Thomas R. Einarson

PREVALENCE OF DEPRESSION DURING PREGNANCY: SYSTEMATIC REVIEW

OBJECTIVE: Current estimates of the prevalence of depression during pregnancy vary widely. A more precise estimate is required to identify the level of disease burden and develop strategies for managing depressive disorders. The objective of this study was to estimate the prevalence of depression during pregnancy by trimester, as detected by validated screening instruments (ie, Beck Depression Inventory, Edinburgh Postnatal Depression Score) and structured interviews, and to compare the rates among instruments. DATA SOURCES: Observational studies and surveys were searched in MEDLINE from 1966, CINAHL from 1982, EMBASE from 1980, and HealthSTAR from 1975. METHODS OF STUDY SELECTION: A validated study selection/data extraction form detailed acceptance criteria. Numbers and percentages of depressed patients, by weeks of gestation or trimester, were reported. TABULATION, INTEGRATION, AND RESULTS: Two reviewers independently extracted data; a third party resolved disagreement. Two raters assessed quality by using a 12-point checklist. A random effects meta-analytic model produced point estimates and 95% confidence intervals (CIs). Heterogeneity was examined with the χ2 test (no systematic bias detected). Funnel plots and Begg-Mazumdar test were used to assess publication bias (none found). Of 714 articles identified, 21 (19,284 patients) met the study criteria. Quality scores averaged 62%. Prevalence rates (95% CIs) were 7.4% (2.2, 12.6), 12.8% (10.7, 14.8), and 12.0% (7.4, 16.7) for the first, second, and third trimesters, respectively. Structured interviews found lower rates than the Beck Depression Inventory but not the Edinburgh Postnatal Depression Scale. CONCLUSION: Rates of depression, especially during the second and third trimesters of pregnancy, are substantial. Clinical and economic studies to estimate maternal and fetal consequences are needed.

Drug-Related Hospital Admissions

OBJECTIVE: To review and summarize studies reporting rates of drug-related hospital admissions. DATA SOURCES: Manual and computerized literature searches using MEDLINE, Index Medicus, and International Pharmaceutical Abstracts as databases (key words: Drug, drug-related, or iatrogenic; admission, hospital admission, or hospitalization; and ADR or adverse drug reaction). References from retrieved articles were searched to locate further studies. STUDY SELECTION: Included were English-language studies of humans admitted to the hospital because of medications. Problems investigated were admissions prompted by adverse drug reactions (ADRs) when drugs were used by the patient and admissions resulting from a patients noncompliant or unintentionally inappropriate drug use. Excluded were cases involving drug abuse, alcoholism, suicide attempts, intoxication, or inadequate prescribing. DATA SYNTHESIS: Between 1966 and 1989, ADR rates from 49 hospitals or groups of hospitals in a variety of international settings were published in 36 articles. Sample sizes ranged from 41 to 11 891 patients, with a median of 714 (interquartile range [IQR] 275-1245) and a mean of 1412 (SD 2233). The prevalence of reported admissions resulting from ADRs ranged from 0.2 to 21.7 percent; the median was 4.9 percent (IQR 2.9–6.7 percent) and the mean was 5.5 percent (SD 4.1 percent). The weighted meta-analytic estimate was 5.1 percent (95 percent confidence interval 4.4–5.8). Of those ADR admissions, 71.5 percent were side effects, 16.8 percent excessive effects, 11.3 percent hypersensitivity reactions, and 0.4 percent idiosyncratic; 3.7 percent of patients admitted for ADRs died. Eleven reports indicated that 22.7 percent of ADR hospitalizations were induced by noncompliance. CONCLUSIONS: Drug-induced hospitalizations account for approximately five percent of all admissions. Results apply only to people from highly developed industrialized countries. Economic analyses have not been performed. Future research should include the Third World and nonindustrialized nations as well as specific cultural groups.

