Medication use during pregnancy is common [1] and has been increasing over time [2, 3]. Despite this, just 5% of medications have been adequately monitored, tested, and labelled with safety information for use in pregnant and breastfeeding women [4] as pregnant women are usually excluded from premarketing clinical trials of new medications [5]. Instead, information on medication safety in pregnancy is mainly based on post-marketing surveillance using pregnancy registries or electronic healthcare databases [6–8].

When evaluating medication utilisation or the safety of medications taken during pregnancy, the reliability of medication exposure data in electronic healthcare databases is an important consideration. There is no ‘gold standard’ to assess maternal medication exposure, and each source of information is prone to bias. Prescription databases do not include over-the-counter (OTC) medicines, medicines bought online, or medicines given to hospital inpatients, outpatients, or in Accident & Emergency departments. They may also over-estimate medication exposure if patients do not redeem issued prescriptions [9, 10] and if dispensed prescriptions are not taken or are taken much later [11]. Self-reported data may be susceptible to recall [12] or social desirability bias, [13] and accuracy of recall may be influenced by factors such as questionnaire design, potential stigma, time between use and interview, age, education level, route of administration, and presence and severity of comorbidities [14–18]. The recall of intermittently used medications is lower than those used daily for chronic conditions [15, 16, 19–23].

Two Northern Ireland (NI) electronic healthcare databases may be suitable for medication utilisation or safety research. The Northern Ireland Maternity System (NIMATS) database captures pregnancy and perinatal information for all women giving birth in NI. At the first antenatal visit (typically 10-12 weeks gestation), a midwife records pregnancy and general health-related information, including the medications a woman reports taking, using a standardised reporting template. All women have a booking interview conducted by a midwife whether they go on to be cared for by a midwife or obstetrician during their pregnancy. This is potentially a rich source of medication information, as it should include OTC, hospital-prescribed medications, and general practitioner (GP)-prescribed medications. The NI Enhanced Prescribing Database (EPD) records GP-prescribed medicines dispensed by pharmacists. Neither of these datasets were developed for research purposes, meaning the quality of the data must first be assessed to determine if they are “fit for purpose”. In an earlier study, [24] we examined the prevalence of prescriptions dispensed in the EPD between 2010 and 2016. We found that, excluding supplements, almost half of pregnant women in NI had prescriptions for medications in early pregnancy. There was evidence for variation in medication use with maternal age and area-based deprivation. Younger and older mothers and those living in the most deprived areas were more likely to have medications recorded in the EPD [24].

This study aimed to compare medication use reported by the mother and recorded by midwives at the first antenatal visit in NIMATS to dispensed prescriptions recorded in the EPD in the context of the potential use of these databases for drug utilisation and safety studies.

The detailed methodology of this population-based linked cohort study has been described previously [24]. Women resident in NI who gave birth between 1^st January 2011 and 31^st December 2016 were identified in the NIMATS database. Information extracted from NIMATS included medication recorded at the first antenatal visit (known as the booking interview), gestational age at delivery, and the delivery date. These NIMATS maternity data were linked to the EPD prescription dispensation data using the mother’s Health and Care Number (HCN) or hospital number if the HCN was unavailable, and to the NI Multiple Deprivation Measure (MDM) 2017, based on the mother’s postcode at the booking interview. The linked NIMATS-EPD data included prescriptions issued from 1^st April 2010 to 30^th June 2016 to cover the early pregnancy period for mothers who gave birth between January 2011 and December 2016. During the study period, 13.8% of prescriptions to the NI population, not just to pregnant women, could not be matched to a unique HCN by the data provider. Prescribed medications were free of charge in NI from the start of the study period [25].

Between 2010 and 2016, there were 139,687 pregnancies booked by 106,206 women; see Table 1 for sample characteristics. The mean gestational age at booking was 10.7 weeks (range < 5-20 weeks), with 86.0% of pregnancies booked by 12 weeks. The mean maternal age was 29.3 years, and the mean gestational age at delivery was 39.0 weeks. Most women (71.9%) had one pregnancy during the period, with a quarter (24.9%) having two and the rest (3.4%) 3+ pregnancies recorded during the period.

