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Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations has been controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically-controlled processes in the embryo that result in structural malformations. We propose that development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to assess the validity of preeclampsia, congenital cardiac malformations, and persistent pulmonary hypertension of the newborn (PPHN) diagnoses in the US Medicaid Analytic eXtract (MAX), a nationwide health care utilization database that may be useful for perinatal research., Methods: Using the 2000-2007 MAX, we identified more than 1 million pregnancies ending in live birth. We identified potential cases based on claims, reviewed their hospital medical records, and calculated the positive predictive values (PPVs) and 95% confidence intervals (CIs) using records as the reference., Results: Among 183 women with any preeclampsia diagnoses, the PPV was 66.5% (53.6, 77.4%), but it increased to 94.5% (84.0, 98.3%) for inpatient preeclampsia diagnoses. The PPV for inpatient PPHN diagnoses (N = 82) was 68.3% (57.6, 77.4%), but it increased to 89.6% (CI: 77.8, 95.5%) when restricting to infants not transferred to another facility shortly after birth (N = 48). The PPV for cardiac malformations was 77.6% (65.7, 86.2%) when requiring inpatient codes on more than one date (N = 63)., Conclusions: These PPVs are conservative, particularly when patients were transferred or received outpatient diagnoses, because we reviewed records from a single hospitalization only. PPVs improve with stringent identification criteria, at the cost of sensitivity, and can be used to correct for measurement error., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Our goal is to study the triggers of spontaneous preterm delivery using a case-crossover design., Methods: In a pilot study, we enrolled 50 women with spontaneous preterm labour (PTL) and 50 with preterm premature rupture of membranes (PPROM) between 2011 and 2012. To assess non-transient risk factors, we also enrolled a control group of 158 pregnant women at their regular prenatal care visits matched to cases by gestational age and calendar time. The index time was defined as the onset of PTL/PPROM (for cases) or interview (for controls). Detailed data were collected through structured interviews regarding factors of interest during the 72 h that preceded the index time. Within case subjects, we compared the frequency of transient factors from 0 to 24 h before index time with that from 48 to 72 h before index time, and estimated matched odds ratios (OR) and 95% confidence intervals (CI)., Results: Previously hypothesised chronic risk factors for spontaneous preterm delivery, including mood disorders and stressful events, were more common among cases than among controls. Within cases, skipped meals [OR 4.3, 95% CI 1.2, 15.2], disturbed sleep [OR 4.5, 95% CI 1.5, 13.3], sexual activity [OR 6.0, 95% CI 0.7, 69.8], and intake of spicy foods [OR 7.0, 95% CI 1.6, 30.8] were associated with an increased risk for PTL/PPROM within the subsequent 24 h. For physical exertion and other potential risk factors evaluated, the OR was close to the null., Conclusion: Skipping meals and disturbed sleep may be associated with imminent PTL/PPROM; sexual activity and spicy food may trigger PTL/PPROM in susceptible women. Larger case-crossover studies will be able to evaluate the impact of modifiable risk factors and acute predictors of PTL/PPROM, and might help guide obstetrical management., (© 2014 John Wiley & Sons Ltd.)

Background: Propensity scores are useful for confounding adjustment in the commonly observed setting of many potential confounders, frequent exposure, and rare events. However, with few exposed outcomes to inform covariate selection and many candidate confounders, optimal approaches to construct and implement propensity-score-based confounding adjustment remain unclear., Methods: In a cohort study on the effect of anticonvulsant drugs on cardiovascular risk among adult patients from the HealthCore Integrated Research Database, we compared the performance for confounding control of various covariate-selection strategies for propensity-score estimation (expert knowledge only, expert knowledge informed by empirical covariate selection via high-dimensional propensity-score, and high-dimensional propensity-score empirical specification only) and propensity-score-based adjustment methods (propensity-score-matching and propensity-score-decile stratification). This article focuses on the first 90 days of follow-up because any treatment effect identified in this temporal window almost certainty originates from residual confounding rather than pharmacologic action., Results: We identified 166,031 new users and 564 ischemic cardiovascular events. Among those, 12,580 patients initiated anticonvulsants that strongly induce cytochrome P450 enzymes and experienced 68 events. The unadjusted hazard ratio was 1.72 (95% confidence interval = 1.34-2.22). Adjustment for investigator-identified covariates led to 41% to 59% reductions in the hazard ratio; adjustment for both investigator-identified and high-dimensional propensity-score empirically identified covariates led to larger reductions (54% to 72%). A selection strategy based on high-dimensional propensity-score empirical specification alone produced less-attenuated and more-volatile hazard ratio estimates. This volatility seemed to be slightly attenuated in a trimmed propensity-score-stratified analysis., Conclusions: The high-dimensional propensity-score algorithm complements expert knowledge for confounding adjustment, but in settings with few exposed outcomes, its performance without investigator-specified covariates is less clear and may be associated with an increased likelihood of bias. In our example, investigator specification of variables combined with high-dimensional propensity-score empirical selection and the use of trimmed propensity-score-stratified analysis seem to improve effect estimation. Plotting the relation of effect estimates to the increasing number of empirical covariates is a useful diagnostic.

This commentary reviews the recent history of explanations to crossover paradoxes such as the birth weight and gestational age paradoxes, with a special emphasis on the current proposal by Kramer et al. in this issue of the Journal (Am J Epidemiol. 2014;179(3):361-367). We contend that the causal structure of these paradoxes is essentially identical to that of several well-known selection biases. We then consider the pros and cons of using composite outcomes to circumvent these selection biases.

Objective: To assess the possible effects of topiramate and zonisamide use during pregnancy on fetal growth., Methods: The study population was the singleton liveborns born to women who enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2012. Data were collected through telephone interviews at enrollment, 7 months of gestation, and postpartum. The prevalence of small for gestational age at birth among neonates exposed to topiramate and to zonisamide when either was used as monotherapy during pregnancy was compared with that among neonates exposed to lamotrigine monotherapy, a weight-neutral therapy, and the most common antiepileptic drug in the Registry. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated with multivariable log-binomial regression to control for potential confounders., Results: Data were available for 347 topiramate, 98 zonisamide, and 1,581 lamotrigine-exposed neonates. The mean gestational length was 39 weeks for all comparison groups. Prenatal exposure to topiramate or zonisamide was associated with a mean lower birth weight of 221 and 202 g, respectively, and a mean lesser neonatal length of 1 cm as compared with lamotrigine exposure (p<.01). The prevalence of small for gestational age was 6.8% for lamotrigine, 17.9% for topiramate (RR 2.4, 95% CI 1.8-3.3) and 12.2% for zonisamide (RR 1.6, 0.9-2.8). Similar results were found when a group of 457 unexposed neonates was used as the reference., Conclusions: Topiramate and zonisamide have been shown to reduce weight in adults. Our finding of a decrease in mean birth weight and length among neonates exposed in utero raises concern., Level of Evidence: II.

