Showing papers by "Gideon Koren published in 2000"

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies

Abstract: Background Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age Information regarding human pregnancy outcome with corticosteroids is limited Methods We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure The primary outcome was the rate of major birth defects A meta-analysis of all epidemiological studies was conducted The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals A cumulative summary odds ratio was also calculated by combining studies in chronological order Chi-squared for homogeneity was determined to establish the comparability of the studies Results In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 145 [95% CI 080, 260] and 303 [95% CI 108, 854] when Heinonen et al ('77) was removed This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids In addition, summary odds ratio for case-control studies examining oral clefts was significant (335 [95% CI 197, 569]) Conclusions Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 34-fold the risk of oral cleft, which is consistent with the existing animal studies Teratology 62:385–392, 2000 © 2000 Wiley-Liss, Inc

Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular Tachycardia

Abstract: The heterogeneous distribution of ion channels in ventricular muscle gives rise to spatial variations in action potential (AP) duration (APD) and contributes to the repolarization sequence in healthy hearts. It has been proposed that enhanced dispersion of repolarization may underlie arrhythmias in diseases with markedly different causes. We engineered dominant negative transgenic mice that have prolonged QT intervals and arrhythmias due to the loss of a slowly inactivating K(+) current. Optical techniques are now applied to map APs and investigate the mechanisms underlying these arrhythmias. Hearts from transgenic and control mice were isolated, perfused, stained with di-4-ANEPPS, and paced at multiple sites to optically map APs, activation, and repolarization sequences at baseline and during arrhythmias. Transgenic hearts exhibited a 2-fold prolongation of APD, less shortening (8% versus 40%) of APDs with decreasing cycle length, altered restitution kinetics, and greater gradients of refractoriness from apex to base compared with control hearts. A premature impulse applied at the apex of transgenic hearts produced sustained reentrant ventricular tachycardia (n=14 of 15 hearts) that did not occur with stimulation at the base (n=8) or at any location in control hearts (n=12). In transgenic hearts, premature impulses initiated reentry by encountering functional lines of conduction block caused by enhanced dispersion of refractoriness. Reentrant VT had stable (>30 minutes) alternating long/short APDs associated with long/short cycle lengths and T wave alternans. Thus, optical mapping of genetically engineered mice may help elucidate some electrophysiological mechanisms that underlie arrhythmias and sudden death in human cardiac disorders.

Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies.

Abstract: Background. This study was designed to examine whether there is an increased risk for major malformations following the use of fluoxetine during the first trimester of pregnancy.Methods. Published and unpublished reports were identified through computerized and manual searches of bibliographical databases, reference lists from primary articles, and letters to editors, agencies, foundations and content experts. Meta-analysis was undertaken of prospective controlled and uncontrolled studies on the use of fluoxetine during first trimester of pregnancy.Results. The pooled relative risk and 95% confidence interval for major malformations does not suggest an association between the use of fluoxetine during the first trimester and an increased risk of major malformations. Combination of controlled and uncontrolled studies shows a weighted risk of 2·6% (95% CI 1–4·2%). The summary odds ratio from the two controlled studies (OR = 1·33, 95% CI 0·49–3·58) was not significant. Homogeneity testing shows that the effect sizes are similar throughout all studies. Power analysis indicates that 26 controlled studies of similar size, would be required, to reverse this finding.Conclusions. The use of fluoxetine during the first trimester of pregnancy is not associated with measurable teratogenic effects in human.

