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\begin{document}

\title{Associations between late-onset preeclampsia and the use of
calcium-based antacids and proton pump inhibitors during pregnancy: a
prospective cohort study}



\author[1]{Marleen van Gelder}%
\author[1]{Pim Beekers}%
\author[2]{Yrea van Rijt-Weetink}%
\author[1]{Joris van Drongelen}%
\author[1]{Nel Roeleveld}%
\author[3]{Luc Smits}%
\affil[1]{Radboudumc}%
\affil[2]{Netherlands Pharmacovigilance Centre}%
\affil[3]{Maastricht University}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: To determine associations of calcium-based antacid and PPI
use during pregnancy with late-onset preeclampsia ([?]34 weeks of
gestation), taking into account dosage and timing of use. Design:
Prospective cohort study. Setting: This study used data from the PRIDE
Study (2012-2019) and Dutch Pregnancy Drug Register (2014-2019). Sample:
A total of 9,058 pregnant Dutch women aged [?]18 years. Methods: Data were
collected through web-based questionnaires and obstetric records. We
estimated risk ratios (RRs) for late-onset preeclampsia for any use and
trajectories of calcium-based antacid and PPI use before gestational day
238, and hazard ratios for time-varying exposures after gestational day
237. Main outcome measure: Late-onset preeclampsia. Results: Late-onset
preeclampsia was diagnosed in 2.6\% of pregnancies. Any use of
calcium-based antacids (RR 1.2 {[}95\% CI 0.9-1.6{]}) or PPIs (RR 1.4
{[}95\% CI 0.8-2.4{]}) before gestational day 238 was not associated
with late-onset preeclampsia. Use of low-dose calcium-based antacids in
gestational weeks 0-16 (\textless{}1g/day; RR 1.8 {[}95\% CI 1.1-2.9{]})
and any use of PPIs in gestational weeks 17-33 (RR 1.6 {[}95\% CI
1.0-2.8{]}) seemed to increase risks of late-onset preeclampsia. We did
not observe associations between late-onset preeclampsia and use of
calcium-based antacids and PPIs after gestational day 237. Conclusions:
In this prospective cohort study, use of calcium-based antacids and PPIs
during pregnancy was not found to reduce the risk of late-onset
preeclampsia. Funding: Netherlands Organisation for Health Research and
Development {[}ZonMw; grant number 848018010{]}.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Preeclampsia is a common pregnancy complication, affecting approximately
4.6\% of pregnancies worldwide, with a wide variation across different
regions.\textsuperscript{1} It is characterized by the new onset of
hypertension and proteinuria after gestational week 20 and is one of the
leading causes of maternal and perinatal morbidity and
mortality.\textsuperscript{2-5} The only curative treatment is delivery,
which emphasizes the need for preventive measures. A promising
intervention seems to be calcium supplementation: in a meta-analysis,
the risk of preeclampsia was decreased by more than 50\% after both
low-dose calcium supplementation (\textless{}1 g/day, risk ratio
{[}RR{]} 0.38, 95\% confidence interval {[}CI{]} 0.28-0.52; 9 trials)
and high-dose calcium supplementation ([?]1 g/day, RR 0.45, 95\% CI
0.31-0.65; 13 trials) compared to placebo.\textsuperscript{6} In
addition to calcium supplements, multivitamin-multimineral supplements,
and nutritional intake, many over-the-counter antacids represent a
substantial source of calcium with up to 680 mg of calcium carbonate per
tablet. Antacids are used to treat symptoms of gastroesophageal reflux
and are among the most commonly used medications during pregnancy, with
prevalence estimates up to 37\%.\textsuperscript{7,8} Whether using
calcium-based antacids during pregnancy is associated with a decreased
risk of preeclampsia, however, has not been studied yet.

If symptoms of gastroesophageal reflux persist, second-line treatment
options include histamine-2 receptor antagonists (H\textsubscript{2}RA)
and proton pump inhibitors (PPI). The latter are also hypothesized to
have the potential for preventing preeclampsia by reducing the secretion
of soluble fms-like tyrosine kinase 1 (sFlt-1) from primary placental
cells, placental tissue, and primary endothelial
cells.\textsuperscript{9,10} The few epidemiologic studies on the
association between PPIs and preeclampsia generally showed no decreased
risks,\textsuperscript{11-13} with the exception of PPI use recorded
after gestational week 28 in a study using data from the Swedish
Pregnancy Register.\textsuperscript{11}

Potential beneficial effects of gastroesophageal reflux medication
during pregnancy on the risk of preeclampsia may influence the choice of
treatment. However, the current level of knowledge is insufficient to
make a fair benefit-risk assessment. Therefore, we aimed to determine
the potential beneficial side effects of using calcium-based antacids
and PPIs during pregnancy in the prevention of late-onset preeclampsia,
taking dosage and timing of use into account.

