Introduction and Objective
The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or ...systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities.
Methods
This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk–benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems.
Results
The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website (
http://www.entis-org.eu/cde
).
Discussion
With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.
Evidence on the use of drugs during pregnancy in Switzerland is lacking.
To evaluate utilisation of prescribed drugs during pregnancy in outpatient care in Switzerland, focusing on treatments for ...pain, infections, gastro-oesophageal reflux, nausea/vomiting, and constipation.
We conducted a descriptive study using the Swiss Helsana claims database (2014–2018). We established a cohort of pregnancies by identifying deliveries and estimating the date of the last menstrual period. We identified claims for the following drugs during pregnancy; analgesics (opioids, paracetamol, and nonsteroidal anti-inflammatory drugs NSAIDs), oral antibiotics, antacids, proton pump inhibitors (PPIs), anti-nausea drugs (propulsives and 5HT3-antagonists), and laxatives. Within these drug groups we quantified exposure prevalence to the most prescribed drugs (to >1% of pregnancies) during pregnancy as well as to specific potentially teratogenic or fetotoxic drugs during specific risk periods. Results were extrapolated relative to the demographic distribution of the Swiss population.
We identified an extrapolated population of 369,371 pregnancies, with a weighted mean maternal age of 32.0 years (weighted standard deviation 5.1). Analgesics were claimed in 34.5% (95% confidence interval CI 33.9–35.0%) of pregnancies, most frequently paracetamol (30.3%, 29.8–30.8%), followed by NSAIDs (8.6%, 8.3–8.8%), and opioids (2.6%, 2.4–2.8%). NSAIDs were claimed in 1.3% (1.2–1.4%) of pregnancies after week 24, and opioids were claimed in 1.3% (1.2–1.4%) in trimester 3. Antibiotics were dispensed in 26.3% (25.8–26.8%) of pregnancies, most frequently amoxicillin (14.6%, 95% CI 14.2–14.9%). Claims for potentially teratogenic or fetotoxic antibiotics during risk periods were each recorded in <0.6% of pregnancies. PPIs were claimed in 16.0% (15.6–16.3%) and antacids in 10.6% (10.3–11.0%) of pregnancies, but several antacid products are not reimbursed and thus not present in insurance claims. Anti-nausea drugs were claimed in 16.4% (16.0–16.7%) of pregnancies, most frequently metoclopramide in 14.4% (14.0–14.7%). Ondansetron was mainly dispensed in trimester 1, 1.0% (0.9–1.1%). In total, 6.4% (6.2–6.7%) of pregnancies had a claim for laxatives, most frequently for macrogol (2.4%, 95% CI 2.2–2.5%).
The observed pattern of claimed drugs during pregnancy is in line with existing treatment guidelines. Exposure to potentially teratogenic and fetotoxic drugs was small, but given the lack of recorded diagnosis, we cannot determine if their use was clinically indicated.
With COVID-19 vaccination hesitancy at around 50% in the obstetric population, it is critical to identify which women should be addressed and how. Our study aimed to assess COVID-19 vaccination ...willingness among pregnant and postpartum women in Europe and to investigate associated determinants. This study was a cross-sectional, web-based survey conducted in Belgium, Norway, Switzerland, The Netherlands, and United Kingdom (UK) in June-August 2021. Among 3194 pregnant women, the proportions of women vaccinated or willing to be vaccinated ranged from 80.5% in Belgium to 21.5% in Norway. The associated characteristics were country of residence, chronic illness, history of flu vaccine, trimester of pregnancy, belief that COVID-19 is more severe during pregnancy, and belief that the COVID-19 vaccine is effective and safe during pregnancy. Among 1659 postpartum women, the proportions of women vaccinated or willing to be vaccinated ranged from 86.0% in the UK to 58.6% in Switzerland. The associated determinants were country of residence, chronic illness, history of flu vaccine, breastfeeding, and belief that the COVID-19 vaccine is safe during breastfeeding. Vaccine hesitancy in the obstetric population depends on medical history and especially on the opinion that the vaccine is safe and on the country of residence.
