecal carriage of Enterobacter sakazakii was observed for up to 18 weeks, emphasising the potential for cross-infection.

Population baseline of meconium fatty acid ethyl esters among infants of nondrinking women in Jerusalem and Toronto.

The detection of fatty acid ethyl esters (FAEE) in meconium may provide an objective estimate of prenatal alcohol exposure independent of maternal history. The authors report the results of the first population-based study conducted to investigate basal FAEE levels in the meconium of neonates not exposed to alcohol. Two hundred seven nondrinking women and their neonates were recruited from Toronto and Jerusalem. FAEE were extracted from meconium by solid-phase extraction and analyzed by GC/FID. Similar procedures were conducted in six neonates born to confirmed heavy drinkers. Low levels of meconium FAEE were detected from both cohorts (mean, 1.37 nmol/g vs. 2.08 nmol/g, Toronto vs. Jerusalem). Ethyl stearate, oleate, and linoleate were below the limit of detection in >80% of all samples, whereas ethyl laurate and palmitate were detected in >50% of the samples. Ethyl myristate was the FAEE most commonly detected (>80%). All six meconium samples with confirmed maternal drinking histories tested positive for FAEE at significantly higher levels (mean, 11.08 nmol/g). The use of 2 nmol total FAEE/g meconium as the positive cutoff, when lauric and myristic acid ethyl esters were excluded, yielded the greatest sensitivity (100%) and specificity (98.4%). The authors conclude that certain FAEE are present at measurable levels in the meconium of neonates not exposed to maternal drinking, and correction is needed to allow high specificity.

Use of antibiotic and analgesic drugs during lactation.

During lactation, multiple situations can arise that require maternal pharmacological treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse effects when used during lactation, and even temporary interruption of breast feeding can be difficult for the nursing dyad, decisions regarding maternal medication use during breast feeding should be based on accurate and up-to-date information. This article reviews available data on the most commonly used antibiotics and analgesics.The use of most antibiotics is considered compatible with breast feeding. Penicillins, aminopenicillins, clavulanic acid, cephalosporins, macrolides and metronidazole at dosages at the low end of the recommended dosage range are considered appropriate for use for lactating women. Fluoroquinolones should not be administered as first-line treatment, but if they are indicated, breast feeding should not be interrupted because the risk of adverse effects is low and the risks are justified.Paracetamol (acetaminophen), low-dose aspirin (acetylsalicylic acid) [up to 100 mg/day] and short-term treatment with NSAIDs, codeine, morphine and propoxyphene are considered compatible with breast feeding.Safer alternatives should be considered instead of dipyrone, aspirin at a dosage >100 mg/day and pethidine (meperidine).In the light of the many safe alternatives for pain control, breast-feeding mothers should not be allowed to experience pain or be made to feel that they must choose between analgesia and breast feeding.

β-Defensin expression in human mammary gland epithelia.

Milk of mammalian species contains a wide spectrum of anti-infectious factors, some of which are heat stable. Focusing on recently discovered heat-stable antibacterial peptides called defensins, which are expressed in epithelial tissues such as airway, skin, and kidney, we hypothesized that mammary gland epithelia produce and secrete defensins onto the epithelial surface and into milk. Using a reverse-transcription PCR assay, we identified the human β-defensin-1 (hBD-1) gene transcript in a human mammary gland epithelial cell line, MCF-12A, and in mammary glandular tissue of nine nonlactating women. Epithelial cells harvested from milk of lactating women also expressed hBD-1 mRNA. Presence of hBD-1 peptide in mammary epithelia was confirmed by immunostaining with an hBD-1 antibody. In contrast, expression of human β-defensin-2 was not apparent both at mRNA and protein levels. Our findings suggest a biologic role of hBD-1 in the human mammary gland.

Pregnancy outcome after in utero exposure to valproate : evidence of dose relationship in teratogenic effect.