Background: Several studies have reported an association between use of specific antihistamines in early pregnancy and certain specific birth defects., Objective: To test 16 previously hypothesized associations between specific antihistamines and specific birth defects, and to identify possible new associations., Methods: We used 1998-2010 data from the Slone Epidemiology Center Birth Defects Study, a multicenter case-control surveillance program of birth defects in North America. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors, and details on the use of prescription and nonprescription medications. We compared first trimester exposure to specific antihistamines between 13,213 infants with specific malformations and 6982 nonmalformed controls by using conditional logistic regression to estimate odds ratios and 95% confidence intervals (CIs), with adjustment for potential confounders, including indication for use., Results: Overall, 13.7% of controls were exposed to antihistamines during the first trimester. The most commonly used medications were diphenhydramine (4.2%), loratadine (3.1%), doxylamine (1.9%), and chlorpheniramine (1.7%). When estimates were stable, none supported the previously hypothesized associations. Among more than 100 exploratory comparisons of other specific antihistamine-defect pairs, 14 had odds ratios ≥1.5, of which 6 had 95% CI bounds excluding 1.0 before but not after adjustment for multiple comparisons., Conclusion: Our findings do not provide meaningful support for previously posited associations between antihistamines and major congenital anomalies; at the same time, we identified associations that had not been previously suggested. We suspect that previous associations may be chance findings in the context of multiple comparisons, a situation that may also apply to our new findings., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: This paper aimed to assess the prescription of medications during pregnancy by primary care physicians in the UK., Methods: We identified both completed pregnancies and pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths) in women aged 13-49 years enrolled in The Health Improvement Network (THIN) between 1996 and 2010 following an algorithm with three sequential cycles that searched for Read Code groups in hierarchical order: (1) indicators of conception; (2) delivery or pregnancy loss; and (3) other codes suggestive of pregnancy. Completed pregnancies were linked to liveborn infants by means of the family identification number and date of birth. Prescription of specific drugs during the first trimester and time trends during the last decade were calculated., Results: A total of 191 000 pregnancies were identified, including 148 544 completed pregnancies and 42 456 (22.2%) pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths). Of the completed pregnancies, 131670 (88.6%) were successfully linked with the offspring. The most commonly prescribed drugs were antibiotics, antimycotics, asthma/allergy medications, and analgesics. From 1996 to 2010, the proportion of completed pregnancies with at least one prescription during the first trimester increased for antidepressants (1.8% to 4.2%), thyroid hormones (0.7% to 1.6%), and opiods (1.5% to 2.6%), among other drugs., Conclusion: In conclusion, the prescription of several medications by primary care physicians during the first trimester of pregnancy has risen in the UK during the last decade. We discuss how, when important challenges are considered, THIN may be a promising resource to study specific therapies during pregnancy., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Prior studies suggest that women who use antidepressants during pregnancy have an increased risk for preeclampsia, yet the comparative safety of specific antidepressants remains unclear. US nationwide Medicaid Analytic eXtract (MAX) data have not been used to study medication safety during pregnancy., Methods: We identified 100,942 pregnant women with depression from 2000 to 2007 MAX data. We used pharmacy dispensing records to ascertain exposure to selective serotonin reuptake inhibitor (SSRI), serotonin-norepenephrine reuptake inhibitor (SNRI), tricyclic, bupropion, other antidepressant monotherapy or polytherapy, and specific antidepressants, during the second trimester and first half of the third trimester. Relative risks (RRs) and 95% confidence intervals (CIs) were adjusted for delivery year, preeclampsia risk factors, depression severity proxies, other antidepressant indications, other medications, and healthcare utilization., Results: The risk of preeclampsia was 5.4% among women with depression and no antidepressant exposure. Compared with these women, the risk for preeclampsia was higher among those receiving SNRI (RR: 1.52, 95% CI = 1.26-1.83) and tricyclic monotherapy (RR: 1.62, 95% CI = 1.23-2.12), but not SSRI monotherapy (RR: 1.00, 95% CI = 0.93-1.07) or other antidepressants. Compared with women receiving SSRI monotherapy, preeclampsia risk was higher among women with SNRI (RR: 1.54, 95% CI = 1.28-1.86) and tricyclic (RR: 1.64, 95% CI = 1.25-2.16) monotherapy. None of the specific SSRIs was associated with preeclampsia. The RR with venlafaxine was 1.57 (95% CI = 1.29-1.91) and with amitriptyline 1.72 (95% CI = 1.24-2.40)., Conclusions: In this population, SNRIs and tricyclics were associated with a higher risk of preeclampsia than SSRIs.

Objective: To determine whether use of serotonin or non-serotonin reuptake inhibitors near to delivery is associated with postpartum hemorrhage., Design: Cohort study., Setting: 2000-07 nationwide Medicaid data (Medicaid Analytic eXtract)., Population: 106,000 pregnant women aged 12-55 with a diagnosis of mood or anxiety disorder. Women were categorized into four mutually exclusive exposure groups according to pharmacy dispensing data: current (delivery date), recent (1-30 days before delivery date), past (1-5 months before delivery date), and no exposure (reference group)., Main Outcome Measures: Risk of postpartum hemorrhage by timing of exposure and by serotonin or non-serotonin reuptake inhibitors, classes of antidepressant, and antidepressant types. Relative risks and 95% confidence intervals adjusted for delivery year, risk factors for postpartum hemorrhage, indicators of severity of mood/anxiety disorder, other indications for antidepressants, and other drugs. High dimensional propensity score (hdPS) methods were used to empirically identify and adjust for additional factors., Results: 12,710 (12%) women had current exposure to serotonin reuptake inhibitor monotherapy, and 1495 (1.4%) women had current exposure to non-serotonin reuptake inhibitor monotherapy. The risk of postpartum hemorrhage was 2.8% among women with mood/anxiety disorders but no exposure to antidepressants, 4.0% in the current users of serotonin reuptake inhibitors, 3.8% in the current users of non-serotonin reuptake inhibitors, 3.2% in the recent users of serotonin reuptake inhibitors, 3.1% in the recent users of non-serotonin reuptake inhibitors, 2.5% in the past users of serotonin reuptake inhibitors, and 3.4% in the past users of non-serotonin reuptake inhibitors. Compared with no exposure, women with current exposure to serotonin reuptake inhibitors had a 1.47-fold increased risk of postpartum hemorrhage (95% confidence interval 1.33 to 1.62) and women with current non-serotonin reuptake inhibitor exposure had a 1.39-fold increased risk (1.07 to 1.81). Results were similar with hdPS adjustment. Women with current exposure to serotonin reuptake inhibitors had an adjusted excess risk of 1.26% (0.90% to 1.62%), with a number needed to harm of 80, and for women with current exposure to non-serotonin reuptake inhibitors the excess risk was 1.03% (0.07% to 1.99%), with a number needed to harm of 97. For exposure to serotonin reuptake inhibitors the relative risk was 1.19 (1.03 to 1.38) for recent exposure and 0.93 (0.82 to 1.06) for past exposure; for non-serotonin reuptake inhibitors the figures were 1.17 (0.80 to 1.70) and 1.26 (1.00 to 1.59), respectively. Current exposure to selective serotonin reuptake inhibitor monotherapy was also associated with postpartum hemorrhage (1.42, 1.27 to 1.57), as was current serotonin norepinephrine (noradrenaline) reuptake inhibitor (1.90, 1.37 to 2.63) and tricyclic monotherapy (1.77, 0.90 to 3.47). All types of selective serotonin reuptake inhibitors available for analysis and venlafaxine, a serotonin norepinephrine reuptake inhibitor, were significantly associated with postpartum hemorrhage., Conclusions: Exposure to serotonin and non-serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics, close to the time of delivery was associated with a 1.4 to 1.9-fold increased risk for postpartum hemorrhage. While potential confounding by unmeasured factors cannot be ruled out, these findings suggest that patients treated with antidepressants during late pregnancy are more likely to experience postpartum hemorrhage.