Metformin is considered as first-line treatment for type 2 diabetes and an effective treatment for polycystic ovary syndrome (PCOS). However, evidence regarding its safety in pregnancy is limited. We ...conducted a systematic review and meta-analysis of major congenital malformations (MCMs) risk after first-trimester exposure to metformin in women with PCOS and pregestational diabetes mellitus (PGDM). Randomized controlled trials (RCTs) and observational cohort studies with a control group investigating risk of MCM after first-trimester pregnancy exposure to metformin were searched until December 2021. ORs and 95% CIs were calculated separately according to indications and study type using Mantel-Haenszel method; outcome data were combined using random-effects model. Eleven studies (two RCTs; nine observational cohorts) met the inclusion criteria: four included pregnant women with PCOS, four included those with PGDM and three evaluated both indications separately and were considered in both indication groups. In PCOS group, there were two RCTs (57 exposed, 52 control infants) and five observational studies (472 exposed, 1892 control infants); point estimates for MCM rates in RCTs and observational studies were OR 0.93 (95% CI 0.09 to 9.21) (I2=0%; Q test=0.31; p value=0.58) and OR 1.35 (95% CI 0.37 to 4.90) (I2=65%; Q test=9.43; p value=0.05), respectively. In PGDM group, all seven studies were observational (1122 exposed, 1851 control infants); the point estimate for MCM rates was OR 1.05 (95% CI 0.50 to 2.18) (I2=59%; Q test=16.34; p value=0.01). Metformin use in first-trimester pregnancy in women with PCOS or PGDM do not meaningfully increase the MCM risk overall. However, further studies are needed to characterize residual safety concerns.
ObjectivesGlucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks ...associated with GLP1-RA exposure during early pregnancy.DesignThis multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022.SettingData were collected from the databases of six Teratology Information Services.ParticipantsThis study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women.ResultsExposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses.ConclusionsThis study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.
Pregnant individuals with coronavirus disease 2019 (COVID-19) are at increased risk of severe disease, prematurity, and stillbirth. In March 2021, vaccination for at risk pregnant women was ...recommended in Switzerland, expanding this to all pregnant women in May 2021. Our aim was to assess the safety of mRNA COVID-19 vaccines in pregnancy.
This multicentre prospective cohort study describes early adverse events and perinatal outcomes in pregnant women who received at least one dose of mRNA vaccine between March 1st and December 27th, 2021 in Switzerland, using the COVI-PREG registry. Early adverse events were collected at least one month following vaccine administration. Pregnancy and neonatal outcomes were extracted from medical records using the maternity discharge letters providing follow-up information up to 5 days after birth.
Of 1012 vaccinated women, 894 (88·3%) received both injections during pregnancy, with BNT162b2 (n = 271) or mRNA-1273 (n = 623) vaccines. Local events (mainly local pain) were reported in 81·3% and 80·5% after the first and second doses. Rates of systemic reactions (mainly fatigue and headache) were similar after the first dose and most frequent after the second dose of mRNA-1273. Of the 1012 women, four (0·4%; 95%CI 0·1-1·0) severe early adverse events occurred: pulmonary embolism, preterm premature rupture of membranes, isolated fever with hospitalisation, and herpes zoster. Of 107 patients vaccinated before 14 weeks, one (0·9%; 95%CI 0·0-5·1) early spontaneous abortions was reported (8 weeks). Of 228 vaccinated before 20 weeks one (0·4%; 95%CI 0·0-2·4) late spontaneous abortion was reported (16 weeks). Of 513 women exposed before 37 weeks, 33 (6·4%; 95%CI 4·5-8·9) delivered preterm. Among 530 patients exposed in pregnancy, no stillbirth was reported and 25 (4·7%; 95%CI 3·0-6·8) neonates were admitted to intensive care unit.
Frequent local and systemic effects were described after exposure to mRNA COVID-19 vaccines during pregnancy but severe events were rare. Women vaccinated during pregnancy did not experience higher adverse pregnancy or neonatal outcomes when compared to historical data on background risks in the obstetric population.
