Tr Einarson

Pregnancy outcome after cyclosporine therapy during pregnancy: A meta-analysis

BACKGROUNDnCyclosporine (CsA) therapy must often be continued during pregnancy to maintain maternal health in such conditions as organ transplantation and autoimmune disease. This meta-analysis was performed to determine whether CsA exposure during pregnancy is associated with an increased risk of congenital malformations, preterm delivery, or low birthweight.nnnMETHODSnVarious health science databases were searched to identify relevant articles. Articles selected for inclusion in the study were required to be free of any apparent selection bias and report outcomes in at least 10 newborns exposed to CsA in utero, specifically commenting on the presence or absence of congenital malformations. Article selection and data extraction were performed by two independent reviewers, with adjudication in cases of disagreement. To assess risks of CsA exposure, a summary odds ratio was calculated. Prevalence of malformations was calculated as a rate for all cyclosporine-exposed live births and for the subgroups identified. Ninety-five percent confidence intervals were constructed for both the odds ratio and prevalence rates.nnnRESULTSnFifteen studies (6 with control groups of transplant without use of cyclosporine; total patients: 410) met the inclusion criteria for major malformations, 10 for preterm delivery (4 with control groups; total patients: 379) and 5 for low birth weight (1 with control groups; total number of patients: 314). The calculated odds ratio of 3.83 for malformations did not achieve statistical significance (CI 0.75-19.6). The overall prevalence of major malformations in the study population (4.1%) also did not vary substantially from that reported in the general population. OR for prematurity [1.52 (CI 1.00-2.32)] did not reach statistical significance although the overall prevalence rate was 56.3%. The OR for low birth weight [1.5 (CI 0.95-2.44 based on 1 study)].nnnCONCLUSIONSnCsA does not appear to be a major human teratogen. It may be associated with increased rates of prematurity. More research is needed to evaluate whether cyclosporine increases teratogenic risk.

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.

Abstract Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. Design Meta-analysis. Setting: Studies from 1966 to present. Subjects: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. Interventions:Data extraction and quality assessment were done independently and in duplicate. Main outcome measures: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. Results:Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1.35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). Conclusions:Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.

Methods for Quantification of Exposure to Cigarette Smoking and Environmental Tobacco Smoke: Focus on Developmental Toxicology

Active and passive smoking have been associated with an array of adverse effects on health. The development of valid and accurate scales of measurement for exposures associated with health risks constitutes an active area of research. Tobacco smoke exposure still lacks an ideal method of measurement. A valid estimation of the risks associated with tobacco exposure depends on accurate measurement. However, some groups of people are more reluctant than others to disclose their smoking status and exposure to tobacco. This is particularly true for pregnant women and parents of young children, whose smoking is often regarded as socially unacceptable. For others, recall of tobacco exposure may also prove difficult. Because relying on self-report and the various biases it introduces may lead to inaccurate measures of nicotine exposure, more objective solutions have been suggested. Biomarkers constitute the most commonly used objective method of ascertaining nicotine exposure. Of those available, cotinine has gained supremacy as the biomarker of choice. Traditionally, cotinine has been measured in blood, saliva, and urine. Cotinine collection and analysis from these sources has posed some difficulties, which have motivated the search for a more consistent and reliable source of this biomarker. Hair analysis is a novel, noninvasive technique used to detect the presence of drugs and metabolites in the hair shaft. Because cotinine accumulates in hair during hair growth, it is a unique measure of long-term, cumulative exposure to tobacco smoke. Although hair analysis of cotinine holds great promise, a detailed evaluation of its potential as a biomarker of nicotine exposure, is needed. No studies have been published that address this issue. Because the levels of cotinine in the body are dependent on nicotine metabolism, which in turn is affected by factors such as age and pregnancy, the characterization of hair cotinine should be population specific. This review aims at defining the sensitivity, specificity, and clinical utilization of different methods used to estimate exposure to cigarette smoking and environmental tobacco smoke.