\textbf{METHODS}

\textbf{Study population}

For this study, we used data from 2 ongoing prospective cohorts among
pregnant women in The Netherlands. The PRegnancy and Infant DEvelopment
(PRIDE) Study aims to identify factors that affect maternal and child
health during or after pregnancy.\textsuperscript{14,15} The Dutch
Pregnancy Drug Register is a national registry for medication use during
pregnancy and lactation at the Netherlands Pharmacovigilance Centre
Lareb aiming to provide information on the safety of medication use and
modelled after the PRIDE Study.\textsuperscript{16} For both cohorts,
women aged [?]18 years were invited for participation as early in
pregnancy as possible by participating midwives and gynaecologists, as
well as through the `Moeders voor Moeders' initiative and online
advertisements in the PRIDE Study. In the Netherlands, the data
collection for the International Registry of Antiepileptic Drugs and
Pregnancy EURAP\textsuperscript{17} is embedded in The Dutch Pregnancy
Drug Register, so women with epilepsy were oversampled. In both cohorts,
participating women were asked to complete Web-based questionnaires at
baseline, in gestational weeks 17 and 34, and at multiple time points
postpartum, starting 2 months after the estimated date of delivery.
Through these questionnaires, we gathered data on demographic
characteristics, obstetric history, maternal health including medication
use, lifestyle factors, pregnancy complications, and infant health.
Furthermore, PRIDE Study participants were asked consent for obtaining
records from prenatal care providers. The Regional Committee on Research
Involving Human Subjects approved the set-up of both cohorts. All
participants provided informed consent digitally.

\textbf{Outcomes}

The primary outcome was late-onset preeclampsia, defined as new-onset
hypertension accompanied by proteinuria after gestational week 34
(gestational day 237) irrespective of
severity.\textsuperscript{18}Details on the diagnostic criteria for
hypertensive disorders of pregnancy in The Netherlands are outlined in
Text S1.\textsuperscript{19} Data on the diagnosis of preeclampsia were
obtained from previously validated questionnaires (sensitivity 88\%,
specificity 100\%).\textsuperscript{20} In case of loss to follow-up,
outcome data were extracted from obstetric records whenever possible.

\textbf{Exposures}

Data on medication exposures were obtained from the three prenatal
questionnaires and the first postpartum questionnaire. For a wide range
of indications, including heartburn and acid reflux, women reported the
name of the medication taken, time period of use, frequency of use, and
quantity taken. Missing data on the duration of treatment, frequency, or
quantity were replaced with the median cohort value for that variable
specific for the medication of interest. Medications were coded
according to the Anatomical Therapeutic Chemical (ATC) Classification
System.\textsuperscript{21} Exposure to calcium-based antacids was
defined as reported use of antacids (ATC code A02) containing any amount
of calcium carbonate. The dose of calcium on each day was calculated by
multiplying the amount of calcium carbonate in mg per medication unit by
the number of units taken per day. The doses for multiple calcium-based
antacids per day were summed. PPI exposure was defined as report of
medication belonging to ATC group A02BC. Dosage was converted to Defined
Daily Dose (DDD) per day. Following, daily doses were expressed as the
average daily dose (milligrams per day for calcium-based antacids and
DDDs per day for PPIs) per week. For calcium-based antacids, we
considered a daily dose of [?]1 g calcium as high,\textsuperscript{6}while
a high dose for PPIs was \textgreater{}1 DDD. The sensitivity of the
questionnaires was 0.89 (95\% CI 0.86-0.93) for gastroesophageal reflux
medication.\textsuperscript{22}

We adhered to a recently published guidance on longitudinal methods for
modelling medication exposures in pregnancy.\textsuperscript{23} We
evaluated exposure binarily (any versus none) in the first 237 days of
pregnancy, further subdivided into early pregnancy (gestational weeks
0-16) and mid-pregnancy (gestational weeks 17-33), reflecting the
temporality of data collection in both sources (in weeks 17 and 34).
Furthermore, we clustered women with similar individual trajectories of
calcium dose or DDDs of PPIs in gestational weeks 0-33 using\emph{k}
-means clustering with the R statistical software package ``\emph{kml}
''.\textsuperscript{24} This unsupervised learning approach makes no
\emph{a priori} assumptions about trajectory shape or
membership.\textsuperscript{25} We considered daily and cumulative dose
in each gestational week allowing for \emph{k} = 2 to \emph{k} = 8
clusters. We selected the number of clusters based on (a) optimization
of three statistical quality criteria,\textsuperscript{25} (b) clinical
relevance of the clusters, and (c) at least 100 pregnancies per cluster.

