Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling.

PURPOSE: Estimating causal effects in observational pharmacoepidemiology is a challenging task, as it is often plagued by confounding by indication. Restricting the sample to those with an indication for drug use is a commonly performed procedure; indication-based sampling ensures that the exposed and unexposed are exchangeable on the indication-limiting the potential for confounding by indication. However, indication-based sampling has received little scrutiny, despite the hazards of exposure-related covariate control. METHODS: Using simulations of varying levels of confounding and applied examples we describe bias amplification under indication-based sampling. RESULTS: We demonstrate that indication-based sampling in the presence of unobserved confounding can give rise to bias amplification, a self-inflicted phenomenon where one inflates pre-existing bias through inappropriate covariate control. Additionally, we show that indication-based sampling generally leads to a greater net bias than alternative approaches, such as regression adjustment. Finally, we expand on how bias amplification should be reasoned about when distinct clinically relevant effects on the outcome among those with an indication exist (effect-heterogeneity). CONCLUSION: We conclude that studies using indication-based sampling should have robust justification - and that it should by no means be considered unbiased to adopt such approaches. As such, we suggest that future observational studies stay wary of bias amplification when considering drug indications.

Mode of delivery and maternal sexual wellbeing: A longitudinal study.

OBJECTIVES: To investigate the association between mode of delivery and subsequent maternal sexual wellbeing. DESIGN: Prospective birth cohort study. SETTING: Avon (in Bristol area), UK. POPULATION: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: Mode of delivery was abstracted from obstetric records and sexual wellbeing measures were collected via a self-report questionnaire. Missing data were imputed using multiple imputation, and ordinal logistic regression models for ordered categorical outcomes were adjusted for the covariates maternal age at delivery, pre-pregnancy body mass index, diabetes during pregnancy, socio-economic position, parity, depression and anxiety. MAIN OUTCOME MEASURES: Sexual enjoyment and frequency at four time points postpartum (between 33 months and 18 years) and two types of sex-related pain (pain in the vagina during sex and elsewhere after sex) at 11 years postpartum. RESULTS: We found no association between mode of delivery and sexual enjoyment (e.g. adjusted odds ratio [OR] 1.11, 95% confidence interval [95% CI] 0.97-1.27 at 33 months) or sexual frequency (OR 0.99, 95% CI 0.88-1.12 at 33 months). Caesarean section was associated with an increased odds of pain in the vagina during sex at 11 years postpartum as compared with vaginal delivery in the adjusted model (OR 1.74, 95% CI 1.46-2.08). CONCLUSIONS: These findings provide no evidence supporting associations between caesarean section and sexual enjoyment or frequency. However, mode of delivery was shown to be associated with dyspareunia, which may not be limited to abdominal scarring.

Caesarean section and its relationship to offspring general cognitive ability: a registry-based cohort study of half a million young male adults.

BACKGROUND: A relationship between caesarean section and offspring cognitive ability has been described, but data are limited, and a large-scale study is needed. OBJECTIVE: To determine the relationship between mode of delivery and general cognitive ability. METHODS: A cohort of 579 244 singleton males, born between 1973 and 1987 who conscripted before 2006, were identified using the Swedish population-based registries. Their mode of delivery was obtained from the Swedish Medical Birth registry. The outcome measure was a normalised general cognitive test battery (mean 100, SD 15) performed at military conscription at around age 18. FINDINGS: Males born by caesarean section performed poorer compared with those born vaginally (mean score 99.3 vs 100.1; adjusted mean difference -0.84; 95% CI -0.97 to -0.72; p<0.001). Both those born by elective (99.3 vs 100.2; -0.92; 95% CI -1.24 to -0.60; p<0.001) and non-elective caesarean section (99.2 vs 100.2; -1.03; 95% CI -1.34 to -0.72; p=0.001), performed poorer than those born vaginally. In sibling analyses, the association was attenuated to the null (100.9 vs 100.8; 0.07; 95% CI -0.31 to 0.45; p=0.712). Similarly, neither elective nor non-elective caesarean section were associated with general cognitive ability in sibling analyses. CONCLUSION: Birth by caesarean section is weakly associated with a lower general cognitive ability in young adult males. However, the magnitude of this association is not clinically relevant and seems to be largely explained by familial factors shared between siblings. CLINICAL IMPLICATION: Clinicians and gravidas ought not to be concerned that the choice of mode of delivery will impact offspring cognitive ability.