BIAS AGAINST THE NULL HYPOTHESIS: THE REPRODUCTIVE HAZARDS OF COCAINE

To examine whether studies showing no adverse effects of cocaine in pregnancy have a different likelihood of being accepted for presentation by a large scientific meeting, all abstracts submitted to the Society of Pediatric Research between 1980 and 1989 were analysed. There were 58 abstracts on fetal outcome after gestational exposure to cocaine. Of the 9 negative abstracts (showing no adverse effect) only 1 (11%) was accepted, whereas 28 of the 49 positive abstracts were accepted (57%). This difference was significant. Negative studies tended to verify cocaine use more often and to have more cocaine and control cases. Of the 8 rejected negative studies and the 21 rejected positive studies, significantly more negative studies verified cocaine use, and predominantly reported cocaine use rather than use of other drugs. This bias against the null hypothesis may lead to distorted estimation of the teratogenic risk of cocaine and thus cause women to terminate their pregnancy unjustifiably.

Use of antidepressants by pregnant women: Evaluation of perception of risk, efficacy of evidence based counseling and determinants of decision making

SummaryBackground: The World Health Organization predicts that by 2012, depression will be the number one disease in the world. Thus, many women who become pregnant will require treatment with antidepressants. We are aware that women and their health care providers remain hesitant to prescribe and take these drugs during pregnancy, despite evidence of the relative safety.Objectives: 1) To determine perception of risk of antidepressant drugs by pregnant women with depression, 2) to determine the efficacy of evidence-based counseling, and 3) to identify determinants that influence women in their decision making regarding the continuation/discontinuation of antidepressants during pregnancy.Methods: Women who called The Motherisk Program requesting information about the safety of an antidepressant during pregnancy were compared with two other groups: 1) Women who called about antibiotic use (i.e., non-teratogenic drugs used short-term) and 2) women who called about gastric medications (i.e., non-teratogenic drugs used long-term). Their perception of risk was measured before and after evidenced-based information was given and determinants of decision making was also evaluated.Results: We recruited 100 women taking antidepressants during pregnancy and 100 in each comparison group. Despite receiving evidence-based reassuring information, 15% of antidepressant users, compared to 4% using gastric drugs and 1% using antibiotics, chose to discontinue their medication. The main determinants of decision making were based on: information received prior to calling Motherisk, family and friends advice, the internet, sequence of advice given and if a women was undecided at the time of call.Conclusions: Women continue to fear taking antidepressants during pregnancy, more so than non psychiatric drugs, however, evidence based counseling can lower this fear, although not totally. Deciding whether to continue to take a medication or not during pregnancy, is a complex decision for women and their healthcare providers to make.

A Case-Control Study on the Association Between First Trimester Exposure to Lithium and Ebstein's Anomaly

Lithium carbonate is considered to be a first-line drug in the management of manic depressive psychosis. According to Food and Drug Administration figures 0.1% of pregnant women are using this medication.1 During the last 2 decades accumulated data have suggested that lithium carbonate may be teratogenic in humans.2 The Danish registry has accumulated over 200 cases, among which there was a 10% occurrence rate of cardiac malformations.3 This rate appears high when compared to the 0.1% risk for such malformations in the general population.2 In particular, the Danish registry reported 8 cases of the rare Ebsteins anomaly which occurs spontaneously in only 1 of every 20,000 births, suggesting a relative risk of 500-fold above that in the general population. n nHowever, the information in this registry has been collected by a voluntary reporting system and does not represent systematically collected data. It has been argued that families and physicians caring for malformed babies are more likely to report adverse fetal outcomes to the registry than normal outcomes,4 as was the case with retinoic acid.5 This reporting bias may create a false impression of a teratogen when, in fact, the drug may not be teratogenic. The implication of wrongful incrimination of a drug like lithium may be immense; women may not be optimally treated during conception and pregnancy or, if treated before pregnancy was recognized, they may wish to terminate pregnancy to avoid an increased teratogenic risk. Since our team provides counselling for women in greater Toronto on the safety of drugs and chemicals, we are continuously witnessing both these options being taken by women. n nTo the best of our knowledge no controlled studies have tried to define the teratogenic risk of lithium in humans. In dealing with a rare malformation such as the Ebsteins anomaly, a sample size > 400 women exposed to lithium and a similar group of nonexposed women would have to be collected prospectively in order to detect a 10-fold increased risk with an alpha of 0.05 and power of 0.8. n nA more realistic approach to try to address this question would therefore be the case-control study where one focuses on the rare event, namely the Ebsteins anomaly, and compares maternal drug exposure in pregnancy of children having this malformation with those of a control group. n nBecause our cardiology division is the tertiary referral center for a population of about 6 million, we have had the rare opportunity to ascertain a large number of cases of Ebsteins anomaly and thus to test the association between first trimester exposure to lithium and this malformation.