\emph{K} -means clustering requires all pregnancies to have the same
gestational length to avoid including exposure after the diagnosis of
preeclampsia and on postpartum days.\textsuperscript{26} Moreover,
immortal time bias could be introduced if we would apply the binary
exposure categories after gestational day 237, as pregnancies without
preeclampsia and pregnancies with longer gestations have more
opportunity for exposure.\textsuperscript{27,28} Therefore, we modelled
time-dependent changes in dose on each gestational day between 238 and
the end of follow-up, defined as diagnosis of preeclampsia or delivery,
allowing for daily changes in use (none/any) and dose (none/low/high).
We determined exposure time by dividing the average number of
person-weeks in each exposure category by the number of women with any
exposure to each level after day 237. Women could contribute
person-weeks to multiple dose levels.\textsuperscript{29}

\textbf{Covariates}

For each exposure-outcome association, we identified a minimally
sufficient set of confounders using directed acyclic graphs (Figure
S1).\textsuperscript{30,31} These included maternal age (continuous),
parity (0 vs. [?]1 previous delivery), pre-pregnancy Body Mass Index (BMI;
continuous), maternal asthma (yes vs. no), maternal depression (yes vs.
no), and smoking (yes vs. no), alcohol consumption (yes vs. no), and use
of calcium-containing supplements (yes vs. no) during pregnancy. All
confounder data were obtained from the prenatal questionnaires.

\textbf{Inclusion and exclusion criteria}

We selected all PRIDE Study participants with an estimated date of
delivery in 2012-2019 (N = 9,054) and participants in The Dutch
Pregnancy Drug Register with an estimated date of delivery in 2014-2019
(N = 3,911). Participants included in both cohorts were included only
once, retaining the record with most complete information. Participants
who were diagnosed with early-onset preeclampsia (pathophysiology
differs from late-onset preeclampsia)\textsuperscript{18} or who
delivered before gestational week 34 (not at risk for the outcome of
interest) were excluded.

\textbf{Statistical analysis}

We used modified Poisson regression to estimate RRs with 95\% CIs
between exposure groups before gestational day 238 and late-onset
preeclampsia.\textsuperscript{32} Cox proportional hazard models with
time since gestational day 238 were used to estimate hazard ratios (HR)
for exposure after gestational day 237. We used robust standard errors
to account for correlation within women who participated with
\textgreater{}1 pregnancy in the PRIDE Study.\textsuperscript{33,34}

The models were weighted using inverse probability of censoring weights
and adjusted for a sufficient set of confounders. We used inverse
probability of censoring weights to account for potential selection bias
resulting from differential loss-to-follow-up,\textsuperscript{35} by
fitting logistic regression models to predict not being lost-to-follow
up using determinants of attrition. We used the models' predicted
probabilities to calculate inverse weights for loss-to-follow-up. Under
the assumption that data were missing at random, we imputed missing data
on confounders through multiple imputation (25 imputations; Text S1).

We conducted a number of sensitivity analyses to assess the robustness
of the primary analysis. Firstly, we selected gestational hypertension
as secondary outcome measure, distinguishing between exposure in
gestational weeks 0-19 and after gestational week 20, as some studies
indicate a protective effect of calcium supplements on this outcome as
well.\textsuperscript{6} Women with chronic hypertension (N=85) were
excluded from these analyses. Secondly, we used an externally validated
prediction model to select women at high risk of developing
preeclampsia, with a risk threshold of 3\%,\textsuperscript{36,37} and
replicated the main analyses in this population. Finally, we restricted
the analyses to women who did not use calcium-containing supplements
during pregnancy. All statistical analyses were performed using Stata/SE
16.0.

