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Medication Safety in Pregnancy

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WP6 - Monitoring of Safety Recommendations: Drug Utilisation Studies



Work Undertaken (Deliverables)

  • Spreadsheet with national guidelines relating to prescription of anti-asthmatics, antiepileptic drugs (AEDs), insulin analogues and selective serotonin reuptake inhibitors (SSRIs) in European countries (Deliverable 23)
  • Study on use of healthcare databases for drug safety in pregnancy studies (Deliverable 24)
  • Study on effectiveness of pregnancy prevention programmes for teratogenic drugs in Europe (Deliverable 25)
  • Drug utilisation study on use of antidepressants during pregnancy in Europe (Deliverable 26)
  • Drug utilisation study on use of AEDs during pregnancy in Europe (Deliverable 27)
  • Drug utilisation study on use of antidiabetic medicines during pregnancy in Europe (Deliverable 28)
  • Drug utilisation study on use of anti-asthmatics during pregnancy in Europe (Deliverable 29)


WP6 Results and Foreground


The main objective of WP6 was to conduct drug utilisation studies for antidepressants, AEDs, antidiabetics and anti-asthmatics in pregnant women in Europe.  WP6 also collected prescription guidelines of these medicines in European countries and conducted a study on use of healthcare databases for drug safety in pregnancy studies. 

Drug utilisation studies in relation to pregnant women


To our knowledge these were the first studies to include pre- and post-pregnancy prescribing in multiple areas of Europe.  A common protocol was implemented, accessing databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the Clinical Practice Research Datalink representing the rest of the UK.  The UK databases captured all prescriptions issued and the non-UK databases captured prescriptions actually dispensed.  The study captured over 1.2 million pregnancies and demonstrated that regional differences exist in the prevalence of prescribing to women during and surrounding pregnancy for all four medicine classes under study. Regional differences were also observed in national prescribing guidelines and the specific products within each medicine class most commonly prescribed.  In addition, inconsistencies were identified between prescribing practices and what is recommended in the guidelines or known from the scientific literature.



The study found marked differences in the extent of SSRI prescribing to women before, during and after pregnancy (Figure 6.1). 

Figure 6.1  Prevalence of selective serotonin reuptake inhibitor (SSRI) prescribing in women with a delivery between 2004 and 2010, during each of the 3-month time periods of interest 


Final Report Figure 3.8

Considerably higher levels of prescribing were observed in the UK compared with Denmark, the Netherlands and Italy and the higher pre-pregnancy prescribing in the UK resulted in higher first trimester exposures.  SSRI prescribing was at its lowest in all databases during the second and third trimesters of pregnancy.  After pregnancy, SSRI prescribing increased more rapidly in the UK databases than other regions and unlike the other regions, the post-pregnancy prevalence of use in the UK was considerably higher than pre-pregnancy.  Fluoxetine and citalopram were the SSRIs of choice during pregnancy in Denmark and the UK databases, whilst in Italy and the Netherlands, despite studies in the literature reporting an increased risk of congenital heart defects and other anomalies, paroxetine was more commonly prescribed.


The variations observed in the type and extent of SSRI prescribing indicates an absence of European consensus on prescribing to pregnant women of childbearing age.  When a woman becomes pregnant, the benefit-risk profile of SSRI medicine changes and this was evident from the reduction in SSRI use observed in all European regions during pregnancy.  Further research should investigate whether women with mild depression in regions with higher SSRI prescribing are being inappropriately prescribed antidepressants during pregnancy, deriving no established benefit but exposing the fetus to possible risk.


For antiepileptics

Geographic variations were identified in the prevalence of AED prescribing, however, in all regions prescribing declined during pregnancy.  In Denmark, Norway and the UK, lamotrigine was the most commonly prescribed AED, whilst in the Italian regions, the older AEDs such as sodium valproate, phenobarbital and carbamazepine were the most popular throughout the study period. The prescribing guidelines in all regions acknowledged the increased risk of some major congenital anomalies and neurodevelopmental problems associated with sodium valproate exposure during pregnancy, and the increased risk of neural tube defects associated with carbamazepine.  It was therefore unclear what was continuing to drive the higher use of carbamazepine and valproate in Italy.  The Italian guidelines were the only ones that did not refer to an increased risk of congenital anomalies associated with phenobarbital and Italy was the only country where phenobarbital was commonly prescribed.  The prescribing guidelines in all regions recommended that women prescribed AEDs were co-prescribed folic acid in advance of becoming pregnant and in the majority of regions this was for high dose folic acid (>0.5mg).  Despite these recommendations, we found no evidence that co-prescribing of folic acid was usual practice during the pre-conception period.

