Last month, the research roundup provided you with an overview of articles looking at adverse drug reactions (Robertson, 2023). This month, three articles will be reviewed that look at the complex issues encountered when prescribing during pregnancy will be reviewed. The first article looks at polypharmacy and associated risks, the second examines the use of antidepressants and the risk of gestational diabetes and the third looks at the impact of regulatory safety notices on prescribing valproate in women with childbearing potential.
Polypharmacy during pregnancy and associated risk factors
This article was published in BMC Medicine, used a retrospective cohort study approach to examine data between 2000 and 2019 (Subramanian et al, 2023). The author's main driver to conduct this research was to shed light on the prevalence of the use of multiple medications in pregnancy and to identify risk factors for polypharmacy. They accessed the Pregnancy Register in the Clinical Practice Research Datalink, which contains the anonymised medical records of over 20 million patients in 973 GP practices. In the pregnancy section, data could be gathered on estimated start and end dates of pregnancy as well as estimated dates for each trimester. GP-issued prescriptions were also accessible during that time.
The database contained 3 202 461 pregnancies and of those 81 2 354 took place over the selected time period. Of these, 1 521 317 met the inclusion and exclusion criteria, with 81 2 354 and 77 4247 pregnancies had complete follow-up through the first trimester and the entire pregnancy respectively. The prescription records for 577 medication categories (as defined by the BNF) were also obtained.
The researchers found that of the 81 2354 records competing the first trimester, the prevalence of polypharmacy increased from 8.7% to 18.7% between the period 2000 and 2019. Looking at numbers of medicines from 2–11 or more, the prevalence ranged from 24.6% at the low end to 0.1% at the upper. When comparing this to the data from the whole pregnancy (774 247), prevalence ranged from 58.7% at 2+ to 1.4% at 11+ medications.
A review of prescribed medication revealed that the most commonly prescribed medications were broad-spectrum penicillins, which accounted for 6.6% of the total; non-opioid compound analgesics, which accounted for 4.5% and antifungal treatments, which accounted for 4.3%. If the researchers filtered this to only account for patients with multimorbidity, the most common were selective serotonin reuptake inhibitors, selective beta 2 agonists and broad-spectrum penicillins.
In an analysis of risk factors for polypharmacy in the first trimester (defined as taking two or more medications), the authors found that obesity, being from an ethnic minority group smoking, and a history of smoking were all associated with an increased likelihood of receiving multiple medications.
Additionally, those who were of lower (15–19 years) or higher (45–49 years) ages were more likely to be being prescribed medicines than those in the middle of this range. Another factor was the increased number of co-morbidities and increased social deprivation.
The study found that higher gravidity was associated with an increased risk of polypharmacy compared to women in their first pregnancy. According to the authors, the prevalence of polypharmacy during pregnancy has risen over the past two decades and is most common among women who are younger or older, obese, smokers, have multiple health conditions, or come from deprived areas. The authors called for further research to examine the potential impact of increased drug use during pregnancy on fetal development.
Antidepressant use during pregnancy and the risk for gestational diabetes
This article, which was published in the Journal of Maternal-Fetal and Neonatal Medicine (Wang et all, 2023), aimed to review published research on the relationship between the use of antidepressants during pregnancy and the risk of developing gestational diabetes. The authors carried out this study because of an observed increase in the use of antidepressants during pregnancy for depression and anxiety, as well as their use in OCD, fibromyalgia and headache. The authors acknowledge gestational diabetes as a relatively common condition of pregnancy and conducted a systematic literature review and meta-analysis to assess the association, if any, between antidepressant use and the onset of gestational diabetes.
The authors used PubMed and EMBASE databases to search for publications up to 2019, with the meta-analysis for observational studies in epidemiology (MOOSE) checklist being used as a reporting guideline (Stroup et al, 2000). The authors' search strategy was well outlined, and there was good adherence to inclusion and exclusion criteria.
The authors initially identified 488 potential articles in the two databases. After removing duplicates (36), excluding articles after further critical scrutiny (432) and full-text evaluation (15), only five articles were eligible for inclusion. Based on these articles, the authors' meta-analysis suggests that mothers who take antidepressant medications during pregnancy are at a significantly higher risk of developing gestational diabetes, with a relative risk of 1.20 and a 95% confidence interval.
The authors acknowledged the possibility of confounding by indication, and when this was considered, there was no clear evidence of a link between antidepressant use in pregnancy and an increased risk of gestational diabetes. They also suggested that the risk may be different for each class of antidepressant, with SSRIs being the lowest risk compared to venlafaxine or amitriptyline. Based on their small-sized review, the authors concluded that any significant association between antidepressant use during pregnancy and gestational diabetes may be overestimated and that the evidence remains insufficient to form a firm link. The authors suggested that larger prospective cohort studies are needed to clarify any effects.
Regulatory safety notices, valproate prescribing and pregnancy outcome
This article, published in BMJ Open (McTaggart et al, 2022), looked at the impact of regulatory safety notices on valproate prescribing and pregnancy using a population-based cohort study. The Medicines and Healthcare products Regulatory Agency issued strong guidance on prescribing valproate to women and girls of childbearing potential after a Europe-wide review of its impact on fetal development in 2014.
The researchers identified all valproate prescriptions issued to women aged between 14 and 45 years old January 2011 and December 2019. This study was carried out in Scotland and accessed linked records using NHS numbers and the unique Community Health Index number. Data were linked by Public Health Scotland and approved by appropriate Caldicott Guardians. Data from the National Prescribing Information Service were used to ascertain valproate prescriptions reimbursed during the time of review. Pregnancy outcomes were also reviewed, looking at live birth, stillbirth, miscarriage and termination.
In total, 21 983 women meeting the inclusion criteria were prescribed valproate between January 2011 and December 2019. They report that the annual prevalence rate of valproate prescribing declined from 40.5% in 2011 to 18.3% in 2019 per 10 000 population. Statistically significant changes occurred around the times of the Medicines and Healthcare products Regulatory Agency safety alerts.
The authors concluded that the impact of the safety alerts has been positive and has resulted in a major reduction in valproate use in women of childbearing potential, and that a pregnancy prevention plan has been successful in reducing pregnancies occurring in women prescribed the drug. They suggested a national surveillance capacity could continue to minimise in-utero exposure to valproate with better long-term outcomes.
Conclusion
Prescribing during pregnancy can be a worry to many prescribers, both medical and non-medical, and the premise is often to only give medications if the benefit to the mother outweighs the risk to the fetus. For many expectant mothers, there are pre-existing health conditions that necessitate medication, and these should be well monitored. Avoidance of unnecessary polypharmacy is something prescribers should strive for in all populations but especially here. It is important to be mindful of side effects that may not occur in a non-pregnant woman and monitor accordingly.