\textbf{RESULTS}

\textbf{Cohort and trajectory group characteristics}

A total of 9,058 pregnancies were included in this study (Figure S2).
The characteristics of the pregnancies included and those
lost-to-follow-up are shown in Table S1, and the characteristics of
participants stratified by cohort are shown in Table S2. Calcium-based
antacid use in gestational weeks 0-33 was reported in 21.1\% of
pregnancies. Women who used calcium-based antacids in gestational weeks
0-33 seemed to be more likely to have a high level of education, to have
asthma, to be primiparous, and to have used calcium-containing
supplements compared to non-users (Table 1). In 3.8\% of pregnancies,
PPI use in gestational weeks 0-33 was reported, with exposed women being
more likely to have a low/intermediate level of education, asthma,
depression, and a higher BMI, while more exposed women smoked in
pregnancy, but fewer used alcohol. Late-onset preeclampsia was diagnosed
in 2.6\% of pregnancies at a mean gestational age of
37\textsuperscript{+6} weeks.

Two trajectories best described intake of calcium from antacids in the
first 33 weeks of gestation (Figure 1). The low use trajectory is
characterized by negligible use in the first 15 weeks of pregnancy, with
moderate intake thereafter, whereas the high use trajectory showed a
steep increase in dose after the first trimester up to 2,500-3,250
mg/day after gestational week 17. Maternal and pregnancy characteristics
of the trajectory groups are shown in Table S3. In the longitudinal
cluster analyses, we did not identify trajectories describing intake of
calcium from antacids in gestational weeks 0-16 and 17-33 separately or
trajectories that described PPI use that fulfilled the selection
criteria.

\textbf{Exposure in early and mid-pregnancy and late-onset preeclampsia}

Any use of calcium-based antacids in gestational weeks 0-33 was not
associated with the risk of late-onset preeclampsia (adjusted RR 1.2
{[}95\% CI 0.9-1.6{]}; Table 2). The results did not differ
substantially in the analyses on dosage or using the trajectories. An
increased risk of late-onset preeclampsia was observed for women who
used a low dose of calcium-based antacids (\textless{}1g/day) in
gestational weeks 0-16 (adjusted RR 1.8 {[}95\% CI 1.1-2.9{]}) compared
to women who did not use calcium-based antacids in gestational weeks
0-16. An excess risk was not observed among women who used calcium-based
antacids in gestational weeks 17-33.

We did not observe clear associations between PPI use in gestational
weeks 0-33 and the risk of late-onset preeclampsia either. However,
late-onset preeclampsia seemed to occur more often among women who used
PPIs in gestational weeks 17-33 (4.8\%) than among women who did not use
PPIs in these gestational weeks (2.5\%; adjusted RR 1.6 {[}95\% CI
1.0-2.8{]}).

\textbf{Exposure in late pregnancy and late-onset preeclampsia}

Table 3 shows the results for the use of calcium-based antacids and PPIs
after gestational week 33. No associations were observed between any
calcium-based antacid use (adjusted HR 1.0 {[}95\% CI 0.6-1.5{]}) or PPI
use (adjusted HR 1.4 {[}95\% CI 0.7-2.9{]}) and late-onset preeclampsia.
Using a high dose of PPIs after gestational week 33 seemed to increase
the risk of late-onset preeclampsia (crude HR 2.7 {[}95\% CI
0.9-8.5{]}), but this observation was based on a small number of exposed
pregnancies (N=55).

\textbf{Sensitivity analyses}

The prevalence of gestational hypertension was 7.7\% with a median
gestational age at diagnosis of 37\textsuperscript{+0} weeks
(interquartile range 34\textsuperscript{+2} to
38\textsuperscript{+6}weeks). A high dose of calcium-based antacids ([?]1
g/day) in gestational weeks 0-19 was associated with an increased risk
of gestational hypertension (adjusted RR 1.6 {[}95\% CI 1.2-2.1{]},
Table S4). Use of calcium-based antacids after gestational week 19 and
use of PPIs in early and late pregnancy was not associated with the risk
of gestational hypertension (Tables S4 and S5).

Within the PRIDE Study, 38.4\% of women (N = 2,078) was at high risk of
developing preeclampsia. Among these women, excess risks for exposure in
early and mid-pregnancy were more evident compared to the total
population with an adjusted RR of 2.3 (95\% CI 1.2-4.4) for low-dose
calcium-based antacids in gestational weeks 0-16 and 2.2 (95\% CI
1.2-4.3) for any PPI use in gestational weeks 0-33 (Table S6). The
latter was attributable to PPI use in gestational weeks 17-33, as no
increased risk was observed for PPI use in gestational weeks 0-16
(adjusted RR 1.4 {[}95\% CI 0.5-4.3{]}). We did not observe associations
between late-onset preeclampsia and any calcium-based antacid use
(adjusted HR 0.7 {[}95\% CI 0.3-1.3{]}) or PPI use (adjusted HR 2.1
{[}95\% CI 0.8-5.2{]}) after gestational week 33 among women at high
risk of developing preeclampsia (Table S7). Restricting the analyses to
women who did not use calcium-containing supplements during pregnancy
(N=1,482) did not materially change the results, although these analyses
were hampered by small numbers (Tables S8 and S9).