Sensitivity of Patient Outcomes to Pharmacist Interventions. Part I: Systematic Review and Meta-Analysis in Diabetes Management

Background: Hypertension is a major health concern worldwide due to its deleterio us impact. Few studies have quantitatively assessed pharmacists’ interventions in hypertensive patients. Objectives: To identify and quantify outcomes sensitive to pharmacists’ interventions. Methods: International Pharmaceutical Abstracts, MEDLINE, Cochrane Central, and EMBASE were searched from inception through December 2006. Two independent reviewers identified articles; results were compared and resolved through consensus. Data extracted included intervention type, patient numbers, demographics, study characteristics, instruments used, data compared, and outcomes reported. A random effects meta-analysis was used to combine data. Study quality was assessed using the Downs–Black scale. Results: Of 203 potential articles identified, 98 were selected and their abstracts were read. Nine of these were reviewed full-text and 19 more were identified from references, resulting in a total of 28 articles. Research designs included 18 randomized controlled trials, 6 single-arm clinical trials, 3 nonrandomized comparative trials, and 1 database study. Average quality score was 66% ± 12% (fair). Medication management (82%) and hypertension education (68%) were the interventions most used. Thirty-nine study results (57% of all outcomes evaluated) were sensitive to pharmacists’ interventions. Meta-analysis of 2246 patients in 13 studies found that pharmacists’ interventions significantly reduced systolic blood pressure (10.7 ± 11.6 mm Hg; p = 0.002), while controls remained unchanged (3.2 ± 12.1 mm Hg; p = 0.361). Pharmacists’ interventions further reduced systolic blood pressure (6.9 ± 12.1 mm Hg;p = 0.047) over controls. Nonsensitive results included further reduction in diastolic blood pressure (3.6 ± 3.7 mm Hg; p = 0.06), quality of life (1 of 8 significant), and adherence (5 of 13 significant). Conclusions: Systolic blood pressure is sensitive to pharmacists’ interventions. Other outcomes may also be sensitive; however, more high-quality studies are needed for a comprehensive quantitative assessment

Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: Evidence from a meta-analysis

BACKGROUND Rates of patient adherence (compliance) to pharmacotherapy range from <5% to >90%. Negative determinants include multiple daily dosing (MDD), chronic duration, and asymptomatic disease. Reports suggest that once-daily (QD) dosing may improve adherence, but their findings are inconclusive. OBJECTIVE The purpose of this study was to compare the rates of adherence with QD, twice-daily (BID), and MDD antihypertensive drug regimens. METHODS MEDLINE, Embase, and International Pharmaceutical Abstracts databases were searched to identify comparative trials of patient adherence to antihypertensive medication in solid, oral formulations. Data were combined using a random-effects meta-analytic model. RESULTS Eight studies involving a total of 11,485 observations were included (1,830 for QD dosing, 4405 for BID dosing, 4147 for dosing >2 times daily [>BID], and 9655 for MDD), in which the primary objective was to assess adherence. The average adherence rate for QD dosing (91.4%, SD = 2.2%) was significantly higher (Z = 4.46, P < 0.001) than for MDD (83.2%, SD = 3.5%). This rate was also significantly higher (Z = 2.22, P = 0.026) than for BID dosing (92.7% [SD = 2.3%] vs 87.1% [SD = 2.9%]). The difference in adherence rates between BID dosing (90.8%, SD = 4.7%) and >BID dosing (86.3%, SD = 6.7%) was not significant (Z = 1.82, P = 0.069). CONCLUSIONS The results of this meta-analysis demonstrate that with antihypertensive medications, QD dosing regimens are associated with higher rates of adherence than either BID or MDD regimens.

