Interpretation
This is the first study to evaluate the potential of calcium-based
antacids to reduce the risk of preeclampsia. Several mechanisms through
which calcium intake could prevent preeclampsia have been proposed.
Calcium may protect endothelial cells from endothelial activation by
multiple activators, including necrotic trophoblast debris and
inflammatory cytokines, and prevent hypertension by increasing the
production of nitric oxide, which is a potent
vasodilator.38 Additionally, low serum calcium could
increase blood pressure by inducing parathyroid release, which
stimulates renin release, resulting in increased intracellular calcium
leading to vasoconstriction.39,40 Indeed, calcium
supplementation has been shown to substantially decrease the risk of
preeclampsia based on data from randomized controlled trials, although
publication bias cannot be excluded.6 Only a few
observational studies on the association between calcium supplementation
and hypertensive disorders of pregnancy have been conducted, indicating
that beneficial effects may only apply to women with a diet low in
calcium or observing no effect at all.41-43 In
exploratory analyses in the current study, we did not observe a
decreased risk of late-onset preeclampsia associated with calcium-based
antacid use among women at high risk of developing preeclampsia or among
women who did not use calcium supplementation either.
In line with previous studies,11-13 we did not find
the risk of late-onset preeclampsia to be reduced after use of PPIs,
neither in early or mid-pregnancy or in late pregnancy. The latter,
however, is in contrast with the results from Hastie et
al.,11 who observed a reduced risk of preterm
preeclampsia (delivery <37 weeks of gestation; adjusted odds
ratio 0.63 [95% CI 0.41-0.96]) and early preeclampsia (delivery
<34 weeks of gestation; adjusted odds ratio 0.41 [95% CI
0.20-0.82]) associated with PPI use after gestational week 28. In
addition to a different outcome definition applied in our study (i.e.
late-onset preeclampsia: any preeclampsia diagnosed after
33+6 weeks of gestation), this difference in results
could be explained by the analytical approach. The extended Cox model
applied in our study accounts for PPI use to be a function of time,
whereas the standard time-independent model used by Hastie et al. may be
biased by immortal time,27,44,45 leading to
overestimation of the protective effects of PPI use.
Mechanistically, PPIs may be more likely to prevent preterm preeclampsia
than term preeclampsia, in which the relative difference in sFlt-1
levels between those affected and those who are not is smaller than in
preterm preeclampsia.46 Therefore, PPI use may prevent
the development of early-onset preeclampsia in particular. We excluded
cases with this subtype, however, due to etiologic and prognostic
heterogeneity,18 as small numbers prevented us from
including these cases as a separate outcome group.
Instead of the hypothesized decreased risk, we actually observed an
increased risk of late-onset preeclampsia associated with use of
low-dose calcium-based antacids in gestational weeks 0-16 or use of PPIs
in gestational weeks 17-33, in particular among women at high risk of
developing preeclampsia. We did not identify other studies with similar
results on calcium in early pregnancy, but slightly increased risks of
overall preeclampsia associated with PPI use in pregnancy were also
observed in other studies.11-13 However, these results
may be biased by confounding by indication, as illustrated by the
attenuated RR in comparisons with an H2RA-exposed group
in a nationwide cohort study in South Korea.13Furthermore, reverse causation cannot be excluded, since epigastric pain
is one of the symptoms consistent with preeclampsia.47