Psychosocial morbidity among women with nausea and vomiting of pregnancy: Prevalence and association with anti-emetic therapy

Abstract: Unlike severe nausea and vomiting of pregnancy (NVP), it is not known whether milder forms of NVP have been associated with psychosocial morbidity. We undertook the study to explore the prevalence of psychosocial morbidity by severity of NVP, and determine whether, after correction for severity of nausea/vomiting, there is a relationship between psychosocial morbidity and women's decisions to take anti-emetics as a reflection of their distress due to NVP. From 1996-97, an NVP Healthline was advertised. Callers underwent semi-structured interviews about both their NVP and associated psychosocial morbidity in a previous pregnancy. Most of the 3201 callers resided in Canada, worked outside the home, reported on planned pregnancy (a median of) 4 years before, and described severe (> 5 episodes/day of) nausea and vomiting. More severe nausea/vomiting was associated with more frequent feelings of depression, consideration of termination of pregnancy, adverse effects on women's relationships with their partners or their partners' everyday lives, and the perceived likelihood that NVP would harm their baby (p < 0.0001). However, all psychosocial factors were reported by a clinically important proportion of women with mild nausea/vomiting (0-1 episodes/day). The severity of vomiting was most closely related to women's decisions to take anti-emetics, but other psychosocial factors were also independently associated with anti-emetic therapy. We conclude that psychosocial morbidity is evident across the spectrum of severity of nausea and vomiting among women with NVP. The severity of nausea or vomiting does not appear adequately to reflect the distress caused by NVP, as reflected by women's decisions to take anti-emetic therapy.

Anticonvulsants and breast feeding: a critical review.

Abstract: 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.

Combined analgesia and local anesthesia to minimize pain during circumcision

Abstract: Background: Pain of circumcision is only partially relieved by single modalities, such as penile nerve block, lidocaine-prilocaine cream, and sucrose pacifiers. Objective: To assess the effectiveness of a combination of interventions on the pain response of infants undergoing circumcision. Methods: Cohort study. Group 1 included infants circumcised using the Mogen clamp and combined analgesics (lidocaine dorsal penile nerve block, lidocaineprilocaine, acetaminophen, and sugar-coated gauze dipped in grape juice). Group 2 included infants circumcised using the Gomco clamp and lidocaine-prilocaine. Infants were videotaped during circumcision, and pain was assessed using facial activity scores and percentage of time spent crying. Results: There were 57 infants in group 1 and 29 infants in group 2. Birth characteristics did not differ between groups. Infants in group 1 were older than infants in group 2 (17 days vs 2 days) (P,.001). The mean duration of the procedure was 55 seconds and 577 seconds for infants in group 1 and 2, respectively (P,.001). Facial action scores and percentage of time spent crying were significantly lower during circumcision for infants in group 1 (P,.001). The percentage of time spent crying was 18% and 40% for infants in groups 1 and 2, respectively. No adverse effects were observed in infants in group 1; 1 infant in group 2 had a local skin infection. Conclusions: Infants circumcised with the Mogen clamp and combined analgesia have substantially less pain than those circumcised with the Gomco clamp and lidocaineprilocaine cream. Because of the immense pain during circumcision, combined local anesthesia and analgesia using the Mogen clamp should be considered. Arch Pediatr Adolesc Med. 2000;154:620-623

A randomized prospective crossover trial of amlodipine in pediatric hypertension

Abstract: Amlodipine has potential advantages in children since it can be dissolved into a liquid preparation and has a long elimination half-life, allowing for once-daily administration. The objective of this study was to compare the efficacy and compliance of amlodipine with that of standard long-acting calcium channel blockers (felodipine or nifedipine) in hypertensive children. A randomized, prospective, crossover study of 11 hypertensive children (9-17 years of age, 10 renal transplant patients) was performed with electronic monitoring of compliance. Each treatment arm was 30 days. No significant differences were observed in mean systolic (SBP) and diastolic blood pressures (DBP) between amlodipine and the other calcium channel blockers. Using 24-h blood pressure monitoring there were no significant differences over each drug treatment period in both mean day-time and night-time SBP and DBP. Patient compliance was similar in both the amlodipine and the nifedipine/felodipine treatment periods. These data suggest that amlodipine is as effective in pediatric nephrology patients as nifedipine and felodipine. Amlodipine may be optimally suited for treatment of young children because at present it is the only calcium channel blocker which can be administered once daily as a liquid preparation.

