DISCUSSION
In this prospective study with medication diaries as the reference
standard, we observed that majority of medications dispensed were
reported to be used, ranging from 69% (medication for occasional and
short-term use) to 88% (medication for chronic conditions). A
substantial proportion of women, however, did not take the medication as
prescribed: the overall implementation adherence was 74.2%. Achieving
an implementation adherence of ≥80% ranged between 19% for medication
for occasional and short-term use and 70% for medication for chronic
conditions. Implementation adherence of pregnancy-related medication
seemed lower for women aged >30 years, women with an income
≥\euro3,500, and non-smoking women, whereas women who smoked during
pregnancy seemed to have a lower implementation for medication for
occasional and short-term use.
Self-report based on interviews or questionnaires is generally
acknowledged to result in underreporting of medication use during
pregnancy [17-22]. This may explain why the proportion of
medications dispensed that is actually reported to be taken is higher in
the current study compared with previous studies, in which this measure
ranged between 43 and 57% [14, 19]. However, consistent patterns of
actual use are observed between studies when focusing on individual
medications or groups of medications, with high levels of actual use for
medication for chronic conditions, and substantially lower for
medication for occasional and short-term use [14, 15, 19-21, 31-34].
Part of these lower levels of actual use for medication for occasional
and short-term use may be explained by forgetfulness when using
interviews or questionnaires that cover a prolonged period of pregnancy
[22], but remained when using diaries as reference standard
[21]. This disagreement may be worrisome for some maternal
conditions, including infections (antibiotics) and fever (antipyretics),
in which pharmacological treatment is often recommended to prevent
maternal and infant morbidity and mortality [35-38]. In an Italian
cross-sectional study, 3.2% of women reported intentionally avoiding a
prescribed antibiotic in pregnancy [39].
Although actual use gives an indication of medication adherence among
pregnant women, it does not assess whether medication is actually used
as prescribed in terms of timing and dosage. As human fetal development
is strictly sequenced with specific organ systems being formed at
particular stages of pregnancy, timing of exposure is of utmost
importance when assessing medication safety in pregnancy. In the current
study, 42% of medications were not initiated on the date of
prescription fill, but 1-7 days afterwards. These relatively small
differences may result in exposure misclassification for the
etiologically relevant time window when relying on prescription
databases.
In our study, suboptimal implementation adherence could result from two
distinct deviations of prescription instructions: an incorrect dosage
and a shorter duration of use (persistence). Comparable to our study, de
Jonge et al. [16] observed that a substantial proportion of women
(30%) did not adhere to treatment recommendations, often using a lower
dose or for a shorter duration than prescribed. Inadequate treatment of
infections and pregnancy-related and chronic conditions, such as
hypothyroidism [40], asthma [41], and diabetes [42], is
associated with increased risk of adverse birth outcomes. Therefore,
adequate and continuous dosage should be aimed for during pregnancy.
To date, there is no strong evidence for certain maternal and pregnancy
characteristics to be associated with not following treatment
recommendations. In addition to the associations with maternal age,
household income, and smoking observed in this study, others identified
associations with educational level, marital status, disease severity,
and alcohol consumption [19-21, 31, 39, 43]. None of these findings
have consistently been reported; only smoking status has been implicated
in multiple studies [19, 20]. Identification of characteristics
linked to non-adherence may facilitate the implementation of
personalized preventive measures.
The clinical implications of non-adherence are relatively
straightforward: it may endanger maternal and child health and increase
healthcare costs [2, 3]. Enhancing adherence among pregnant women,
however, is not straightforward. Improved counseling may attenuate some
of the incorrect risk perceptions of medication safety among pregnant
women, but for many medications, robust data on fetal safety are lacking
[44-48]. This may hamper evidence-based decisions on whether the
potential risks of pharmacological treatment outweigh the burden of the
underlying maternal condition. Non-adherence also affects research on
medication safety in pregnancy, as many studies rely on administrative
databases for exposure assessment [23]. Not taking medication as
prescribed, or not taking the medication at all, will lead to exposure
misclassification and may bias studies determining associations with
infant outcomes [49].
A major strength of the current study is the use of a diary to assess
actual medication use, thereby reducing the probability of
underreporting due to forgetfulness [24, 25]. The amount of details
collected with these diaries enabled us to look beyond actual use by
assessing initiation and implementation. Furthermore, the study
population was considered large compared to some earlier studies, but
still limited in the ability to assess adherence to individual
medications and associations between maternal characteristics and
implementation. Another limitation includes the relatively short time
frame of only 6 weeks in mid-pregnancy. Adherence is expected to be
lower in the first trimester of pregnancy because of fear for
teratogenicity, but it was considered not feasible to administer diaries
immediately after inclusion in the PRIDE Study until delivery due to
participant burden. Mobile applications to daily record medication
intake may improve the feasibility of intensive long-term data
collection [50]. Social desirability might have increased reporting
of medication use when not actually taken, but was considered unlikely
as participants were unaware of the aim of this study. Also, we were
unable to distinguish between intentional and unintentional avoidance of
medication use. Some women may have discontinued treatment or
implemented dose changes following consultation with a healthcare
professional before the registered end date of the prescription, which
may have decreased implementation adherence unjustly.
In conclusion, actual use of medication dispensed during pregnancy was
high in this study compared with previous studies, but many women did
not adhere to treatment recommendations regarding dosage and therapy
duration. As this behavior may be detrimental to maternal and fetal
health, future efforts should focus on identifying reasons for
non-adherence and associated preventive measures. Furthermore, the
results of this studies may inform and facilitate quantitative bias
analyses in studies on medication safety in pregnancy relying on
administrative databases or registries.