Long-Term Neurodevelopmental Risks in Children Exposed in Utero to Cocaine: The Toronto Adoption Studya

ABSTRACT: Children exposed in utero to cocaine are at risk for long‐term neurobehavioral damage not just because of the drug itself, but also because of clustering of other health determinants, including low socioeconomic status, low maternal education, and maternal addiction, to mention a few. One methodologic approach to separate the direct neurotoxic effects of cocaine from these synergistic insults is to follow up a cohort of children exposed in utero to cocaine and given up for adoption to middle‐upper class families.

Adverse effects of antidepressant use in pregnancy: an evaluation of fetal growth and preterm birth†

Objective: To compare the rates of low birth weight, preterm delivery and small for gestational age (SGA), in pregnancy outcomes among women who were exposed and nonexposed to antidepressants during pregnancy. Methods: At The Motherisk Program, we analyzed pregnancy outcomes of 1,243 women in our database who took various antidepressants during their pregnancy. Nine hundred and twenty‐eight of these women and 928 nonexposed women who delivered a live born infant were matched for age, (±2 years), smoking and alcohol use and specific pregnancy outcomes were compared between the two groups. Results: There were 82 (8.8%) preterm deliveries in the antidepressant group and 50 (5.4%) in the comparison group. OR: 1.7 (95% CI: 1.18–2.45). There were 89 (9.6%) in the antidepressant group and 76 (8.2%) in the comparison group who delivered babies evaluated as SGA; OR: 1.19 (95% CI: 0.86–1.64). The mean birth weight in the antidepressant group was 3,449±591u2009g and 3,455±515u2009g in the comparison group (P=.8). Conclusion: The use of antidepressants in pregnancy appears to be associated with a small, but statistically significant increased rate in the incidence of preterm births, confirming results from several other studies. It is difficult to ascertain whether this small increased rate of preterm births is confounded by depression, antidepressants, or both. However, we did not find a statistically significant difference in the incidence of SGA or lower birth weight. This information adds to limited data available in the literature regarding these outcomes following the use of antidepressants in pregnancy. Depression and Anxiety, 2010.

Effect of iron content on the tolerability of prenatal multivitamins in pregnancy

BackgroundGastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation. In a previous study, suboptimal tolerability was observed among pregnant women taking a large tablet (18 mm × 8 mm × 8 mm) multivitamin with high elemental iron content (60 mg as ferrous fumarate). The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were randomized to commence supplementation with a small-tablet prenatal multivitamin, containing either low or high iron content.MethodsPregnant women who called the Motherisk Program (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospective, randomized, open-label, 2-arm study. Women were randomized to take a small-size (16 mm × 9 mm × 4 mm), low elemental iron content (35 mg as ferrous fumarate) multivitamin (35 mg group); or a small-size (5 mm radius, 5 mm thickness), high elemental iron content (60 mg as ferrous sulphate) multivitamin (60 mg group). Follow-up interviews documented pill intake and adverse events. Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves.ResultsOf 167 randomized women, 92 in the 35 mg group and 75 in the 60 mg group were included in the analysis. Despite ideal conditions and regular follow-ups, mean adherence based on pill intake recall, in both groups was approximately 50%. No statistically significant difference was detected in proportions of women who actually started taking either multivitamin. Among those who started, no difference was detected in rates of adherence or reported adverse events.ConclusionThe present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins. Combined with our previous study, tablet size may be the more definitive factor affecting adherence.

Hospitalization and surgical rates in patients with Crohn's disease treated with infliximab: a matched analysis

The majority of subjects with Crohns Disease (CD) will be hospitalized and will receive surgery for their disease. These interventions account for most of the direct costs of the disease. We sought to explore the association between infliximab use and CD‐related surgery and hospitalizations.