Sonia Hernandez-Diaz

A Structural Approach to Selection Bias

The term “selection bias” encompasses various biases in epidemiology. We describe examples of selection bias in case-control studies (eg, inappropriate selection of controls) and cohort studies (eg, informative censoring). We argue that the causal structure underlying the bias in each example is essentially the same: conditioning on a common effect of 2 variables, one of which is either exposure or a cause of exposure and the other is either the outcome or a cause of the outcome. This structure is shared by other biases (eg, adjustment for variables affected by prior exposure). A structural classification of bias distinguishes between biases resulting from conditioning on common effects (“selection bias”) and those resulting from the existence of common causes of exposure and outcome (“confounding”). This classification also leads to a unified approach to adjust for selection bias.

Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects

Background Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. Methods We assessed exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs in 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects and also in 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use during pregnancy. Results The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second o...

Medication Use During Pregnancy, With Particular Focus On Prescription Drugs: 1976-2008

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.

Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increase in upper gastrointestinal complications. There is no agreement, however, on whether all conventional NSAIDs have a similar relative risk (RR), and epidemiologic data are limited on acetaminophen. We studied the association between these medications and the risk of upper gastrointestinal bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. Our nested case-control analysis included 2,105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper gastrointestinal bleed/perforation. Compared with non-users, users of acetaminophen at doses less than 2 gm did not have an increased risk of upper gastrointestinal complications. The adjusted RR for acetaminophen at doses greater than 2 gm was 3.6 [95% confidence interval (95% CI) = 2.6–5.1]. The corresponding RRs for low/medium and high doses of NSAIDs were 2.4 (95% CI = 1.9–3.1) and 4.9 (95% CI = 4.1–5.8). The RR was 3.1 (95% CI = 2.5, 3.8) for short plasma half-life, 4.5 (95% CI = 3.5–5.9) for long half-life, and 5.4 (95% CI = 4.0–7.1) for slow-release formulations of NSAIDs. After adjusting for daily dose, the differences in RR between individual NSAIDs tended to diminish except for apazone. Users of H2 receptor antagonists, omeprazole, and misoprostol had RRs of 1.4 (95% CI = 1.2–1.8), 0.6 (95% CI = 0.4–0.9), and 0.6 (95% CI = 0.4–1.0), respectively. Among NSAID users, use of nitrates was associated with an RR of 0.6 (95% CI = 0.4–1.0).

Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study

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.

The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents

Most anti-inflammatory drugs have been associated with an increased risk of serious upper gastrointestinal complications. Epidemiological studies have estimated the magnitude of the risk for specific anti-inflammatory drugs. The risk of upper gastrointestinal tract bleeding or perforation increases around twofold with use of oral steroids or low dose aspirin, and increases around fourfold with use of nonaspirin nonsteroidal anti-inflammatory drugs. Acetaminophen at daily doses of 2000 mg and higher has also been associated with an increased risk. Overall, the risk is dose dependent and is greater with more than one anti-inflammatory drug taken simultaneously. Hence, whenever possible, anti-inflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of serious upper gastrointestinal complications.

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects

BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).

Beyond the intention to treat in comparative effectiveness research

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.

Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications

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.

Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs

The use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with upper gastrointestinal bleeding and perforation (UGIB), acute liver injury, acute renal injury, heart failure, and adverse reproductive outcomes. This article summarizes the effects of various factors, such as NSAID dose, duration of treatment, patient age, and ulcer history, on the incidences of these adverse side effects. We used the UK General Practice Research Database to study further the principal safety concern related to NSAIDs, namely, UGIB.