Safety of metronidazole in pregnancy: A meta-analysis

OBJECTIVE Our purpose was to determine from published experience in humans whether metronidazole exposure during the first trimester of pregnancy is associated with an increased teratogenic risk. STUDY DESIGN All published articles reporting on metronidazole use during pregnancy were screened by two independent reviewers to select those including pregnant patients exposed during the first trimester and comparing the outcomes of their pregnancies with that of patients either not exposed to metronidazole or exposed only during the third trimester. The outcome under consideration was the occurrence of birth defects in live-born infants. The overall odds ratios of first-trimester exposure versus no first-trimester exposure was calculated by combining the selected studies in a meta-analysis according to the procedure of Mantel and Haenszel. RESULTS From 32 identified studies, 7 met the inclusion criteria for meta-analysis. Six were prospective and included 253 women exposed to the drug in the first trimester of pregnancy; one was retrospective and reported on 1083 exposed women. The overall weighted odds ratio of exposure versus no exposure during the first trimester calculated by meta-analysis of the 7 studies was 0.93 (95% confidence interval 0.73 to 1.18). The odds ratio calculated from the 6 prospective studies was 1.02 (95% confidence interval 0.48 to 2.18). CONCLUSION Metronidazole does not appear to be associated with an increased teratogenic risk.

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.

Prenatal Multivitamin Supplementation and Rates of Congenital Anomalies: A Meta-Analysis

BACKGROUND The use of folic acid-fortified multivitamin supplements has long been associated with decreasing the risk of neural tube defects. Several studies have also proposed the effectiveness of these supplements in preventing other birth defects; however, such effects have never been systematically examined. OBJECTIVE We conducted a systematic review and meta-analysis to evaluate the protective effect of folic acid-fortified multivitamin supplements on other congenital anomalies. METHODS We searched Medline, PubMed, EMBASE, Toxline, Healthstar, and Cochrane databases for studies describing the outcome of pregnancies in women using multivitamin supplements that were published in all languages from January 1966 to July 2005. The references from all collected articles were reviewed for additional articles. Two independent reviewers who were blinded to the source and identity of the articles extracted data based on predetermined inclusion and exclusion criteria. Using a random effects model, rates of congenital anomalies in babies born to women who were taking multivitamin supplements were compared with rates in the offspring of controls who were not. RESULTS From the initial search, 92 studies were identified; 41 of these met the inclusion criteria. Use of multivitamin supplements provided consistent protection against neural tube defects (random effects odds ratio[OR] 0.67, 95% confidence intervals [95% CI] 0.58-0.77 in case control studies; OR 0.52, 95% CI 0.39-0.69 in cohort and randomized controlled studies), cardiovascular defects (OR 0.78, 95% CI 0.67-0.92 in case control studies; OR 0.61, 95% CI 0.40-0.92 in cohort and randomized controlled studies), and limb defects (OR 0.48, 95% CI 0.30-0.76 in case control studies; OR 0.57, 95% CI 0.38-0.85 in cohort and randomized controlled studies). For cleft palate, case control studies showed OR 0.76 (95% CI 0.62-0.93), and cohort and randomized controlled studies showed OR 0.42 (95% CI 0.06-2.84); for oral cleft with or without cleft palate, case control studies showed OR 0.63 (95% CI 0.54-0.73), and cohort and randomized controlled studies showed OR 0.58 (95% CI 0.28-1.19); for urinary tract anomalies, case control studies showed OR 0.48 (95% CI 0.30-0.76), and cohort and randomized controlled studies showed OR 0.68 (95% CI 0.35-1.31); and for congenital hydrocephalus case control studies showed OR 0.37 (95% CI 0.24-0.56), and cohort and randomized controlled studies showed OR 1.54 (95% CI 0.53-4.50). No effects were shown in preventing Down syndrome, pyloric stenosis, undescended testis, or hypospadias. CONCLUSION Maternal consumption of folic acid-containing prenatal multivitamins is associated with decreased risk for several congenital anomalies, not only neural tube defects. These data have major public health implications, because until now fortification of only folic acid has been encouraged. This approach should be reconsidered.

Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses.