\textbf{DISCUSSION}

\textbf{Main findings}

In this prospective cohort study, we did not observe decreased risks of
late-onset preeclampsia after use of calcium-based antacids or PPIs
during pregnancy, irrespective of the timing of use. In contrast, low
dose calcium-based antacid use in gestational weeks 0-16 and any PPI use
in gestational weeks 17-33 were associated with a modestly increased
risk of late-onset preeclampsia.

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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,\textsuperscript{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.,\textsuperscript{11} who observed a reduced risk of preterm
preeclampsia (delivery \textless{}37 weeks of gestation; adjusted odds
ratio 0.63 {[}95\% CI 0.41-0.96{]}) and early preeclampsia (delivery
\textless{}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\textsuperscript{+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,\textsuperscript{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.\textsuperscript{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,\textsuperscript{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.\textsuperscript{11-13} However, these results
may be biased by confounding by indication, as illustrated by the
attenuated RR in comparisons with an H\textsubscript{2}RA-exposed group
in a nationwide cohort study in South
Korea.\textsuperscript{13}Furthermore, reverse causation cannot be
excluded, since epigastric pain is one of the symptoms consistent with
preeclampsia.\textsuperscript{47}

\textbf{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.\textsuperscript{22}Studies 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),\textsuperscript{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.\textsuperscript{49-51}Differential 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.\textsuperscript{52}Although 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.\textsuperscript{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).

\textbf{CONCLUSION}

This study adds to the growing body of evidence that PPIs do not prevent
preeclampsia, despite their ability to reduce the secretion of sFlt-1.
Furthermore, calcium-based antacids did not reduce the risk of
preeclampsia in this population of pregnant women, even in high doses.
Based on these results, choice of treatment of symptoms of
gastroesophageal reflux does not need to be influenced by potential
beneficial side effects with regard to the risk of preeclampsia.
Nevertheless, benefit-risk assessment should also include other relevant
outcomes for maternal and child health, which slightly favour the choice
of calcium-based antacids.\textsuperscript{53} Future research may focus
on identifying specific groups of women for whom calcium-based antacids
or PPIs might reduce the risk of preeclampsia, in particular early-onset
preeclampsia.

\textbf{ACKNOWLEDGEMENTS}

We would like to thank all participants as well as prenatal care
providers and pharmacists involved in the PRIDE Study and The Dutch
Pregnancy Drug Register for their continuing efforts in data collection.
We also wish to thank Prof Eug\selectlanguage{ngerman}ène van Puijenbroek for his comments on an
earlier version of this manuscript.

\textbf{DISCLOSURE OF INTEREST}

The authors have no relevant financial or non-financial interests to
disclose.

\textbf{CONTRIBUTION TO AUTHORSHIP}

\textbf{Marleen van Gelder:} Conceptualization (lead); data curation
(equal); formal analysis (lead); funding acquisition (lead);
investigation (equal); methodology (lead); supervision (lead); writing
-- original draft (lead); writing -- review and editing
(equal).\textbf{Pim Beekers:} Conceptualization (supporting); formal
analysis (supporting); investigation (equal); writing -- review and
editing (equal). \textbf{Yrea van Rijt-Weetink:} Data curation (equal);
investigation (equal); writing -- review and editing
(equal).\textbf{Joris van Drongelen:} Conceptualization (supporting);
writing -- review and editing (equal). \textbf{Nel Roeleveld:}
Conceptualization (supporting); funding acquisition (supporting);
methodology (supporting); writing -- review and edition (equal).
\textbf{Luc Smits:}Conceptualization (equal); funding acquisition
(supporting); methodology (supporting); supervision (supporting);
writing -- review and editing (equal).

