Main findings
This study used primary care electronic health records to describe polypharmacy prevalence and common medications prescribed during pregnancy in the UK. During the first trimester, where exposure to teratogens is of highest concern, one in four pregnancies of all women (24.6%) and one in two pregnancies of women with multimorbidity (49.8%) were prescribed two or more medications. During the entire pregnancy period, the prevalence of two or more medications being prescribed was even higher (58.7% and 80.3% respectively). Over the last two decades between 2000 and 2019, a significant increasing trend in the prevalence of polypharmacy was observed both among all pregnancies and pregnancies of women with multimorbidity.
Commonly prescribed medications during pregnancy were medications typically used to manage (1) pregnancy-related symptoms or illnesses such as oral iron, analgesia, laxatives, antiemetics and antacids; (2) bacterial or fungal infections such as broad-spectrum penicillin and preparation for vaginal and vulva candidiasis; (3) common mental health conditions such as SSRI; and (4) asthma and atopic conditions such as selective beta 2 agonists and topical corticosteroids.
The 10 most common pairs of medications prescribed to manage two different long-term health conditions for pregnant women with multimorbidity in the first trimester all included pairings with either SSRI or selective beta 2 agonist.
Pregnant women of younger or older age groups (<25 and >35 years) with higher pre-gravid BMI, higher levels of socio-economic deprivation, smoking or history of smoking and increasing levels of multimorbidity were associated with higher odds of prescription of 2 and 5 or more medications
Comparison with existing literature
The prevalence of polypharmacy during pregnancy observed in this study (defined as 2 or more medications prescribed) (58.7%) was comparable to the findings from a study in the Netherlands (62.4%) [32]. However, this was higher than the estimates reported in population-based studies from Denmark (42.7%) [33], Ireland (29.4%) [12], China (9.2%) [9] and the Netherlands (4.9%) [34]. Similarly, the prevalence of polypharmacy for other numerical definitions estimated in this study is higher than the estimates reported by a Danish study (41.0% versus 2.7%, for the definition 3+ medication) [11], a North American study (27.8% versus 4.9%, for the definition 4+ medication) [3] and a Finnish study (2.2% versus 0.2%, for the definition 10+ medication) [14].
Several reasons could be attributable to the higher prevalence of polypharmacy during pregnancy reported in this study. A variety of methods have been used in the literature to capture prescription data including pharmacy records [9, 33, 34], national registries [11, 14, 15] and self-reported medication use [6, 12, 35,36,37]. In this study, we captured medications that were prescribed based on primary care records, which may or may not have been dispensed or taken, whereas in the other studies whereby pharmacy records or surveys were used, medication consumption would have been captured more accurately. Some of the studies collected data from an earlier time period than this study [11, 14], which corresponds with the lower prevalence of polypharmacy observed in the earlier period of our study, with an increasing trend thereafter. In our study, we included vitamins and minerals (apart from folic acid), which are commonly taken during pregnancy, although prescription for these recorded within primary care is likely to reflect therapeutic use (such as therapeutic dose of oral iron for iron deficiency) as opposed to supplements, which are generally purchased over the counter. These prescriptions were excluded from a number of other studies [3, 11, 38]. The wide range of prevalence estimates reported in the literature may also be attributable to the differences in practices and healthcare systems internationally, such as payment for prescriptions out of pocket deterring patients from requesting prescriptions and the types of drugs that are available over the counter.
Common medications and the prevalence of their prescriptions observed during pregnancy in our study are broadly comparable to other previous studies. This includes antibiotics and treatments for asthma, allergy and anaemia [13, 32, 35]. Some differences in our findings from previously published literature [6], such as lower prevalence of products used against nausea and vertigo, may reflect the purchase of these products over the counter as opposed to procurement through prescription, which are best captured through self-reports and surveys than through primary care records as in our study.