Choice of breastfeeding and physicians' advice: a cohort study of women receiving propylthiouracil.

Abstract: Objective To examine the gap between the current social/medical practice and the evidence-based recommendation in favor of breastfeeding during maternal propylthiouracil (PTU) therapy Design Prospective, observational, cohort study Subjects Women requiring PTU during pregnancy, and endocrinologists and family physicians in Ontario, Canada Interventions Questionnaire Main Outcome Measures Women were interviewed postpartum regarding their choice of infant feeding method and relevant advice received from physicians Physicians were questioned about their advice to nursing women receiving PTU Results Of 78 women, 66 had live births Thirty-six required PTU postpartum (group 1), and 30 did not (group 2) Thirty-six healthy women served as controls (group 3) Breastfeeding initiation rates for groups 1, 2, and 3 were 44%, 83%, and 83%, respectively In group 1, 15 women who breastfed received advice from 22 physicians regarding breastfeeding (20 in favor, 1 against, and 1 equivocal) Eleven who formula fed received advice from 17 physicians (4 in favor, 12 against, and 1 equivocal) A logistic regression analysis of group 1 showed that physicians9 advice was the only significant predictor of the woman9s choice to breastfeed during PTU therapy (relative risk: 548; 95% confidence interval: 128–2340) The physician survey showed that 44% of endocrinologists do not recommend breastfeeding during PTU therapy Conclusions A substantial proportion of the lactating patients on PTU still receive advice against breastfeeding from their physicians Physicians9 advice and attitudes toward breastfeeding during PTU therapy are a major factor in women9s final decision to breastfeed Physicians9 compliance with evidence-based data will facilitate breastfeeding in this group propylthiouracil, breastfeeding, decision-making

Prospective, controlled, multicentre study of loperamide in pregnancy.

Abstract: BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies.

Glucose metabolism is elevated and vascular resistance and maternofetal transfer is normal in perfused placental cotyledons from severely growth-restricted fetuses.

Abstract: We hypothesized that placental resistance was elevated and transfer reduced in cotyledons from intrauterine growth-restricted (IUGR) fetuses. We perfused 10 cotyledons from term, normally grown fetuses, six from preterm, normally grown fetuses with normal umbilical arterial end-diastolic velocities (EDV), and six from preterm IUGR fetuses (<3rd centile) with absent or reversed umbilical arterial EDV. Perfused cotyledons were pressure-fixed, and villi were observed by scanning electron microscopy. The groups did not differ in fetoplacental resistance at baseline; neither did they differ in the change in resistance that followed the administration of nitroglycerin or angiotensin II. The increase in resistance during hypoxia was similar in the two preterm groups but greater in the term than in the preterm normally grown group (p < 0.05). Groups did not differ in net maternofetal transfer of oxygen or glucose, or in clearance of aminoisobutyric acid or antipyrine. However, glucose consumption was doubled in cotyledons of preterm IUGR versus preterm normally grown fetuses (p < 0.05). Terminal villi of perfused cotyledons from preterm IUGR fetuses displayed less terminal villous branching and budding than preterm controls, as anticipated from previous work. IUGR fetuses with absent or reversed umbilical arterial EDV in vivo may have high placental resistance due to a vasoconstrictive rather than anatomic abnormality and an elevated placental glucose consumption that may impair glucose transfer.

Attitudes and practices of physicians and naturopaths toward herbal products, including use during pregnancy and lactation.