Previous studies suggested that early pregnancy exposure to specific oral decongestants increases the risks of several birth defects. Using January 1993-January 2010 data from the Slone Epidemiology Center Birth Defects Study, we tested those hypotheses among 12,734 infants with malformations (cases) and 7,606 nonmalformed control infants in the United States and Canada. Adjusted odds ratios and 95% confidence intervals were estimated for specific birth defects, with controlling for potential confounders. Findings did not replicate several hypotheses but did support 3 previously reported associations: phenylephrine and endocardial cushion defect (odds ratio = 8.0; 95% confidence interval: 2.5, 25.3; 4 exposed cases), phenylpropanolamine and ear defects (odds ratio = 7.8; 95% confidence interval: 2.2, 27.2; 4 exposed cases), and phenylpropanolamine and pyloric stenosis (odds ratio = 3.2; 95% confidence interval: 1.1, 8.8; 6 exposed cases). Hypothesis-generating analyses involving multiple comparisons identified a small number of associations with oral and intranasal decongestants. Accumulating evidence supports associations between first-trimester use of specific oral and possibly intranasal decongestants and the risk of some infrequent specific birth defects.

Background: In the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000-2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail., Methods: Among females ages 12-55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness., Results: From 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy., Conclusions: Mother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases.

Background: Few studies have evaluated the prevention of upper gastrointestinal complications (UGIC; bleeding or perforation) in patients with uncomplicated peptic ulcer (PU). We assessed the effect of proton pump inhibitors (PPI) in a non-randomized setting. To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU, i.e., a clear indication. To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis., Methods: Within a population of subjects aged 40-84 years from The Health Improvement Network database, 1997-2006, we identified 3,850 patients with incident PU. Among them, we confirmed 74 first UGIC episodes during a mean follow-up of 4 years. Exposure was prescription coverage during the month following PU diagnosis. We performed a nested case-control analysis and compared UGIC cases with 400 controls matched for age, sex, year and duration of follow-up. Relative risks (RR) and 95 % confidence intervals (CI) were estimated., Results: The overall incidence of UGIC was 4.6 cases/1,000 person-years; it was highest during the months after PU diagnosis, increased with age, and it was higher in men and subjects with Helicobacter pylori infection, anemia, and alcohol use at PU diagnosis. The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 (95 % CI 0.31-1.0). The RR for NSAIDs with and without a PPI was 1.72 (0.68-4.45) and 3.27 (0.85-12.67), respectively., Conclusions: Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC.

Objective: To evaluate the association between the use of medications potentially containing phthalates and urinary concentrations of specific phthalate metabolites around conception., Methods: Women enrolled in the Environment and Reproductive Health project from 2006 to 2009 completed questionnaires about the use of medications and provided multiple urine samples before and after conception. We compared the mean urinary concentration of phthalate metabolites between users of phthalate containing medications and a matched unexposed control group., Results: One woman used Asacol(®) (mesalamine), which utilizes dibutyl phthalate (DBP) as a delayed release coating material, and had a mean urinary concentration of the main DBP metabolite 200 times higher than the controls (8176μg/L vs. 37.5μg/L). The three users of stool softeners had a higher concentration of the main diethyl phthalate (DEP) metabolite (8636μg/L vs. 714.2μg/L). Neither the three additional Prilosec(®) (omeprazole) users nor one cyclobenzaprine user had higher urinary concentration than controls., Conclusion: Selected medications may be important sources of DBP and DEP exposures around conception., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The risk of depression in women is greatest at childbearing age. We sought to examine and explain national trends in antidepressant use in pregnant women., Methods: This was a cohort study including pregnant women aged 12-55 who were enrolled in Medicaid during 2000-2007. We examined the proportion of women taking antidepressants during pregnancy by patient characteristics (descriptive), by region (mixed-effects model) and over time (interrupted time series)., Results: We identified 1,106,757 pregnancies in 47 states; mean age was 23 years, and 60% were nonwhite. Nearly 1 in 12 used an antidepressant during pregnancy. Use was higher for older (11.2% for age ≥30 vs. 7.6% for <30) and white (14.4% vs. 4.0% for nonwhite) women. There was a four- to fivefold difference in rate of antidepressant use among states. Of the 5.3% of women taking antidepressants at conception, 33% and 17% were still on treatment 90 and 180 days, respectively, into pregnancy; an additional 4% began use during pregnancy. Labeled pregnancy-related health advisories did not appear to affect antidepressant use., Conclusions: Antidepressant use during pregnancy remains high in this population; treatment patterns vary substantially by patient characteristics and region. Comparative safety and effectiveness data to help inform treatment choices are needed in this setting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Prior studies have reported increased risks of congenital heart defects (CHD) and pyloric stenosis (PS) after prenatal exposure to macrolide antibiotics. We sought to assess the association between maternal use of erythromycin and nonerythromycin macrolides and the risks of CHD and PS., Study Design: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 through 2008, we identified 4132 infants with CHD and 735 with PS as cases, and 6952 infants without any malformation as controls. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of erythromycin or nonerythromycin macrolides in each trimester using conditional logistic regression and adjusting for risk factors for CHD and PS, fever, specific types of infections, and their associated treatments., Results: During the first trimester, 0.4% and 0.7% of control women had used erythromycin and nonerythromycin macrolides, respectively. Compared to non-use during pregnancy, first-trimester exposure to erythromycin was not associated with an increased risk of CHD (OR, 1.3; 95% CI, 0.6-2.6) or PS (OR, 0.9; 95% CI, 0.3-3.0). The corresponding ORs for nonerythromycin macrolides were 0.7 (95% CI, 0.4-1.3) for CHD and 1.7 (95% CI, 0.6-4.6) for PS. We found no association between third-trimester exposure to erythromycin or nonerythromycin macrolides and the risk of PS. Hypothesis generation analyses did not identify appreciable associations between maternal use of macrolides and other common specific birth defects., Conclusion: We found no meaningful associations between the risks of CHD, PS, and other common malformations in relation to use of macrolides in pregnancy., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Purpose: The role of administrative databases for research on drug safety during pregnancy can be limited by their inaccurate assessment of the timing of exposure, as the gestational age at birth is typically unavailable. Therefore, we sought to develop and validate algorithms to estimate the gestational age at birth using information available in these databases., Methods: Using a population-based cohort of 286,432 mother-child pairs in British Columbia (1998-2007), we validated an ICD-9/10-based preterm-status indicator and developed algorithms to estimate the gestational age at birth on the basis of this indicator, maternal age, singleton/multiple status, and claims for routine prenatal care tests. We assessed the accuracy of the algorithm-based estimates relative to the gold standard of the clinical gestational age at birth recorded in the delivery discharge record., Results: The preterm-status indicator had specificity and sensitivity of 98% and 91%, respectively. Estimates from an algorithm that assigned 35 weeks of gestational age at birth to deliveries with the preterm-status indicator and 39 weeks to those without them were within 2 weeks of the clinical gestational age at birth in 75% of preterm and 99% of term deliveries., Conclusions: Subtracting 35 weeks (245 days) from the date of birth in deliveries with codes for preterm birth and 39 weeks (273 days) in those without them provided the optimal estimate of the beginning of pregnancy among the algorithms studied., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: We evaluated whether younger age in class is associated with poorer academic performance and an increased risk of being prescribed stimulants for attention-deficit/hyperactivity disorder (ADHD)., Methods: This was a nationwide population-based cohort study, linking data from national registries of prescribed drugs and standardized scholastic examinations. The study population comprised all children born in 1994-1996 who took standardized tests in Iceland at ages 9 and 12 (n = 11 785). We estimated risks of receiving low test scores (0-10th percentile) and being prescribed stimulants for ADHD. Comparisons were made according to children's relative age in class., Results: Mean test scores in mathematics and language arts were lowest among the youngest children in the fourth grade, although the gap attenuated in the seventh grade. Compared with the oldest third, those in the youngest third of class had an increased relative risk of receiving a low test score at age 9 for mathematics (1.9; 95% confidence interval [CI] 1.6-2.2) and language arts (1.8; 95% CI 1.6-2.1), whereas at age 12, the relative risk was 1.6 in both subjects. Children in the youngest third of class were 50% more likely (1.5; 95% CI 1.3-1.8) than those in the oldest third to be prescribed stimulants between ages 7 and 14., Conclusions: Relative age among classmates affects children's academic performance into puberty, as well as their risk of being prescribed stimulants for ADHD. This should be taken into account when evaluating children's performance and behavior in school to prevent unnecessary stimulant treatment.