\textbf{DETAILS OF ETHICAL APPROVAL}

This study was performed in line with the principles of the Declaration
of Helsinki. Approval for the PRIDE Study was granted by the Regional
Committee on Research Involving Human Subjects Arnhem-Nijmegen (CMO
2009/305). The Regional Committee on Research Involving Human Subjects
Arnhem-Nijmegen has confirmed that no ethical approval is required for
The Dutch Pregnancy Drug Register.

\textbf{FUNDING}

This work was supported by the Netherlands Organisation for Health
Research and Development {[}ZonMw; grant number 848018010{]}. The
awarded grant included external peer review for scientific quality,
including priority assessment by a patent involvement panel. The funder
had no role in conducting the research, writing the paper, or the
decision to submit the paper for publication.

\textbf{REFERENCES}

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\textbf{Table 1. Cohort characteristics by use of calcium-based antacids
and proton pump inhibitors in gestational weeks 0-33. Data from the
PRIDE Study (2012-2019) and The Dutch Pregnancy Drug Register
(2014-2019).}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Characteristic} & \textbf{Calcium-based antacid
use\textsuperscript{a}} & \textbf{Calcium-based antacid
use\textsuperscript{a}} & \textbf{Calcium-based antacid
use\textsuperscript{a}} & \textbf{Calcium-based antacid
use\textsuperscript{a}} & \textbf{Proton pump inhibitor
use\textsuperscript{a}} & \textbf{Proton pump inhibitor
use\textsuperscript{a}} & \textbf{Proton pump inhibitor
use\textsuperscript{a}} & \textbf{Proton pump inhibitor
use\textsuperscript{a}}\tabularnewline
\midrule
\endhead
& \textbf{No (N=6,964)} & \textbf{No (N=6,964)} & \textbf{Yes (N=1,863)}
& \textbf{Yes (N=1,863)} & \textbf{No (N=8,502)} & \textbf{No (N=8,502)}
& \textbf{Yes (N=332)} & \textbf{Yes (N=332)}\tabularnewline
Maternal age, mean (SD) & 31.4 & (3.7) & 31.4 & (3.7) & 31.4 & (3.7) &
31.6 & (3.8)\tabularnewline
Maternal country of birth, n (\%) & & & & & & & &\tabularnewline
The Netherlands & 6,629 & (95.2) & 1,781 & (95.6) & 8,096 & (95.2) & 319
& (96.1)\tabularnewline
Other & 264 & (3.8) & 66 & (3.5) & 321 & (3.8) & 11 &
(3.3)\tabularnewline
Level of education, n (\%) & & & & & & & &\tabularnewline
Low/intermediate & 1,629 & (23.4) & 383 & (20.6) & 1,920 & (22.6) & 90 &
(27.1)\tabularnewline
High & 5,278 & (75.8) & 1,465 & (78.6) & 6,510 & (76.6) & 241 &
(72.6)\tabularnewline
Chronic conditions, n (\%) & & & & & & & &\tabularnewline
Asthma & 398 & (5.7) & 149 & (8.0) & 509 & (6.0) & 34 &
(10.2)\tabularnewline
Chronic hypertension & 19 & (0.3) & 9 & (0.5) & 26 & (0.3) & 2 &
(0.6)\tabularnewline
Depression & 113 & (1.6) & 24 & (1.3) & 125 & (1.5) & 12 &
(3.6)\tabularnewline
Pre-existing diabetes & 16 & (0.2) & 6 & (0.3) & 21 & (0.2) & 1 &
(0.3)\tabularnewline
Pre-pregnancy BMI, mean (SD) & 23.6 & (4.0) & 24.2 & (4.5) & 23.6 &
(4.1) & 25.6 & (5.4)\tabularnewline
Parity, n (\%) & & & & & & & &\tabularnewline
0 previous deliveries & 3,764 & (54.0) & 1,059 & (56.8) & 4,658 & (54.8)
& 176 & (53.0)\tabularnewline
[?]1 previous delivery & 3,179 & (45.6) & 797 & (42.8) & 3,818 & (44.9) &
154 & (46.4)\tabularnewline
History of preeclampsia, n (\%) & & & & & & & &\tabularnewline
Yes & 131 & (1.9) & 36 & (1.9) & 160 & (1.9) & 8 & (2.4)\tabularnewline
No & 6,746 & (96.9) & 1,813 & (97.3) & 8,243 & (97.0) & 323 &
(97.3)\tabularnewline
Smoking during pregnancy, n (\%) & & & & & & & &\tabularnewline
Yes & 330 & (4.7) & 114 & (6.1) & 415 & (4.9) & 28 &
(8.4)\tabularnewline
No & 6,470 & (92.9) & 1,709 & (91.7) & 7,898 & (92.9) & 299 &
(90.1)\tabularnewline
Alcohol during pregnancy, n (\%) & & & & & & & &\tabularnewline
Yes & 1,095 & (15.7) & 292 & (15.7) & 1,351 & (15.9) & 37 &
(11.1)\tabularnewline
No & 5,722 & (82.2) & 1,536 & (82.4) & 6,981 & (82.1) & 291 &
(87.7)\tabularnewline
Calcium-containing supplements, n (\%) & & & & & & & &\tabularnewline
Yes & 4,073 & (58.5) & 1,143 & (61.4) & 5,025 & (59.1) & 194 &
(58.4)\tabularnewline
No & 1,211 & (17.4) & 266 & (14.3) & 1,433 & (16.9) & 48 &
(14.5)\tabularnewline
\bottomrule
\end{longtable}