Some of the risk factors for polypharmacy during pregnancy observed in our study have previously been described in other studies by Zhang et al. [9] and Cleary et al. [12], including higher maternal age and smoking as risk factors for higher number of medications used and prescription of US Food and Drug Administration (FDA) category D/X medications (with a positive evidence of human foetal risk) during pregnancy. However, neither of the studies suggested younger maternal age as a risk factor.
Strengths and limitations
This study has important strengths, including the large cohort size of 1.5 million eligible pregnancies and 812,354 of them with complete follow-up of their first trimester, from a primary care database that is broadly generalizable to the UK. To our knowledge, this is the first study reporting on polypharmacy prevalence and common prescriptions, both individually and in pairs during pregnancy (1) over the last two decades, (2) within the UK and (3) in a sub-cohort of pregnant women with multimorbidity.
However, our specified definition of polypharmacy (prescription of multiple medications, ranging from 2 to 11 or more medications within a pre-defined pregnancy period, either the first trimester or the entire pregnancy period) had its limitations. It was not possible to determine the appropriateness of the medications prescribed as the indications for medications are not available in our dataset and the size of the cohort would prohibit a case-by-case examination. We are also unable to determine whether medications were prescribed concomitantly. Furthermore, our definition of polypharmacy was based only on primary care prescriptions, we do not know if the medication was actually dispensed and taken [39] and we did not capture over the counter and secondary care medication that could have over- or under-estimated our findings respectively.
Of the pregnancies recorded in the CPRD GOLD pregnancy register, 52.4% were excluded based on standard practice exclusion criteria due to patient or practice ineligibility at the start of pregnancy. Furthermore, 22.1% of pregnancies were excluded due to the incomplete follow-up of their first trimester. To examine for potential selection bias, we conducted a sensitivity analysis to include all eligible pregnancies with or without complete follow-up, in which where we observed similar findings.
Clinical and research implication
Polypharmacy is known to be associated with multimorbidity in the general population [40, 41]. However, much research on polypharmacy has focused on older people [42, 43], with less attention given to pregnant women and women of childbearing age. As observed in our analysis, pregnancy is often associated with the prescription of medications to manage common pregnancy-related symptoms and illnesses such as pain, nausea and dyspepsia. The need for these medications will further add to the medication burden for women with multimorbidity who may already be taking regular medications for their underlying long-term health conditions. This was confirmed in our study findings: the prevalence of polypharmacy was considerably higher among pregnancies of women with multimorbidity compared to all pregnancies in general and the relative difference in their prevalence increased with the number of medications considered in the polypharmacy definition (Fig. 1).
In women with multimorbidity, SSRI was the most prescribed medication during the first trimester (15.2%) and the seventh most common medication prescribed during the entire pregnancy period (17.4%). Also, among the common pairs of medication, SSRI was frequently observed. This reflects the high prevalence of mental health conditions among pregnant women with multimorbidity observed in our previous study [1]. Given the uncertainties of antidepressant treatment safety during pregnancy [44], and the competing risks of untreated mental health conditions [45], this area warrants further research.
Our findings assessing the risk factors for polypharmacy suggested women between the age of 25 and 34 were at the lowest risk of polypharmacy during pregnancy, with risk increasing with both increasing and decreasing maternal age away from the central pregnancy age of 25–34 years. Women who were pregnant during their teenage years had more than twice the odds of being prescribed multiple medications compared to women who were pregnant at the age of 30–34. This may be attributable to women below the age of 20 being entitled to free prescriptions [46]. Furthermore, teenage pregnant women are more likely to receive supplementation for prevention of iron deficiency anaemia and treatments for sexually transmitted infections [47].
There is growing recognition that medications for long-term conditions should be continued during pregnancy if it is safe and if the benefit outweighs the risk. Notably, the assessment of teratogenic risk is primarily focused on the use of individual medications. Less is known about the combined effect of medications taken concomitantly during pregnancy. To empower women and clinicians, we need more research on the effect of combined medications taken during pregnancy to the women and the foetus.