Objective: To describe patterns of disease-modifying antirheumatic drug (DMARD) use during pregnancy in a population-based cohort, and to evaluate the association between autoimmune disease, DMARDs, corticosteroids, and nonsteroidal antiinflammatory drugs (NSAIDs) and preeclampsia., Methods: Using health care utilization databases from British Columbia (1997-2006), we compared the risk for preeclampsia among 44,786 women with and without autoimmune disease with study drug dispensings before pregnancy (past users) and before and during the first 20 gestational weeks (continuous users). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated., Results: Only 414 women (0.1%) had a DMARD dispensing during pregnancy. The incidence of preeclampsia was 2.3% for past DMARD users, 2.7% for past corticosteroid users, and 2.9% for past NSAID users. Compared to past users, the continuous DMARD user RR was 2.29 (95% CI 0.81-6.44), and was 0.89 (95% CI 0.51-1.56) for corticosteroid and 0.84 (95% CI 0.63-1.10) for NSAID users. Compared to women without autoimmune disease, the delivery year-adjusted RR was 2.02 (95% CI 1.11-3.64) for women with systemic lupus erythematosus (SLE). The DMARD results were attenuated when antimalarials were excluded, and the delivery year-adjusted RR was 0.95 (95% CI 0.25-3.55) when the DMARD analysis was restricted to women with autoimmune disease., Conclusion: Few women were exposed to DMARDs during pregnancy. We observed a 2-fold increased risk of preeclampsia among women with SLE and a nonsignificant increase in risk in DMARD users. The DMARD and preeclampsia association was attenuated when antimalarials were excluded and null when restricted to women with autoimmune disease, which suggests the association is likely due to greater autoimmune disease severity in DMARD users., (Copyright © 2012 by the American College of Rheumatology.)

A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997-2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression.

Background: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients)., Objective: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients., Methods: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates., Results: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity--hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)--were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers., Conclusions: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.

Background: The intention-to-treat comparison is the primary, if not the only, analytic approach of many randomized clinical trials., Purpose: To review the shortcomings of intention-to-treat analyses, and of 'as treated' and 'per protocol' analyses as commonly implemented, with an emphasis on problems that are especially relevant for comparative effectiveness research., Methods and Results: In placebo-controlled randomized clinical trials, intention-to-treat analyses underestimate the treatment effect and are therefore nonconservative for both safety trials and noninferiority trials. In randomized clinical trials with an active comparator, intention-to-treat estimates can overestimate a treatment's effect in the presence of differential adherence. In either case, there is no guarantee that an intention-to-treat analysis estimates the clinical effectiveness of treatment. Inverse probability weighting, g-estimation, and instrumental variable estimation can reduce the bias introduced by nonadherence and loss to follow-up in 'as treated' and 'per protocol' analyses., Limitations: These analyse require untestable assumptions, a dose-response model, and time-varying data on confounders and adherence., Conclusions: We recommend that all randomized clinical trials with substantial lack of adherence or loss to follow-up are analyzed using different methods. These include an intention-to-treat analysis to estimate the effect of assigned treatment and 'as treated' and 'per protocol' analyses to estimate the effect of treatment after appropriate adjustment via inverse probability weighting or g-estimation.

Objective: To examine the epidemiology of hypertension in women of reproductive age., Methods: Using NHANES from 1999-2008, we identified 5,521 women age 20-44 years old. Hypertension status was determined using blood pressure measurements and/or self-reported medication use., Results: The estimated prevalence of hypertension in women of reproductive age was 7.7% (95% confidence interval (CI): 6.9%-8.5%). The prevalence of anti-hypertensive pharmacologic therapy was 4.2% (95% CI 3.5%-4.9%). The prevalence of hypertension was relatively stable across the study period; the age and race adjusted odds of hypertension in 2007-2008 did not differ significantly from 1999-2000 (odds ratio 1.2, CI 0.8 to 1.7, p = 0.45). Significant independent risk factors associated with hypertension included older age, non-Hispanic black race (compared to non-Hispanic whites), diabetes mellitus, chronic kidney disease, and higher body mass index. The most commonly used antihypertensive medications included diuretics, angiotensin-converting enzyme inhibitors (ACE), and beta blockers., Conclusion: Hypertension occurs in about 8% of women of reproductive age. There are remarkable differences in the prevalence of hypertension between racial/ethnic groups. Obesity is a risk factor of particular importance in this population because it affects over 30% of young women in the U.S., is associated with more than 4 fold increased risk of hypertension, and is potentially modifiable.

Background: Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence., Aim: To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users., Methods: The General Practice Research Database (UK 1998-2008), the Integrated Primary Care Information database (the Netherlands 1996-2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000-2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated., Results: The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers., Conclusions: The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence.

Purpose: Imperfect recall of exposure timing challenges the ascertainment of medications in interview-based studies., Methods: We propose an algorithm to classify medication exposure, taking into account recall certainty. The availability of medication use details, including duration of use, start and stop dates, and maternal estimates of how certain they were about these dates, allowed classification of subjects as either likely or possibly exposed in the first trimester of pregnancy. We applied the algorithm to study an association between prenatal tetracycline exposure and risk of congenital heart defects previously reported by the National Birth Defects Prevention Study, using 1993-2008 data from 11,517 subjects in the Slone Epidemiology Center Birth Defects Study., Results: Among women exposed to tetracyclines during pregnancy (n = 58), 50% and 19% were likely and possibly exposed, respectively, in the first trimester, and 31% were exposed outside the first trimester. Compared with non-use during pregnancy, the crude OR for exposure outside the first trimester was 1.0 (95%CI 0.4-2.5), and that for exposed (likely or possibly, combined) in the first trimester was 1.7 (95%CI 0.9-3.2); however, the ORs based on the algorithms were 0.9 (95%CI 0.3-3.0) for possibly exposed and 2.2 (95%CI 1.0-4.6) for likely exposed., Conclusions: A "certainty-response" (stronger association with higher level of certainty) was found within exposures in the window of etiological interest. Algorithms for exposure classification that incorporate recall certainty may be useful in interview-based studies., (Copyright © 2011 John Wiley & Sons, Ltd.)