Abstract: Background The popularity of complementary therapies continues to grow, and physicians are asked increasingly by their patients for information regarding these modalities. Purpose To assess the impact of these trends on physicians and medical students, and compare their attitudes and practices with those of the naturopaths and their students, with particular interest in the use of herbal products during pregnancy and breastfeeding. Materials and methods A detailed questionnaire was distributed by a medical student and a naturopathic student to a randomly selected group of physicians, medical students, naturopaths and naturopathic students. They were asked a variety of questions about their background, attitudes and practices concerning herbal products. Results Thirty-eight per cent of the questionnaires were returned, with a total of 242 respondents. Fifty-four per cent of physicians discussed complementary therapies with their patients, whereas 100% of naturopaths discussed conventional medicines with their patients. The most popular product recommended by both medical doctors and naturopaths was echinacea, followed by St John's Wort. Eighty-six per cent of physicians, 74% of medical students, 66% of naturopaths and 50% of naturopathic students think that complementary medical education should be incorporated into the standard medical curriculum. Only one physician actually recommended a herbal product to a pregnant patient compared with 49% of the naturopaths who felt comfortable doing so. Conclusions Complementary medicine has become a reality, and physicians are recommending herbal products to their patients, although on a smaller scale than are naturopaths. However, the two most popular herbal products are the same in each group. Physicians are less likely to recommend herbal products to pregnant and breastfeeding women than are naturopaths.

The Effects of Cocaine and Nicotine on Amino Acid Transport across the Human Placental Cotyledon Perfused In Vitro

Abstract: The inhibitory effects of cocaine and nicotine on placental amino acid transport, as a mechanism contributing to intrauterine growth restriction, were investigated in the in vitro placental perfusion model. Amino acids that represent substrates for known placental transporters were selected: alanine (system A), glutamine (system N), phenylalanine and valine (system l), and arginine (system y(+)). Amino acid accumulation on the fetal side was measured in the absence of cocaine or nicotine (n = 7) and in the presence of 1.2 microg/ml cocaine (n = 6), 120 ng/ml nicotine (n = 6), or both (n = 6). Neither cocaine nor nicotine alone significantly inhibited alanine transport, whereas their combination did (P =.02). Significant inhibition of arginine transport was detected with nicotine (P =.007), cocaine (P =.01), and their combination (P =.01), whereas phenylalanine (P =.03, P =.04) and valine (P =.03, P =.04) transport was affected by cocaine and the combination of cocaine and nicotine, respectively. For glutamine, neither cocaine, nicotine, nor their combination had a statistically significant inhibitory effect. In conclusion, both cocaine and nicotine may contribute to fetal growth restriction by interfering with the activity of amino acids transporters that are necessary to maintain the nutrient gradients associated with normal fetal growth.

The efficacy of oral deferiprone in acute iron poisoning

Abstract: Due to its high cost and need for parenteral administration, the standard iron chelator deferoxamine is not used in many individuals with acute and chronic iron poisoning worldwide. Deferiprone is the first oral iron chelator to be shown to be effective in chronically iron overloaded thalassemia patients. Its efficacy, by oral administration, in acute iron poisoning has not been tested. Our objective was to determine whether orally administered deferiprone can reduce the mortality of rats following acute, toxic, oral doses of iron. Rats were administered 612 mg/kg elemental iron orally, corresponding to LD50 in the species tested. Two other groups received the same oral dose of iron followed by oral deferiprone: 800 mg/kg and 800 mg/kg, followed by another dose of 800 mg/kg 2 hours later. Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007). Mortality was also significantly decreased among animals coadministrated 2 repeated doses of deferiprone of 800 mg/kg with iron, to 0%, 9%, and 18%, and 2, 12, and 24 hours postdrug administration, respectively (P = .04, .05, .04, respectively). Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract. Orally administered deferiprone can decrease morbidity and mortality caused by acute iron overdose in rats. Oral deferiprone holds promise in the treatment of iron poisoning in humans.

Critical appraisal of drug therapy for nausea and vomiting of pregnancy: II. Efficacy and safety of diclectin (doxylamine-B6).

