Strengths and Limitations
A major strength of this study is the availability of detailed, validated self-reported data on the use of calcium-based antacids and PPIs, enabling us to take dosage and timing of exposure into account, despite actual use being slightly underreported.22Studies relying on administrative databases, however, are prone to exposure misclassification due to the wide and uncaptured over-the-counter availability of the medications of interest (underestimation) and non-adherence to prescribed medications (overestimation),48 making them unsuitable to assess the associations of interest. Other strengths include the application of advanced methods to deal with time-varying exposures and the availability of a wide range of confounders, although residual confounding cannot be ruled out completely.
This study also has some limitations. Participants in the PRIDE Study and The Dutch Pregnancy Drug Register differ from the general Dutch population of pregnant women in terms of level of education, but selection into the study has been reported not to bias exposure-outcome associations in comparable cohort studies.49-51Differential loss-to-follow up, however, may affect the effect estimates. Therefore, we applied IPCW, which is a robust method to handle bias resulting from this type of selection.52Although we included a relatively large study population, study power was insufficient for some secondary analyses and to use an active comparator. The validity of self-reported data on the secondary outcome gestational hypertension is considerably lower compared to that of the primary outcome preeclampsia, mainly due to relatively high numbers of false-positive reports.20 Due to a partial lack of data, we could not take dietary calcium intake and the dose of supplementation into account in our confounder definition. Of note, the calcium content in supplementation is usually low (120-200 mg).