We examined the relationship between food insufficiency and antiretroviral therapy (ART) adherence. A cohort of HIV-infected adults in urban Peru was followed for a two-year period after ART initiation. ART adherence was measured using a 30-day self-report tool and classified as suboptimal if <95% adherence was reported. We conducted a repeated measures cohort analysis to examine whether food insufficiency was more common during months of suboptimal adherence relative to months with optimal adherence. 1,264 adherence interviews were conducted for 134 individuals. Participants who reported food insufficiency in the month prior to interview were more likely to experience suboptimal adherence than those who did not (odds ratio [O.R.]:2.4; 95% confidence interval [C.I.]:1.4, 4.1), even after adjusting for baseline social support score (O.R. per 5 point increase:0.91; C.I.:[0.85, 0.98]) and good baseline adherence self-efficacy (O.R.:0.25; C.I.:[0.09, 0.69]). Interventions that ensure food security for HIV-infected individuals may help sustain high levels of adherence.

Background & Aims: We investigated the effect of different prevention strategies against upper gastrointestinal bleeding (UGIB) in the general population and in patients on antithrombotic or anti-inflammatory treatments., Methods: We performed a population-based, nested, case-control study using The Health Improvement Network UK primary care database. From 2000 to 2007, we identified 2049 cases of UGIB and 20,000 controls. The relative risk (RR) of UGIB associated with various gastroprotective agents was estimated by comparing current use (defined as use within 30 days of the index date) with nonuse in the previous year, using multivariate logistic regression., Results: The adjusted RR of UGIB associated with current use of proton pump inhibitors (PPIs) for more than 1 month was 0.58 (95% confidence interval [CI], 0.42-0.79) among patients who received low-dose acetylsalicylic acid (ASA), 0.18 (95% CI, 0.04-0.79) for clopidogrel, 0.17 (95% CI, 0.04-0.76) for dual antiplatelet therapy, 0.48 (95% CI, 0.22-1.04) for warfarin, and 0.51 (95% CI, 0.34-0.78) for nonsteroidal anti-inflammatory drugs. The corresponding estimates for therapy with histamine-2-receptor antagonists (H2RAs) were more unstable, but tended to be of a smaller magnitude. In the general population, PPI use was associated with a reduced risk of UGIB compared with nonuse (RR, 0.80; 95% CI, 0.68-0.94); no such reduction was observed for H2RAs or nitrates., Conclusions: PPI use was associated with a lower risk of UGIB in the general population and in patients on antithrombotic or anti-inflammatory therapy compared with nonuse of PPIs. The reduction in risks of UGIB was smaller in H2RA than in PPI users., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Incidence rate (IR) estimates for peptic ulcer disease (PUD) vary widely among studies. We conducted a systematic review to quantify and examine the discrepancies., Methods: Of 4780 articles identified from PubMed and EMBASE databases, 31 published in the last three decades that had reported IRs of PUD in the general population were included. Random effects meta-analysis and meta-regression were performed to calculate pooled estimates and to identify sources of heterogeneity., Results: The pooled IR estimate per 1000 person-years was 0.90 (95% confidence interval: 0.78-1.04) for uncomplicated PUD, 0.57 (0.49-0.65) for peptic ulcer bleeding, 0.10 (0.08-0.13) for gastrointestinal perforations, and 3.18 (2.05-4.92) for nonspecific PUD. Within specific outcomes definitions, IR estimates were significantly lower in studies with restriction to hospitalized cases, case validation, and case ascertainment directly from hospital or clinical sources versus computerized health care databases. Younger age, female sex, and later calendar time were also associated with lower PUD incidence., Conclusions: We found that the IR of uncomplicated PUD was in the order of one case per 1000 person-years in the general population, and that the IR of peptic ulcer complications was around 0.7 cases per 1000 person-years. Comparisons of IR estimates among studies need to take into account disease definition and other study characteristics, particularly whether outcome validation was performed in computerized claims. The use of claims to identify PUD cases might overestimate the IR by around 45%., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: The objective of the study was to provide information on overall medication use throughout pregnancy, with particular focus on the first trimester and specific prescription medications., Study Design: The study design included the Slone Epidemiology Center Birth Defects Study, 1976-2008, and the National Birth Defects Prevention Study, 1997-2003, which together interviewed more than 30,000 women about their antenatal medication use., Results: Over the last 3 decades, first-trimester use of prescription medication increased by more than 60%, and the use of 4 or more medications more than tripled. By 2008, approximately 50% of women reported taking at least 1 medication. Use of some specific medications markedly decreased or increased. Prescription medication use increased with maternal age and education, was highest for non-Hispanic whites, and varied by state., Conclusion: These data reflect the widespread and growing use of medications by pregnant women and reinforce the need to study their respective fetal risks and safety., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To characterize therapies prescribed during pregnancy to women with rheumatoid arthritis (RA)., Methods: We conducted a cohort study of women with RA with pregnancies using health care utilization data from 2002-2008. We examined the distribution of RA drugs by therapeutic classes, including nonsteroidal antiinflammatory drugs (NSAIDs)/coxibs, glucocorticoids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs, during 90-day pregnancy trimesters and the 180 days prior to pregnancy. Drugs were characterized according to the Food and Drug Administration risk classification system. Differences in exposure by period were determined by chi-square tests., Results: A total of 393 pregnancies were identified among 34,169 women with RA. Seventy-two percent of pregnancies ended in a delivery. Approximately 24% of women with RA received a DMARD during preconception. At any point during pregnancy, 23% of women with deliveries were dispensed ≥1 DMARD and the proportion of use declined from the first to the third trimester (P = 0.03). Similar to DMARD therapy, use of NSAIDs/coxibs and exposure to category D/X medications were significantly lower compared to prepregnancy use (P < 0.05). In contrast, more women were prescribed glucocorticoids during pregnancy than before pregnancy. Use of biologics occurred in 12.5% of pregnancies. Compared to women with deliveries, women who experienced abortions were more frequently exposed to NSAIDs/coxibs (P < 0.05). Dispensing of category D/X medications was also higher in women with spontaneous abortions and primarily involved methotrexate (P < 0.05)., Conclusion: Approximately 24% of women with RA received a DMARD in the 180 days before conception, and the proportion dropped during pregnancy. Glucocorticoid use remained high throughout pregnancy. Our results suggest that continued efforts directed at counseling women and their physicians about the potential risks/benefits of RA therapies during pregnancy are warranted., (Copyright © 2011 by the American College of Rheumatology.)