The regional differences identified in AED prescribing patterns suggest different use, knowledge and/or interpretation of the scientific evidence base, and are unlikely to reflect informed choice of women.  Increased efforts are needed to increase awareness of the potential risks associated with some of the older AEDs and particularly sodium valproate.  More needs to be done to better inform clinicians and women of childbearing age taking AEDs of the need to plan their pregnancy and seek and receive complete preconception care. Preconception care is increasingly being recommended and organised for women with epilepsy, while the situation regarding psychiatric conditions and other indications is less clear. 


For medicines used to treat asthma

Regional differences were identified in the prevalence of prescribing of asthma medicines during and surrounding pregnancy. Regional differences were also identified in the extent to which different classes of asthma medicines were prescribed and the products most commonly prescribed.  In the UK, 90% of women who received a prescription for an asthma medicine during pregnancy received a prescription for a short-acting beta-2-agonist (SABA), compared with only 26% in the Italian regions.  In Italy, however, 85-90% of women with an asthma medicine prescription received an inhaled corticosteroid (ICS) largely beclomethasone, compared with 50% in Norway and 60% in the UK and Denmark.  Norway was the only region where the prevalence of ICS prescribing in a fixed-dose combination with a long-acting beta-2-agonist (LABA) was higher then the prescribing of ICS products not in a fixed-dose combination.  During pregnancy, in all regions except the UK, the prescribing of LABA declined during pregnancy, which may indicate that clinicians and pregnant women worry about using these relatively new inhaled medicines during pregnancy and the lack of information available on their safety.


In all regions, the prescribing guidelines advised that treatment for asthma during pregnancy should geneally be the same as that for non-pregnant groups of patients.  There was general agreement that SABAs were not teratogenic, with salbutamol and terbutaline being the recommended first choice.  Budesonide is the ICS with the highest safety profile, however, Norway and Italy were the only countries where budesonide was recommended as the ICS of choice and Denmark was the only region where this was the ICS most commonly prescribed.  Only the UK guidelines advised that when LABAs were required they should be used with an ICS and ideally as part of a fixed-dose combination product.


For medicines used to treat diabetes

Regional variations were identified in the prevalence of prescribing for pregestational diabetes, which likely reflects regional differences in the prevalence of diabetes.  During the second half of pregnancy, the prescribing of insulins increased in all regions, however, large differences were observed in the extent of the increase, reflecting different prevalences of pharmacologically treated gestational diabetes (Figure 6.2).

Figure 6.2 Prevalence of insulin in women with a delivery, between 2004 and 2010, during each of the 3-month time periods of interest 


Final Report Figure 3.9


These differences are likely to reflect the fact that these European populations are at different risk for developing gestational diabetes, there is no European consensus on screening policies for gestational diabetes screening and that there are regional/national differences in the policies on and attitudes towards the treatment of gestational diabetes.  Oral antidiabetic medicines largely consisted of metformin in all regions and in general were mainly prescribed during the year before pregnancy, followed by much lower levels of prescribing during the first and particularly the second and third trimesters.  Future work is needed to explain the wide range of metformin prescribing patterns observed during the year before the start of pregnancy and to investigate the indications other than diabetes for which it is prescribed.  During the later stages of the study period, increases in metformin prescribing during the second and third trimesters of pregnancy to treat gestational diabetes were observed in the Norwegian and two UK databases, however, in all other regions insulin continued to be the primary treatement for gestational diabetes throughout the study period.

Use of electronic healthcare databases

In addition to providing information on the utilisation of medicines to pregnancy women, the study has also demonstrated some of the strengths and limitations of electronic healthcare databases in Europe for evaluating medicine use and safety in pregnancy.  As part of WP6 and the wider EUROmediCAT study, electronic healthcare databases have proven to be a valuable source of information and beneficial for supplementing the data from congenital anomaly registries.  Of particular note is the large number of pregnancies that are captured, the population-based nature of the data which provides a denominator population enabling the prevalence of prescribing to be calculated, and the fact that prescription data is recorded independently of the women, preventing the possibility of recall bias.


This study did, however, identify areas where data were lacking within some or all of the electronic healthcare databases and this reduced the scope of what could feasibly be evaluated using the data sources available.  These limitations and restrictions in data availability highlighted areas where initiatives to collect and make available additional types of data could substantially enhance the utility of electronic healthcare databases for drug use and safety in pregnancy research, including their use for the evaluation of pregnancy prevention programmes.  The key areas identified were:

  • Availability of data on pregnancies that end in a spontaneous or induced termination
  • Availability of hospital, specialist and private prescribing and hospital pharmacy dispensing data
  • Recording of the indication for prescribing
  • Recording of data on maternal patient characteristics and lifestyle factors such as smoking, alcohol, body-mass-index and socioeconomic status
  • Availability of data on contraception use and prescribing
  • Availability of complete data on dose and defined daily dose (DDD)