This research was funded by a grant from the Swiss Federal Office of Public Health and the CHUV Foundation.
Background. The incidence of diabetes mellitus (both pregestational and gestational) is increasing worldwide, and hyperglycemia during pregnancy is associated with adverse pregnancy outcomes. ...Evidence on the safety and efficacy of metformin during pregnancy has accumulated resulting in an increase in its prescription in many reports. Aims. We aimed to determine the prevalence of antidiabetic drug use (insulins and blood glucose-lowering drugs) before and during pregnancy in Switzerland and the changes therein during pregnancy and over time. Methods. We conducted a descriptive study using Swiss health insurance claims (2012-2019). We established the MAMA cohort by identifying deliveries and estimating the last menstrual period. We identified claims for any antidiabetic medication (ADM), insulins, blood glucose-lowering drugs, and individual substances within each class. We defined three groups of pattern use based on timing of dispensation: (1) dispensation of at least one ADM in the prepregnancy period and in or after trimester 2 (T2) (pregestational diabetes); (2) dispensation for the first time in or after T2 (GDM); and (3) dispensation in the prepregnancy period and no dispensation in or after T2 (discontinuers). Within the pregestational diabetes group, we further defined continuers (dispensation for the same group of ADM) and switchers (different ADM group dispensed in the prepregnancy period and in or after T2). Results. MAMA included 104,098 deliveries with a mean maternal age at delivery of 31.7. Antidiabetic dispensations among pregnancies with pregestational and gestational diabetes increased over time. Insulin was the most dispensed medication for both diseases. Between 2017 and 2019, less than 10% of pregnancies treated for pregestational diabetes continued metformin rather than switching to insulin. Metformin was offered to less than 2% of pregnancies to treat gestational diabetes (2017-2019). Conclusion. Despite its position in the guidelines and the attractive alternative that metformin represents to patients who may encounter barriers with insulin therapy, there was reluctance to prescribe it.
Healthcare professionals' (HCPs') perception of risk associated with drug use in pregnancy may have an impact on the pharmacological treatment of some women. The aim of this study was to examine this ...risk perception in a sample of Swiss HCPs with a special focus on their knowledge and use of available specialised information sources.
An online, French and German, questionnaire was e-mailed to 7,136 members of four Swiss professional societies (gynaecologists, paediatricians, midwives and pharmacists). The questionnaire was designed (a) to collect demographic characteristics, (b) to evaluate the frequency of use of several specialised sources of information on drugs in pregnancy in their daily practice, and (c) to examine the perception of risk associated with drug use during pregnancy.
A total of 1,310 questionnaires were collected (response rate of 18.4%). More than 80% of the respondent HCPs use the Swiss Drug Reference Book (Compendium) to assess the risk associated with drugs during pregnancy and are not aware of available specialised information sources (books, websites or information centres). Despite some disparities between HPCs, the risk related to drug intake was overall highly misperceived. Blinded reading of three product monographs in the Compendium was associated with an overestimated perception of risk (e.g., after reading the "paracetamol" monograph, 38% of the participants stated they would probably not advise the use of this drug to a pregnant patient).
Overall, an overestimation of the risk associated with drug use during pregnancy has been observed in our sample of HCPs, which might be related to the underuse of specialised information source among other factors. These findings evidenced the need for increased training for HCPs in order to optimise medication use during pregnancy. Further studies are needed to confirm these results and identify causes.
Health management of cystic fibrosis (CF) patients should be maximized during pregnancy and breastfeeding because of its significant impact on the maternal and newborn outcomes. Thus, numerous drugs ...will have to be continued during pregnancy and lactation. Most of the drugs representing CF treatment lines cross the placenta or are excreted into human milk. Research addressing the risks and benefits of drugs used in CF patients during pregnancy and lactation is often incomplete or challenged by limited methodology, which often leads to conflicting or inconclusive results. Yet, potential treatment benefits for CF pregnant patients most often outbalance potential risks for the unborn child.
PDF