Background: This study evaluated the risk of upper gastrointestinal bleeding (UGIB) associated with use of low-dose acetylsalicylic acid (ASA) alone and in combination with other gastrotoxic medications., Methods and Results: The Health Improvement Network UK primary care database was used to identify individuals 40 to 84 years of age with a UGIB diagnosis in 2000 to 2007 (n = 2049). An age-, sex-, and calendar year-matched control group (n = 20,000) was identified from the same source population. The relative risk (RR) of UGIB associated with use of low-dose ASA (75 to 300 mg/d), clopidogrel, and other commonly coadministered medications was estimated by multivariate logistic regression. The risk of UGIB was increased in current users of low-dose ASA (RR, 1.80; 95% confidence interval [CI], 1.59 to 2.03) or clopidogrel (RR, 1.67; 95% CI, 1.24 to 2.24) compared with nonusers. Compared with low-dose ASA monotherapy, the risk of UGIB was significantly increased when low-dose ASA was coadministered with clopidogrel (RR, 2.08; 95% CI, 1.34 to 3.21), oral anticoagulants (RR, 2.00; 95% CI, 1.15 to 3.45), low-/medium-dose nonsteroidal antiinflammatory drugs (RR, 2.63; 95% CI, 1.93 to 3.60), high-dose nonsteroidal antiinflammatory drugs (RR, 2.66; 95% CI, 1.88 to 3.76), or high-dose oral corticosteroids (RR, 4.43; 95% CI, 2.10 to 9.34); this was not apparent with coadministration of statins (RR, 0.99; 95% CI, 0.81 to 1.21) or low-dose oral corticosteroids (RR, 1.01; 95% CI, 0.58 to 1.77)., Conclusions: Use of low-dose ASA is associated with an almost 2-fold increase in the risk of UGIB compared with nonuse. This risk is increased further in individuals taking low-dose ASA along with clopidogrel, oral anticoagulants, nonsteroidal antiinflammatory drugs, or high-dose oral corticosteroids.

Background: Asthma is among the most common serious medical problems in pregnancy, and its prevalence may be increasing. Management is problematic because asthma may harm the fetus, yet little is known about fetal risks of asthma medications., Objective: To examine the prevalence, symptom control, and pharmacologic treatment of asthma in pregnancy., Methods: Study participants were a random sample of 3,609 mothers of nonmalformed infants born in Massachusetts between 1998 and 2006. Interviewed within 6 months of delivery, participants were asked specific asthma-related questions and classified as having physician-diagnosed, possible, past, or no asthma; those with physician-diagnosed asthma were classified as having well-controlled, not well-controlled, or poorly controlled asthma. Drug treatments were grouped into corticosteroids, beta(2)-agonists, leukotriene modifiers, combination products, and others., Results: Physician-diagnosed asthma was present in 502 women (13.9%) and possible asthma in an additional 578(16.0%). Higher rates of asthma were observed among women who were younger, white, obese, and less well educated, had lower income, and smoked during pregnancy. Secular changes were unremarkable: leukotriene modifiers were used by only 3.4% of asthmatic women; inhaled steroid use increased only from 19.0% during 1997-1999 to 23.3% in 2003-2005, whereas use of inhaled beta(2)-agonists exceeded 50% in both periods. Less than 40% of women with poorly controlled asthma symptoms reported use of a controller medication., Conclusions: High rates of asthma and asthma symptoms, together with the low rates of use of controller medications, underscore the need to better understand the risks and safety of asthma medications during pregnancy., (Copyright 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The intention-to-treat (ITT) analysis provides a valid test of the null hypothesis and naturally results in both absolute and relative measures of risk. However, this analytic approach may miss the occurrence of serious adverse effects that would have been detected under full adherence to the assigned treatment. Inverse probability weighting of marginal structural models has been used to adjust for nonadherence, but most studies have provided only relative measures of risk. In this study, we used inverse probability weighting to estimate both absolute and relative measures of risk of invasive breast cancer under full adherence to the assigned treatment in the Women's Health Initiative estrogen-plus-progestin trial. In contrast to an ITT hazard ratio (HR) of 1.25 (95% confidence interval [CI] = 1.01 to 1.54), the HR for 8-year continuous estrogen-plus-progestin use versus no use was 1.68 (1.24 to 2.28). The estimated risk difference (cases/100 women) at year 8 was 0.83 (-0.03 to 1.69) in the ITT analysis, compared with 1.44 (0.52 to 2.37) in the adherence-adjusted analysis. Results were robust across various dose-response models. We also compared the dynamic treatment regimen "take hormone therapy until certain adverse events become apparent, then stop taking hormone therapy" with no use (HR = 1.64; 95% CI = 1.24 to 2.18). The methods described here are also applicable to observational studies with time-varying treatments.

Case-only studies are often used to identify interactions between a genetic factor and an environmental factor under the assumption both factors are independent in the population. However, interpreting a statistical association between the genetic and the environmental factors among the cases, as evidence of a mechanistic gene-environment interaction, is not always warranted. Using a mechanistic approach based on the sufficient cause framework, we show association amongst cases can arise between the genetic and environmental factors when there is in fact no mechanistic gene-environment interaction. However, when it can be assumed the genetic and environmental factors themselves can never prevent the outcome, we show a positive association amongst cases implies a mechanistic gene-environment interaction. Without this assumption that the effects of the two factors are never preventive, a multiplicative interaction greater than two is needed to conclude the presence of a mechanistic interaction. We furthermore show these tests for mechanistic interaction can be extended to scenarios in which the genetic and environmental factors are negatively associated in the population rather than independent., ((c) 2009 Wiley-Liss, Inc.)

Objective: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication., Design: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication., Results: Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41-0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22-0.37) for less than 100 cells/microl, 0.33 (0.25-0.44) for 100 to less than 200 cells/microl, 0.38 (0.28-0.52) for 200 to less than 350 cells/microl, 0.55 (0.41-0.74) for 350 to less than 500 cells/microl, and 0.77 (0.58-1.01) for 500 cells/microl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49-0.67) for less than 1 year since initiation to 0.21 (0.14-0.31) for 5 years or more (P value for trend <0.001)., Conclusion: We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Objective: The associations between prenatal exposure to antidepressants and preterm delivery and fetal growth restriction are controversial and poorly understood. We studied the relation between antidepressant use and these outcomes., Methods: Analysis included women with nonmalformed infants interviewed in the Slone Epidemiology Center Birth Defects Study between 1998 and 2008. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for premature and small-for-gestational age (SGA) offsprings, adjusting for sociodemographic, lifestyle, medical, and reproductive factors., Results: The frequencies of preterm delivery were 7.3% among the 5710 nonusers (reference), 8.9% among the 192 selective serotonin reuptake inhibitor (SSRI) users (OR, 1.1; 95% CI, 0.6-2.0), and 15.3% among the 59 non-SSRI antidepressant users (OR, 2.2; 95% CI, 1.0-4.9); the respective frequencies of delivering an SGA offspring were 7.2%, 10.9% (OR, 1.7; 95% CI, 1.0-2.7), and 13.6% (OR, 2.2; 95% CI, 1.0-4.9). Compared with nonusers, the frequencies of preterm delivery (7.6%) and SGA offspring (5.7%) were not increased among the 106 women who discontinued SSRIs before the end of the first trimester. Among women who continued SSRIs beyond the first trimester, 10.5% delivered a preterm infant (OR, 1.3; 95% CI, 0.6-2.8) and 17.4% had an SGA offspring (OR, 3.0; 95% CI, 1.7-5.5)., Conclusions: Women treated with SSRIs late in pregnancy had a higher frequency of delivering SGA infants, and women receiving non-SSRI antidepressants were more likely to deliver premature and SGA offsprings. The findings suggest an effect of underlying mood disorder or an effect common to both drug classes. In any case, prenatal antidepressant use may help identify women at elevated risks of delivering preterm and SGA infants.