In NIMATS, 74.3% of pregnancies had a medication reported at the booking appointment compared to 63.5% with a prescription dispensed in the EPD, see Table 2 (and eTable 3 for numbers). Combining both data sources, 86.9% of women reported taking medication or had a prescription dispensed. Vitamins, iron or folic acid were the only medications reported in NIMATS in 56.1% of pregnancies compared to 14.8% of pregnancies in the EPD. Excluding vitamins, iron, and folic acid, 18.2% of pregnancies had a medication reported in NIMATS compared to 48.7% with a prescription in the EPD. These represented slight to fair agreement based on Cohen’s kappa but the PPV was 81.3%, see Table 3.

In this large population-based linked cohort study we compared medication data reported by the mother and recorded by midwives to dispensed prescription data for all resident mothers in NI. We found that NIMATS commonly records the use of vitamins, iron, and folic acid during early pregnancy. However, less than a fifth of women reported taking non-supplement medications in NIMATS. This compares to just under half of women with prescriptions for non-supplement medication in the EPD. Both the proportion of pregnancies with maternal self-report and dispensed prescriptions in early pregnancy are in keeping with that seen in early pregnancy in other countries [2, 15, 26, 30–33]. However, it is evident that a greater range of medications are recorded in the EPD than NIMATS and that relying on NIMATS would underestimate the proportion of women exposed to non-supplement medications, assuming that the women took the dispensed medications.

The context of prescribing is essential when interpreting data. In NI, prescribed medications are free, and women may prefer to obtain medications that are available OTC by prescription, but this entails a GP visit. GPs may encourage pregnant women to take supplements by prescribing them. GPs may also prescribe medications for early pregnancy symptoms before women have their booking appointments. Our results show that more women buy vitamins and antacids than request prescriptions, suggesting that prescription records should not be relied upon solely to identify their use. A combination of maternal report and prescribing records would also be recommended to identify the use of folic acid. Agreement between maternal report and prescribing records for low-dose folic acid was no better than chance, with >80% of those with a prescription not reporting their low-dose folic acid use in NIMATS. A similar proportion of those reporting low-dose folic acid had no prescription recorded, suggesting they bought it OTC or inaccurate reporting as a result of social desirability bias. While about a quarter of women would be identified as having used low-dose folic acid based on NIMATS (22.5%) or EPD (27.0%) alone, combining them, 45.1% of women had either reported or prescribed or both reported and prescribed low-dose folic acid. If the dose of folic acid taken is important to a research study, prescribing records are vital to identify high-dose folic (5 mg) acid use as this dose can only be obtained by prescription. There were more than three times as many pregnancies with prescribed high-dose folic acid as with reported high-dose folic acid. These findings have important implications beyond the NI context, as maternal folic acid use is a crucial covariate [34] in medication safety research in pregnancy, particularly in relation to the risk of congenital anomalies.

For all medications, except vitamins and antacids, prescribing records suggested more use than maternal reports. Self-report of prescribed medication was particularly low for laxatives, antivirals, antibiotics, antidepressants, steroids, and cardiac medications, with more than ten times as many prescriptions dispensed as reported in NIMATS. Some apparent underreporting in NIMATS for medications such as laxatives likely reflects their intermittent use, as women may not require them following their prescription. However, the underreporting of antiepileptic and cardiac medications, thyroxine, and insulin in NIMATS is surprising, given that agreement between reported and prescribed use of chronic medications is typically good [15, 16, 19–23]. There appears to be substantial underreporting of chronic medication use during pregnancy in antenatal records at booking in NI. While antenatal records may be updated in subsequent appointments, their incompleteness at booking needs investigation as it may impact care.

Some of the discordance between maternity data and prescription records may also reflect non-compliance. In medication utilisation or safety studies, non-compliance is typically less of an issue for dispensed prescriptions, as in the EPD, than for issued prescriptions [10]. However, pregnant women are a unique population, and women may discontinue their medications when they find out they are pregnant due to perceived risk [35]. In terms of the use of data for medication safety studies, very early pregnancy use before discontinuation is still relevant to risk.