Abstract: Nausea and vomiting of pregnancy is the most common condition in pregnancy and affects up to 80% of all pregnant women. There are a large number of pharmacological agents that are effective for the treatment of nausea and vomiting associated with conditions such as motion sickness and gastrointestinal conditions; however, their use in pregnancy is limited by the lack of sufficient data on their potential teratogenic effects. The efficacy of the delayed-release combination of doxylamine and pyridoxine (Bendectin, Diclectin) has been shown in several randomized, controlled trials. The present review aims to refute the unsubstantiated beliefs that Diclectin is unsafe when used in the treatment of nausea and vomiting of pregnancy.

Medication errors in paediatrics: a case report and systematic review of risk factors.

Abstract: The inadvertent administration of drug doses greater than intended is not uncommon in the paediatric patient. These errors may arise from misunderstanding of the prescribed dose by the child’s caregiver or from mistakes of health professionals. Such errors have the potential to cause serious complications and their prevention is of paramount importance. Cyclosporin is an effective immunosuppressant which is most often used in organ transplantation; it is also used increasingly in non-transplant immunological and rheumatological conditions. The long term therapeutic use of cyclosporin is associated with several adverse effects, of which nephrotoxicity and hypertension are the most prominent.[1] Hepatotoxicity and CNS symptoms have also been described.[2-4] Human experience in the context of acute cyclosporin overdose is relatively limited and largely confined to adults.[5-11] Experience in children with accidental oral overdose is scarce.[12-14] The incidence of acute cyclosporin overdose in the paediatric population may increase as use of the drug increases. The objective of this article is to present a case of accidental oral overdose in an infant resulting from a 10-fold error in administration, and to highlight mechanisms and approaches for preventing such errors.

Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma.

Abstract: Background Overexpression of P-glycoprotein in malignant tumors has been associated with poor responses to chemotherapy. It appears biologically plausible that addition of the P-glycoprotein inhibitor cyclosporine (CsA) to standard chemotherapy may improve the outcome. The protective functions of P-glycoprotein in healthy tissues, however, have not been fully elucidated. Addition of CsA may lead to increased systemic chemotherapy toxicity, so we compared the rate and severity of chemotherapy-associated systemic toxicity in the presence and absence of CsA. Procedure Standard chemotherapy consisted of etoposide/ifosfamide (VP16/IFOS) cycles, alternating with vincristine/dactinomycin/cyclophosphamide (VAC) cycles. CsA was given at a median dose of 20 mg/kg with unaltered doses of the antineoplastic drugs. The analysis of toxicity was performed by comparing clinically significant toxicity events recorded during and after chemotherapy cycles with and without CsA. Results Toxicity-related hospital admissions occurred after 93% of VAC cycles with CsA compared to 40% of the cycles without CsA (P < 0.0001); 29% of VP16/IFOS cycles with CsA led to admissions vs. 12% with non-CsA cycles (P = 0.04). Infections or fever and neutropenia were the main reasons for these admissions. Thirty-seven percent of the VAC cycles with CsA were complicated by culture-proved sepsis, which did not occur in cycles without CsA (P < 0.0001). Requirements for blood and platelet transfusions were greatly increased after VAC cycles with CsA compared to VAC cycles without CsA. Conclusions The chemosensitizer CsA increases the systemic toxicity of VAC chemotherapy in patients with sarcomas. Future trials of chemotherapy with chemosensitizers will have to take into account a potential increase in systemic toxicity. Careful monitoring of chemotherapy-related toxicity becomes mandatory in such studies. Med. Pediatr. Oncol. 34:242–249, 2000. © 2000 Wiley-Liss, Inc.

Misdiagnosis of a mexiletine overdose because of a nonspecific result of urinary toxicologic screening.

Abstract: To the Editor: It has been suggested that toxicologic screening rarely leads to changes in medical management in the emergency department.1 We present a case of an overdose that was misdiagnosed be...