Purpose: Computerized databases can be an efficient resource to study the epidemiology of peptic ulcer (PU) and upper gastrointestinal complications (UGIC) if we achieve a high positive predictive value (PPV) of outcome definitions. We assessed the PPV of diagnosis codes in THIN, a primary-care medical-record database, to ascertain individuals with uncomplicated PU, and to identify UGIC and Helicobacter pylori infection status (HPIS) among these patients., Methods: We identified: (1) patients with codes suggesting a first episode of uncomplicated PU; (2) episodes of UGIC among them. The computerized profiles with free-text comments of these individuals were reviewed and classified as definite, possible, or excluded cases. Dates and HPIS were also ascertained. For a sample of definite and possible PU, and for all UGIC cases, primary care physicians were sent a questionnaire for confirmation., Results: The 5296 individuals with codes suggesting PU were classified as definite (49%), possible (25%), and excluded (26%) cases. The PPV for definite/possible PU was 94% (99% for definite, 84% for possible cases). Of the questionnaires with information on HPIS (62%), the PPV and NPV were 100%. The 97 individuals with codes suggesting UGIC were classified as definite (48%), possible (27%), and excluded (22%) cases; the PPV for definite/possible was 95% (100% for definite, 88% for possible cases). Code dates were generally later than medical-record dates., Conclusion: The identification of PU cases and their HPIS and UGIC requires careful review of the computerized clinical information with free-text comments. The validation of a sample is needed to confirm the accuracy of the diagnoses., (2009 John Wiley & Sons, Ltd.)

Objective: To investigate whether pre-eclampsia is more common in first pregnancies solely because fewer affected women, who presumably have a higher risk of recurrence, go on to have subsequent pregnancies., Design: Prospective cohort study., Setting: Swedish Medical Birth Register., Participants: 763 795 primiparous mothers who had their first births in Sweden, 1987-2004., Main Outcome Measures: Pre-eclampsia., Results: The risk of pre-eclampsia was 4.1% in the first pregnancy and 1.7% in later pregnancies overall. However, the risk was 14.7% in the second pregnancy for women who had had pre-eclampsia in their first pregnancy and 31.9% for women who had had pre-eclampsia in the previous two pregnancies. The risk for multiparous women without a history of pre-eclampsia was around 1%. The incidence of pre-eclampsia associated with delivery before 34 weeks' gestation was 0.42% in primiparous women, 0.11% in multiparous women without a history of pre-eclampsia, and 6.8% and 12.5% in women who had had one or two previous pregnancies affected, respectively. The proportion of women who went on to have a further pregnancy was 4-5% lower after having a pregnancy with any pre-eclampsia but over 10% lower if pre-eclampsia was associated with very preterm delivery. The estimated risk of pre-eclampsia in parous women did not change with standardisation for pregnancy rates., Conclusions: Having pre-eclampsia in one pregnancy is a poor predictor of subsequent pregnancy but a strong predictor for recurrence of pre-eclampsia in future gestations. The lower overall risk of pre-eclampsia among parous women was not explained by fewer conceptions among women who had had pre-eclampsia in a previous gestation. Early onset pre-eclampsia might be associated with a reduced likelihood of a future pregnancy and with more recurrences than late onset pre-eclampsia when there are further pregnancies. Findings are consistent with the existence of two distinct conditions: a severe recurrent early onset type affected by chronic factors, genetic or environmental, and a milder sporadic form affected by transient factors.

Objective: The purpose of this study was to assess the effects of treatment with selective serotonin reuptake inhibitors (SSRIs) on the risks of gestational hypertension and preeclampsia., Method: The authors analyzed data from 5,731 women with nonmalformed infants and no underlying hypertension who participated in the Slone Epidemiology Center Birth Defects Study from 1998 to 2007. Gestational hypertension was defined as incident hypertension diagnosed after 20 weeks of pregnancy, with and without proteinuria (i.e., with and without preeclampsia). The risks of gestational hypertension and preeclampsia were compared between women who did and did not receive SSRI treatment during pregnancy. Relative risks and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model, adjusting for prepregnancy sociodemographic, lifestyle, reproductive, and medical factors., Results: Gestational hypertension was present in 9.0% of the 5,532 women who were not treated with SSRIs and 19.1% of the 199 women who were treated with SSRIs. Among women who received treatment, gestational hypertension was present in 13.1% of the 107 women who received treatment only during the first trimester and in 26.1% of the 92 women who continued treatment beyond the first trimester. The occurrence of preeclampsia was 2.4% among women who were not treated with SSRIs, 3.7% among women who were exposed to SSRIs only during the first trimester, and 15.2% among women who continued SSRI treatment beyond the first trimester. Relative to women who did not receive treatment, the adjusted relative risk of preeclampsia was 1.4 for women who discontinued treatment and 4.9 for women who continued treatment., Conclusion: SSRI exposure during late pregnancy-whether a causal factor or not-might identify women who are at an increased risk for gestational hypertension and preeclampsia. Further investigation is needed in order to separate the effects of treatment with SSRIs from those of underlying mood disorders.

Antibiotic use has been associated with an increased risk of cancer in epidemiologic studies. We evaluated the association between antibiotic use and the risk of primary lung cancer by conducting a prospective case-control study nested in a cohort of subjects who were 40 to 84 years old in 1995 to 2004, with at least 2 years of enrollment in The Health Improvement Network. There were 4,336 cases of primary lung cancer. A random sample of 10,000 controls was frequency matched to the cases for age, sex, and calendar year of diagnosis. Antibiotic exposure was measured by the total number of antibiotic prescriptions and the cumulative number of days on antibiotics since enrollment. We discounted exposure 1 year before the date of cancer diagnosis. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Smoking, chronic obstructive pulmonary disease, respiratory infections, body mass index, and health care utilization were introduced in the model. Compared with subjects with no prescription of antibiotics before the index date, the crude RR of lung cancer was 2.52 (95% CI, 2.25-2.83) among those who received 10 or more prescriptions. The corresponding RR was 1.31 (95% CI, 1.10-1.57) upon adjustment for confounders. We used directed acyclic graphs to illustrate that the observed higher risk of lung cancer among antibiotic users may be due to the increased frequency of infections in patients with subclinical cancer and to shared causes between cancer and infections. Current evidence is insufficient to support or refute a carcinogenic effect of antibiotics.

This report explores the low birth weight paradox using two graphical approaches: causal directed acyclic graphs (DAGs), and the empirical curves of the birth weight distribution and birth weight-specific mortality. The birth weight curves are able to represent the associations quantitatively, while the corresponding causal DAGs provide a set of plausible explanations for the findings. Taken together, these two approaches can facilitate discussion of underlying biological mechanisms.