BMI, Body Mass Index; PPI, proton pump inhibitor; SD, standard
deviation.

\textsuperscript{\textbf{a}} Numbers may not add up to totals due to
missing values, ranging from 0.3\% to 0.9\% (level of education, chronic
hypertension, pre-existing diabetes, pre-pregnancy BMI, and parity),
1.0\% to 1.4\% (country of birth, asthma, depression, and history of
preeclampsia), and 2.1\% to 2.3\% (smoking and alcohol during
pregnancy). For calcium-containing supplement use, the percentage of
missing values was 24.2\%, because details on multivitamin use were
unavailable in The Dutch Pregnancy Drug Register.



\textbf{Table 2. Associations between calcium-based antacid and proton
pump inhibitor use in gestational weeks 0-33 and late-onset
preeclampsia. Data from the PRIDE Study (2012-2019) and The Dutch
Pregnancy Drug Register (2014-2019).}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Exposure group} & \textbf{Total} & \textbf{N (\%) with PE} &
\textbf{N (\%) with PE} & \textbf{Crude RR (95\% CI)} & \textbf{Adjusted
RR (95\% CI)\textsuperscript{a}}\tabularnewline
\midrule
\endhead
Calcium-based antacids in GW 0-33 & & & & &\tabularnewline
No use & 6,964 & 171 & (2.5) & Reference & Reference\tabularnewline
Any use & 1,863 & 60 & (3.2) & 1.3 (1.0-1.7) & 1.2
(0.9-1.6)\tabularnewline
Low dose (\textless{}1 g/day) & 959 & 31 & (3.2) & 1.3 (0.9-1.9) & 1.3
(0.9-1.8)\tabularnewline
High dose ([?]1 g/day) & 893 & 29 & (3.3) & 1.3 (0.9-1.9) & 1.2
(0.8-1.8)\tabularnewline
Low use trajectory & 992 & 30 & (3.0) & 1.2 (0.8-1.8) & 1.2
(0.8-1.7)\tabularnewline
High use trajectory & 123 & 3 & (2.4) & 1.0 (0.3-3.1) &
N/A\tabularnewline
Calcium-based antacids in GW 0-16 & & & & &\tabularnewline
No use & 8,276 & 206 & (2.5) & Reference & Reference\tabularnewline
Any use & 728 & 26 & (3.6) & 1.4 (1.0-2.1) & 1.3
(0.9-1.9)\tabularnewline
Low dose (\textless{}1 g/day) & 314 & 16 & (5.1) & 2.0 (1.2-3.4) & 1.8
(1.1-2.9)\tabularnewline
High dose ([?]1 g/day) & 235 & 7 & (3.0) & 1.2 (0.6-2.5) & 1.1
(0.5-2.4)\tabularnewline
Calcium-based antacids in GW 17-33 & & & & &\tabularnewline
No use & 7,201 & 185 & (2.6) & Reference & Reference\tabularnewline
Any use & 1,604 & 45 & (2.8) & 1.1 (0.8-1.5) & 1.0
(0.7-1.4)\tabularnewline
Low dose (\textless{}1 g/day) & 847 & 20 & (2.4) & 0.9 (0.6-1.4) & 0.9
(0.6-1.4)\tabularnewline
High dose ([?]1 g/day) & 690 & 22 & (3.2) & 1.2 (0.8-1.9) & 1.2
(0.8-1.8)\tabularnewline
Proton pump inhibitors in GW 0-33 & & & & &\tabularnewline
No use & 8,502 & 217 & (2.6) & Reference & Reference\tabularnewline
Any use & 332 & 14 & (4.2) & 1.7 (1.0-2.8) & 1.4
(0.8-2.4)\tabularnewline
Low dose ([?]1 DDD/day) & 242 & 11 & (4.6) & 1.8 (1.0-3.2) & 1.5
(0.8-2.8)\tabularnewline
High dose (\textgreater{}1 DDD per day) & 85 & 3 & (3.5) & 1.4 (0.5-4.2)
& N/A\tabularnewline
Proton pump inhibitors in GW 0-16 & & & & &\tabularnewline
No use & 8,868 & 229 & (2.6) & Reference & Reference\tabularnewline
Any use & 170 & 6 & (3.5) & 1.4 (0.6-3.0) & 1.1 (0.5-2.6)\tabularnewline
Low dose ([?]1 DDD/day) & 91 & 4 & (4.4) & 1.7 (0.6-4.5) &
N/A\tabularnewline
High dose (\textgreater{}1 DDD/day) & 53 & 0 & (0.0) & N/A &
N/A\tabularnewline
Proton pump inhibitors in GW 17-33 & & & & &\tabularnewline
No use & 8,544 & 217 & (2.5) & Reference & Reference\tabularnewline
Any use & 289 & 14 & (4.8) & 1.9 (1.1-3.2) & 1.6
(1.0-2.8)\tabularnewline
Low dose ([?]1 DDD/day) & 210 & 9 & (4.3) & 1.7 (0.9-3.2) & 1.5
(0.8-3.0)\tabularnewline
High dose (\textgreater{}1 DDD/day) & 57 & 3 & (5.3) & 2.1 (0.7-6.3) &
N/A\tabularnewline
\bottomrule
\end{longtable}