The Antiemetic Effect of Cetirizine during Pregnancy

Abstract: TO THE EDITOR:The interaction of some nonsteroidal antiinflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors can lead to elevated blood pressure (BP). Coadministration of rofecoxib 25 mg/d, a selective cyclooxygenase-2 (COX-2) inhibitor, and benzapril 10– 40 mg/d, an ACE inhibitor, for four weeks was associated with an average increase in mean arterial pressure of about 3 mm Hg compared with ACE inhibitor monotherapy. 1

Intranasal midazolam for febrile seizures. A step forward in treating a common and distressing condition.

Abstract: Papers p 83 Despite their benign nature and prognosis, uncomplicated febrile seizures are extremely stressful for both families and medical staff. Most parents believe that these seizures are harmful, and during the first episode half of all parents fear that their child is dying.1 For decades children were given long term anticonvulsant drugs to prevent the recurrence of febrile seizures. Although some of these are effective, their serious adverse effects have led to an unacceptable ratio of benefits to risks.2 3 There is, however, a broad consensus that febrile seizures should be treated promptly. Traditionally, benzodiazepines, barbiturates, or other anticonvulsants have been given intravenously, but rectally administered diazepam is now used as an efficacious alternative. The intranasal administration of therapeutic agents is undoubtedly the centre of tremendous interest in the field of therapeutics. That there is extensive and prompt absorption of molecules through the nasal mucosa into a rich vascular bed has long been recognised by cocaine users. In …

Longitudinal change in the treatment of nausea and vomiting of pregnancy in Ontario.

Abstract: BACKGROUND: Health problems associated with untreated nausea and vomiting of pregnancy (NVP) include maternal weight loss, dehydration, and electrolyte and acid-base disturbances. Negative social consequences include the deterioration of domestic, social and occupational function of the affected women. In 1994 it was documented that most physicians in Ontario tended not to treat women with NVP pharmacologically. PURPOSE: To investigate the longitudinal change in therapeutic practice of physicians, with respect to the treatment of NVP. SUBJECTS AND METHODS: A questionnaire was distributed to a randomly selected sample of physicians that included community-based family physicians, hospital-based family physicians, obstetricians and physicians who called the Motherisk Program for information. The participants were questioned about their choices in the pharmacological treatment of NVP. The data from the survey were compared with those from a previously published survey conducted in 1994. RESULTS: In 1999, 90.2% of physicians surveyed reported to have used pharmacological means to treat NVP. In 1999, 95% of the physicians surveyed reported to have prescribed doxylamine succinate-pyridoxine hydrochloric acid (Diclectin), and 11% prescribed dimenhydrinate (Gravol) to treat NVP. These results are significantly different from those found in 1994 (90% prescribed Gravol as the first choice). CONCLUSIONS: In 1999, temporally related to various educational efforts, physicians offered treatment for NVP more readily, including the drug recommended by the regulatory agency. These changes may explain in part the recently documented decrease in hospitalizations due to NVP in Canada.

Can we use anxiolytics during pregnancy without anxiety

Abstract: QUESTIONOne of my patients suffers from anxiety and was using lorazepam to treat it. When she became pregnant, she stopped the medication immediately, but now she is worried about the potential effect on the baby because she was using the drug just after conception. Is this class of drugs safe during pregnancy? What should she do if she needs antianxiety treatment during the rest of her pregnancy?ANSWEREvidence to date from cohort studies did not identify a notable association between use of benzodiazepines and increased risk of major malformations, including oral cleft. In contrast, data from case-control studies show a slightly increased risk of oral cleft. Hence, level 2 ultrasonography is recommended to rule out visible forms of cleft lip. Using benzodiazepines late in pregnancy could cause withdrawal syndrome in newborns.

Pharmacokinetic interaction between zidovudine and trimethoprim/sulphamethoxazole in HIV-1 infected children.

Abstract: OBJECTIVE: To evaluate the effect of the antimicrobial agent trimethoprim/sulphamethoxazole (TMP/SMX) on the pharmacokinetic properties of the antiretroviral drug zidovudine (ZDV).