Objective: To evaluate the effect of antidepressant use on lung cancer risk., Methods: We conducted a case-control study nested in a cohort of patients 40-84 year-old in 1995-2004, without a prior diagnosis of cancer using The Health Improvement Network (THIN) database in the UK. Cases comprised 4,336 patients with a first diagnosis of primary lung cancer. A sample of 10,000 controls was frequency-matched to the cases for age, sex, and the calendar year of diagnosis. The index date for exposure definition was one year before the diagnosis for cases and one year before a random date for controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models adjusted for potential confounders., Results: Selective serotonin reuptake inhibitor (SSRI) use during the year preceding the index date with treatment duration of at least one year had an OR of 0.59 (95% CI 0.41, 0.86). The corresponding OR was 1.23 (95% CI 0.96, 1.58) for tricyclic antidepressants (TCAs)., Conclusions: SSRI use did not increase the lung cancer risk and might be associated with a reduced risk. However, residual confounding might explain the apparent protective effect found for SSRI use, as well as the marginally elevated risk observed among TCA users.

Objective: To investigate the association between infertility treatments and gestational hypertension and preeclampsia., Design: Retrospective observational cohort., Setting: General population, United States and Canada., Patient(s): Five thousand one hundred fifty-one women with non-malformed infants participating in the Slone Epidemiology Center Birth Defects Study between 1998 and 2006., Intervention(s): Women were interviewed within 6 months after delivery about sociodemographic and medical factors, about the onset of gestational hypertension and preeclampsia, and about infertility treatments., Main Outcome Measure(s): We estimated relative risks and 95% confidence intervals by using unconditional logistic regression., Result(s): The incidence of gestational hypertension was 8.9% (423/4,762) among women without infertility treatments and was 15.8% (55/349) among women undergoing infertility treatments. Compared with spontaneous pregnancies, the crude relative risk for gestational hypertension in pregnancies resulting from infertility treatments was 1.9 (95% confidence interval, 1.4-2.6). Multivariate adjustment for parity and prepregnancy body mass index resulted in a relative risk of 1.6 (1.1-2.1). Further adjustment for multiple pregnancies, or restriction of the analyses to singleton pregnancies, moved the relative risk to 1.3. Each specific infertility procedure or drug was associated with a similarly elevated risk, which disappeared after adjustment for multiple gestations. Results were similar for preeclampsia., Conclusion(s): Pregnancies resulting from infertility treatments have a higher incidence of gestational hypertension and preeclampsia than do spontaneous conceptions. This increased risk is largely explained by the higher frequency of multiple gestations.

Purpose: To summarize current evidence on statin use and fracture risk and to explore potential sources of heterogeneity among study results., Methods: A computerized search was conducted on MEDLINE, EMBASE, and the Cochrane databases using the keywords HMG-CoA reductase inhibitor, osteoporosis, and fractures. A meta-analysis was performed to summarize results of studies identified., Results: Statin use was associated with a 23% lower fracture risk (OR = 0.77, 95%CI: 0.66-0.90). An effect of statins was found in case-control (OR = 0.62, 0.45-0.85, n = 6) and cohort (OR = 0.77, 0.59-1.00, n = 8) studies, but not in post hoc analyses of randomized trials (OR = 1.03, 0.91-1.16, n = 4). A reduced risk with statin use was found for fractures of the hip (OR = 0.58, 0.46-0.74, n = 16), spine (OR = 0.65, 0.48-0.88, n = 8) and other sites (OR = 0.77, 0.60-1.00, n = 7), and both in women (OR = 0.80, 0.66-0.96, n = 11) and men (OR = 0.62, 0.36-1.08, n = 3). Among the observational studies that also evaluated the effect of other lipid-lowering drugs, no reduced fracture risk was found for these agents (OR = 0.96, 0.85-1.09, n = 10). The test for heterogeneity was significant for study results of statin use versus no-use (p < 0.01). Meta-regression analyses suggested that study design might partly account for the heterogeneity. There was an indication of publication bias by examining Begg's plot, although Egger's test was not significant (p = 0.13)., Conclusions: Current evidence does not support an effect of statins in preventing fractures given (i) the lack of association in randomized trials, (ii) the heterogeneity among observational studies, (iii) the potential residual confounding, and (iv) the potential publication bias., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Regular aspirin and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use is associated with a reduced risk of colorectal cancer. The effect of NSAIDs on the risk of other cancers remains unclear. To evaluate whether use of aspirin or other specific NSAIDs protects against lung cancer, we conducted a case-control study nested in a cohort of subjects 40-84 years old in 1995-2004, without a diagnosis of cancer before the study start date, and with at least 2 years of enrollment with a general practitioner providing data to the The Health Improvement Network (THIN) database in the UK. Patients who had a first diagnosis of primary lung cancer during the study period were considered cases. A random sample of 10,000 controls was frequency-matched to the cases for age, sex and calendar year. The index date for exposure definition was 1 year before the date of diagnosis for cases and 1 year before a random date within the study period for controls. Relative risks and 95% confidence intervals were estimated using conditional logistic regression stratified for matching factors. Factors such as smoking, chronic obstructive pulmonary disease, cardiovascular diseases and body mass index were introduced in the model. We identified 4,336 cases with primary incident lung cancer (incidence rate 7.6 per 10,000 person-years). Compared with subjects with no prescription of non-aspirin NSAID prior to the index date, the risk of lung cancer was 0.76 (0.61-0.94) among those who received a prescription the previous year and had a treatment duration of at least 1 year. The corresponding relative risk was 1.15 (0.99-1.34) for aspirin. In conclusion, prescription of non-aspirin NSAIDs for at least 1 year might be associated with a slightly reduced risk of lung cancer. Aspirin was not associated with a risk reduction, perhaps due to residual confounding., ((c) 2006 Wiley-Liss, Inc.)

Background: The spontaneous reporting system is the most efficient warning system of adverse drug reactions (ADRs). Pharmacists can play an important role in the detection and reporting of ADRs. The factors that affect under-reporting among these professionals are unknown in Spain., Objective: To identify the factors that influence community pharmacists' ADR under-reporting in Navarra, a Northern Spanish region., Methods: A case-control study was conducted on a population of 802 community pharmacists working in Navarra. Cases were pharmacists who had reported at least two ADRs to the region's drug surveillance unit between 2003 and 2005 and who agreed to participate in the study (18/20; 90%). A random sample of 60 controls was selected from the 762 pharmacists who had not reported any ADR during the same period of time., Results: Factors positively associated with ADR reporting were age, years of work experience as a pharmacist, participation in educational activities related to the detection and resolution of drug-related problems, the habit of detecting ADRs as part of pharmacists' duties, having the basic knowledge needed to report ADRs, and disagreement with the common belief among healthcare professionals that 'to report an ADR it is necessary to be sure that the reaction is related to the use of a particular drug'. The most frequently mentioned reasons for not reporting ADRs were the ADR is not serious, the ADR is already known, uncertainty concerning the causal relationship between the ADR and the drug, forgetting to report the ADR and a lack of time., Conclusions: Pharmacists' knowledge, beliefs, behaviour and motivation play an important role in ADR reporting. Under-reporting might be improved through activities focused on modifying such factors.