AbstractBackground: Valproate is a first-line antiepileptic agent and is also used in the treatment of bipolar disorder and migraine. It is a known human teratogen. The objective of the study was to evaluate the teratogenic risk of valproate. Methods: All callers who contacted the Israeli Teratology Information Service (TIS) between 1994 and 2004 for information about gestational exposure to valproate were enrolled in the study. After the expected date of delivery, these women were followed up by telephone interview about their pregnancy outcome using a structured questionnaire. Data obtained from women who contacted the TIS about valproate exposure during pregnancy were then compared with data obtained from callers who were counselled for nonteratogenic exposures over the same timeframe. The main outcome measure was the rate of major congenital anomalies. Results: The outcomes of 154 valproate-exposed pregnancies (96.1% at least in the first trimester) were compared with those of 1315 pregnancies of women in the TIS database who were counselled for nonteratogenic exposures. The rate of major anomalies (some multiple) in the valproate group exposed in the first trimester was higher compared with controls after exclusion of genetic or cytogenetic anomalies (8 of 120 [6.7%] vs 31 of 1236 [2.5%], p = 0.018, relative risk [RR] = 2.66, 95% CI 1.25, 5.65). There were no cases of neural tube defect in the valproate-exposed group. Five of the eight major anomalies in the valproate group were cardiovascular, two of eight were mentally retarded, two of five male infants with major anomalies had hypospadias and three of eight were suspected of having fetal valproate syndrome. A daily dose ≥1000 mg was associated with the highest teratogenic risk (7 of 32 [21.9%] vs 31 of 1236 [2.5%], RR = 8.72, 95% CI 4.16, 18.30). In the subgroup exposed to polytherapy there was a 4-fold increase in the rate of major anomalies compared with controls. All major anomalies were in the group treated for epilepsy. Conclusion: When valproate treatment cannot be avoided in the first trimester of pregnancy, the lowest effective dose should be prescribed, preferably as monotherapy, to minimize its teratogenic risk.

N-terminal-proB-type natriuretic peptide as a marker for acute anthracycline cardiotoxicity in children.

Background Anthracyclines are widely used in the treatment of pediatric cancer but their use is associated with cardiotoxicity. The cardiotoxic effect may become clinically apparent many years after therapy, and no reliable method exists for early detection of cardiac damage while the patient is receiving the drug. The natriuretic peptides have been established as markers for anthracycline-induced cardiotoxicity in adults and markers for cardiac dysfunction in children. We examined whether N-terminal proB-type natriuretic peptide (NT-proBNP) may be used as a marker for anthracycline-induced cardiotoxicity in children. Methods Twenty-three consecutive pediatric patients with newly diagnosed cancer were enrolled in this study. All patients received anthracycline-containing chemotherapy. Fifty-four age-matched children served as controls. Serial measurements of plasma NT-proBNP levels were taken before and after each anthracycline-containing course. Echocardiograms were performed before initiation of treatment and at the end of the study. Results Plasma levels of NT-proBNP were within normal limits before treatment and increased significantly only after the first anthracycline dose (from 150±112 to 327±321 pg/mL, mean±SD, P=0.02) and not after subsequent doses. This increase was attributed mainly to a subgroup of patients who received more than 25 mg/m2 of doxorubicin. In 14 patients (61%), the highest NT-proBNP level occurred after the first anthracycline dose. All patients had normal echocardiograms and none developed heart failure. Conclusions NT-proBNP increases significantly after the first anthracycline course in a subset of pediatric cancer patients. This increase is not associated with clinical or echocardiographic evidence of cardiac dysfunction. Anthracyclines may be more cardiotoxic in the first course than in subsequent courses. Longer follow-up of these patients is necessary to determine whether NT-proBNP can be used as an early marker for anthracycline-induced cardiotoxicity.

Anticonvulsants and breast feeding: a critical review.

Progress in the diagnosis and management of seizure disorders and the availability of effective anticonvulsive medications has enabled increasing numbers of epileptic women of child-bearing age to raise families. Breast feeding, which these women may wish to choose, provides health, nutritional, immunological, developmental, social, economic and environmental benefits. The traditional anticonvulsants, such as phenytoin, carbamazepine and valproic acid (valproate sodium), are generally considered safe for use during breast feeding; however, observation for adverse effects is recommended. The use of phenobarbital while breast feeding is controversial because of its slow elimination by the nursing infant. The newer anticonvulsants, such as clobazam, felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin, are used mainly as adjunctive therapy. Data on the use of these drugs in pregnancy and lactation, and regarding long term effects on cognition and behaviour, are sparse. Weighing the benefits of breast feeding against the potential risk to the nursing infant, breast feeding is considered to be safe when the mother is taking carbamazepine, valproic acid or phenytoin. Infant monitoring for potential adverse effects is advisable when the mother is taking phenobarbital, clobazam, gabapentin, lamotrigine, oxcarbazepine or vigabatrin. Monitoring of infant serum drug concentrations is advisable but not compulsory. The use of felbamate, tiagabine and topiramate during breast feeding should await further study.