Discontinuation of antidepressants may be contributing to the lower-than-expected [19, 21, 22] agreement between self-report and prescription records. It is estimated that 70%-80% of women discontinue their antidepressants during their pregnancy, [36–38] with antidepressant use typically returning to pre-pregnancy levels, or higher, after delivery [36, 39]. The decision to use antidepressants during pregnancy is complex. The risk of continuing antidepressants for the child must be weighed against the risks for both mother and child of untreated depression. Unfortunately, it is impossible to tell from the data whether medications were discontinued, and if so, if this decision was made in discussion with healthcare providers. There may also be an element of non-disclosure of mental illness due to perceived stigma, [40] which is of concern as it could lead to a lack of or delayed support.

Discontinuation in early pregnancy may also be contributing to the lack of agreement for hormonal medications such as contraceptives. About a quarter of women of reproductive age in NI use the combined oral contraceptive pill or the progesterone-only pill [41]. In trials, it has been estimated that there will be 2.59 pregnancies per 100 women-years [42] using these methods, but there may be as much as a 4-7% failure rate in the first 12 months of typical use [43, 44]. For some planned pregnancies, conception may have occurred immediately after cessation of contraceptives. Contraceptives may also be prescribed to treat polycystic ovary syndrome, and hormones may have been prescribed as part of fertility treatment. These would be discontinued as soon as the woman realised she was pregnant, and so would not be reported to midwives, but would still appear in the EPD record.

In contrast, prescriptions for chronic conditions such as asthma, which may be dispensed with a 90-day supply in the UK, may not be recorded in the EPD if a woman conceived after she redeemed her last prescription, particularly if she had her first antenatal visit before 12 weeks. The additional information in NIMATS is, therefore, useful in such situations. Increasing the time window used here, to include 30 or 90 days before the LMP may increase the agreement for chronically used medications with long dispensing windows and some intermittently used medications such as laxatives. It would however, decrease the agreement for intermittently used medications such as antibiotics. It is therefore important that in medication utilisation or safety studies in pregnancy, the time window used to identify medication use is tailored to the medication of interest.

As with most prescribing databases, the EPD does not record medications dispensed by hospital pharmacies. Inpatient stays would be expected to be rare before booking, and administration of medication while in hospital has been shown to detrimentally impact the ability of mothers to know and recall medication use [22]. However, women may attend early pregnancy clinics, emergency departments or dentists and be discharged home with medications. These would then be reported to midwives, and recorded in NIMATS, but not recorded in the EPD. This may explain some of the reported pregnancy-related or intermittently used medications not present in the EPD, such as antibiotics or antiemetics. In Canada and Europe, antibiotics are the most prescribed medication in pregnancy, with first-trimester prescriptions ranging from 9.7%-12.0% [2, 18, 23] in keeping with what is seen in NI. Indeed, in Australia, Havard et al. (2021) found that antibiotics are used disproportionately more among pregnant women relative to women of childbearing age [45]. As antibiotics are intermittently and briefly used, agreement between reported and prescribed antibiotic use is typically poor to moderate [15, 16, 18, 19, 21, 22, 46] as seen here.

The potential to combine NIMATS and EPD data to examine the use of medications in pregnancy is limited by the categories available in NIMATS to record medication use. To be useful for medication utilisation or safety studies, maternity data should collect information on medicines at the individual drug level and record whether women continued or discontinued their medication upon finding out they were pregnant. The potential for under-reporting of medication use also needs to be considered. There is an option for midwives to record textual information relating to medications, such as medication name or dose. These variables have not been made available for research in NI due to concerns that individuals could be identified from textual data. If they could be made available, approaches such as text-mining could be used to extract additional information from maternal reports of medication use [47], vastly increasing the potential utility of NIMATS for medication utilisation or safety studies.

Medication use during early pregnancy was common in NI, with 86.9% of women reporting medication use or having a prescription dispensed. Maternal reports indicated that women buy, rather than request, prescriptions for vitamins and antacids. For non-supplement medications, there were more dispensed prescriptions than maternal reports. While some women may be non-compliant or discontinue their medications during pregnancy, the reporting of prescribed medications to midwives for chronic illnesses was very incomplete, even for medications for chronic illnesses that may impact care. A combination of maternal report and prescribing data is recommended to identify all medication use in drug safety studies, particularly for folic acid.