CI, confidence interval; DDD, Defined Daily Dose; GW, gestational weeks;
PE, preeclampsia; RR, risk ratio

\textsuperscript{\textbf{a}} Inverse probability of censoring weights;
all models were adjusted for maternal age, asthma, pre-pregnancy BMI,
parity, smoking during pregnancy, alcohol use during pregnancy, and use
of calcium-containing supplements. Models for proton pump inhibitors
were additionally adjusted for depression.



\textbf{Table 3. Associations between calcium-based antacid and proton
pump inhibitor use after gestational week 33 and late-onset
preeclampsia. Data from the PRIDE Study (2012-2019) and The Dutch
Pregnancy Drug Register (2014-2019).}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Time-dependent exposure after GW33}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{N}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{PE}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Person weeks}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Rate (per 1000/week)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Crude HR} \textbf{(95\% CI)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Adjusted HR} \textbf{(95\% CI)\textsuperscript{a}}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Calcium-based antacids\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
No use\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7,897\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
187\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
41,539\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Reference\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Any use\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1,170\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5,078\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.9 (0.6-1.4)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.0 (0.6-1.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Low dose (\textless{}1 g/day)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
589\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2,252\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3.6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.8 (0.4-1.6)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.8 (0.4-1.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
High dose ([?]1 g/day)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
630\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2,826\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.0 (0.6-1.8)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.1 (0.6-1.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Proton pump inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
No use\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9,008\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
216\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
48,594\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Reference\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Reference\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Any use\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
267\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1,168\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6.8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.6 (0.8-3.2)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.4 (0.7-2.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Low dose ([?]1 DDD/day)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
217\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
918\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5.4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.3 (0.5-3.0)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.2 (0.5-2.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
High dose (\textgreater{}1 DDD/day)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
55\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
250\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12.0\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2.7 (0.9-8.5)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

CI, confidence interval; DDD, Defined Daily Dose; GW, gestational week;
HR, hazard ratio; PE, preeclampsia.

\textsuperscript{\textbf{a}} Inverse probability of censoring weights;
all models were adjusted for maternal age, asthma, pre-pregnancy BMI,
parity, smoking during pregnancy, alcohol use during pregnancy, and use
of calcium-containing supplements. Models for proton pump inhibitors
were additionally adjusted for depression.



\textbf{FIGURE CAPTIONS}

\textbf{Figure 1} Mean trajectories (solid lines) with 95\% confidence
intervals (hashed lines) for 33-weeks calcium-based antacid use among
1,115 pregnancies with exposure between LMP and gestational week 33
(Panel A). The average daily calcium intake from antacids and standard
deviation (SD) for each trajectory group are shown in panel B.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/PE-figure-1/PE-figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