BACKGROUND & AIMS The relative efficacies of licensed antiviral therapies for treatment-naive chronic hepatitis B (CHB) infection in randomized controlled trials have not been determined. We evaluated the relative efficacies of the first 12 months of CHB treatments. METHODS Drugs evaluated were lamivudine, pegylated interferon, adefovir, entecavir, telbivudine, and tenofovir, as monotherapies and combination therapies, in treatment-naive individuals. Databases were searched for randomized controlled trials of the first 12 months of therapy in hepatitis B e antigen (HBeAg)-positive and/or HBeAg-negative patients with CHB published in English before October 31, 2009. Bayesian mixed treatment comparisons were used to calculate the odds ratios, including 95% credible intervals and predicted probabilities of surrogate outcomes to determine the relative effects of each treatment. RESULTS In HBeAg-positive patients, tenofovir was most effective in inducing undetectable levels of HBV DNA (predicted probability, 88%), normalization of alanine aminotransferase (ALT) levels (66%), HBeAg seroconversion (20%), and hepatitis B surface antigen loss (5%); it ranked third in histologic improvement of the liver (53%). Entecavir was most effective in improving liver histology (56%), second for inducing undetectable levels of HBV DNA (61%) and normalization of ALT levels (70%), and third in loss of hepatitis B surface antigen (1%). In HBeAg-negative patients, tenofovir was the most effective in inducing undetectable levels of HBV DNA (94%) and improving liver histology (65%); it ranked second for normalization of ALT levels (73%). CONCLUSIONS In the first year of treatment for CHB, tenofovir and entecavir are the most potent oral antiviral agents for HBeAg-positive patients; tenofovir is most effective for HBeAg-negative patients.

DEPRESSION DURING PREGNANCY : OVERVIEW OF CLINICAL FACTORS

Depression during pregnancy is common, affecting an estimated 20% of women. However, conflicting data exist concerning the outcomes of this disorder. Thus, we reviewed studies that presented evidence for the use of antidepressants and those that examined untreated depression during the gestational period, in terms of clinical and epidemiological aspects.Observational studies have provided reassuring evidence of the safety of antidepressant use during pregnancy. However, due to the reluctance of healthcare providers to prescribe and patients to take medication during the obstetric period, approximately three-quarters of those diagnosed with depression remain untreated. Furthermore, healthcare providers apparently do not recognise the disorder in up to 50% of pregnant women who experience depression. Increased antidepressant dosing during pregnancy may be required to maintain euthymia; however, guidelines for effective dosing levels are absent. Consequently, many patients remain inadequately treated. Substantial maternal and fetal morbidity including substance abuse, functional impairment, increased risk of postnatal depression, and poor pregnancy outcomes have resulted from untreated depression.The consequences of those outcomes are likely to be associated with substantial clinical, social and economic burdens. An incidence-based assessment of the consequences of prenatal depression would be useful in order to: (i) establish the impact on the quality of life of these patients and their families; (ii) assess the associated economic burden on individual families and the healthcare system; and (iii) to provide epidemiological data to enable the provision of suitable management strategies for these patients.

Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis.

Objective To determine if first-trimester exposure to ex hormones, and oral contraceptives (OCs) specifically, is associated with an increased risk of external fetal genital malformations. Data Sources MEDLINE and Science Citation Index data bases were searched for the years 1966–1992 for relevant English-language articles on first-trimester sex-hormone ex-posure and fetal genital changes. Methads of Study Selection One hundred eighty-six arti-cles were identified initially. Inclusion criteria were cohort or case-control studies, first-trimester sex-hormone exposure, and live infants or full-term stillborn infants with external genital malformations. Exclusion criteria were diethylstil-bestrol exposure, spontaneous abortions, and teratogen ex-posure. Data Extraction and Synthesis The Methods section of each study was reviewed independently by two authors and two outside reviewers, using the above criteria. Fourteen studies, seven cohort and seven case-control, involving 65,565 women, met the criteria for meta-analysis. Extracted data were entered into 2 × 2 tables. The overall summary odds ratio (OR) was 1.09 (95% confidence interval [CI] 0.90–1.32); subanalysis of OC exposure identified an OR of 0.98 (95% CI 0.24–3.94). Conclusion There was no association between first-trimester exposure to sex hormones generally (or to OCs specifically) and external genital malformations. Thus, women exposed to sex hormones after conception may be assured there is no increased risk of fetal sexual malformation.