The EFEMEREYE Study: prenatal medication exposure and ocular anomaly occurrence in EFEMERIS health database.

PURPOSE: To describe ocular anomalies (OAs) in children and fetuses in a French general population, to estimate their prevalence, and to investigate a possible association between prenatal medication exposure and the occurrence of OA in utero or in early childhood. METHODS: We conducted a case-control study using the EFEMERIS cohort, a database containing pregnancies registered in Haute-Garonne and their outcomes. We collected OA descriptions of fetuses at the time of pregnancy termination or of children at birth and the results of eye examinations of children at 9 months and 2 years of age. RESULTS: The prevalence of overall OAs was 2.13%, of which 0.04% were congenital ocular malformations (COMs). A total of 2,968 cases and 136,619 controls were selected for analysis. There was a significant difference between the two groups with regard to prenatal exposure to medications for the digestive tract and metabolism, the cardiovascular system, and the respiratory system. Multivariate analysis revealed an increased risk of OA in children of mothers exposed to magnesium during and 1 month before pregnancy (OR = 1.24; 95% CI, 1.11-1.38). CONCLUSIONS: This first pharmaco-epidemiological study on OA in France suggests that OA may be associated with exposure to commonly used medications. Given the rarity of COM, larger, international studies are warranted.

Teaching pharmacovigilance to French medical students during the COVID-19 pandemic: Interest of distance learning clinical reasoning sessions.

BACKGROUND: Considering data from the literature in favor of active educational intervention to teach pharmacovigilance, we describe an innovative model of distance learning clinical reasoning sessions (CRS) of pharmacovigilance with 3rd year medical French students. METHODS: The three main objectives were to identify the elements necessary for the diagnosis of an adverse drug reaction, report an adverse drug reaction and perform drug causality assessment. The training was organized in 3 stages. First, students practiced clinical reasoning (CRS) by conducting fictive pharmacovigilance telehealth consultations. Second, students wrote a medical letter summarizing the telehealth consultation and analyzing the drug causality assessment. This letter was sent to the teacher for a graded evaluation. In the third stage was a debriefing course with all the students. RESULTS: Of the 293 third-year medical students enrolled in this course, 274 participated in the distance learning CRS. The evaluation received feedback from 195 students, with an average score of 8.85 out of 10. The qualitative evaluation had only positive feedback. The students appreciated the different format of the teaching, with the possibility to be active. CONCLUSION: Through distance CRS of pharmacovigilance, medical students' competences to identify and report adverse drug reactions were tested. The students experienced the pharmacovigilance skills necessary to detect adverse drug reactions in a manner directly relevant to patient care. The overall evaluation of the students is in favor of this type of method.

Belgian medication exposure during pregnancy (BeMeP), a new nationwide linked database: Linkage methods and prevalence of medication use.

PURPOSE: This study aimed to describe the implementation of a new retrospective Belgian national cohort of pregnant women, the Belgian Medication Exposure during Pregnancy (BeMeP). METHODS: We linked the national dispensing data to birth and death certificates and hospital stay data for a 7-year period between 2010 and 2016 for the first time in Belgium. We presented the characteristics of pregnancy events associated with the mothers enrolled in the linkage study. Next, we constructed a cohort of pregnancies and compared some characteristics computed using the BeMeP database with the national statistics. Finally, we described the use of medications during pregnancy based on the first level of the Anatomical Therapeutic Chemical (ATC) classification. RESULTS: We included 630 457 pregnant women with 900 024 pregnancy-related events (843 780 livebirths, 1937 stillbirths, 6402 ectopic events, and 47 905 abortions) linked to medication exposure information. Overall, 96.3% of live births and 83.5% of stillbirths (national statistics as reference) were captured from the BeMeP. During pregnancy, excluding the week of birth, 78.9% of live birth pregnancies and 79.6% of stillbirth pregnancies were exposed to at least one medication. The most frequently dispensed medications were anti-infectives (ATC code J = 50.2%) for live births and for stillbirths (44.0%). CONCLUSION: We linked information on pregnancies, all reimbursed medications dispensed by community pharmacists, all medications dispensed during hospitalization, sociodemographic status, and infant health to create the BeMeP database. The database represents a valuable potential resource for studying exposure-outcome associations for medication use during pregnancy.

Detection and evaluation of signals associated with exposure to individual and combination of medications in pregnancy: a signal detection study protocol.

INTRODUCTION: Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk-benefit safety profile of their often-complex treatment plan, more research is needed to optimise prescribing. In this study, we aim to detect adverse and protective effect signals of exposure to individual and pairwise combinations of medications during pregnancy. METHODS AND ANALYSIS: Using a range of real-world data sources from the UK, we aim to conduct a pharmacovigilance study to assess the safety of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy. Women aged between 15 and 49 years with a record of pregnancy within the Clinical Practice Research Datalink (CPRD) Pregnancy Register, the Welsh Secure Anonymised Information Linkage (SAIL), the Scottish Morbidity Record (SMR) data sets and the Northern Ireland Maternity System (NIMATS) will be included. A series of case control studies will be conducted to estimate measures of disproportionality, detecting signals of association between a range of pregnancy outcomes and exposure to individual and combinations of medications. A multidisciplinary expert team will be invited to a signal detection workshop. By employing a structured framework, signals will be transparently assessed by each member of the team using a questionnaire appraising the signals on aspects of temporality, selection, time and measurement-related biases and confounding by underlying disease or comedications. Through group discussion, the expert team will reach consensus on each of the medication exposure-outcome signal, thereby excluding spurious signals, leaving signals suggestive of causal associations for further evaluation. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Independent Scientific Advisory Committee, SAIL Information Governance Review Panel, University of St. Andrews Teaching and Research Ethics Committee and Office for Research Ethics Committees Northern Ireland (ORECNI) for access and use of CPRD, SAIL, SMR and NIMATS data, respectively.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Risk of Hypertensive Disorders of Pregnancy in Women Treated With Serotonin-Norepinephrine Reuptake Inhibitors: A Comparative Study Using the EFEMERIS Database.

Background: Among antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) are particularly expected to increase the risk of hypertensive disorders of pregnancy (HDP) with regard to their biological mechanism. We aimed to evaluate the association between prenatal exposure to SNRI and HDP.Methods: In EFEMERIS, a French database including pregnant women covered by the French Health Insurance System of Haute-Garonne (2004-2019), we compared the incidence of HDP among women exposed to SNRI monotherapy during the first trimester of pregnancy to the incidence among 2 control groups: (1) women exposed to selective serotonin reuptake inhibitor (SSRI) monotherapy during the first trimester and (2) women not exposed to antidepressants during pregnancy. We conducted crude and also multivariate logistic regressions.Results: Of the 156,133 pregnancies, 143,391 were included in the study population, including 210 (0.1%) in the SNRI group, 1,316 (0.9%) in the SSRI group, and 141,865 (98.9%) in the unexposed group. After adjustment for depression severity and other mental conditions, the risk of HDP was significantly higher among women exposed to SNRIs (n = 20; 9.5%) compared to women exposed to SSRIs (n = 72; 5.5%; adjusted odds ratio [aOR] [95% CI] = 2.32 [1.28-4.20]) and to unexposed women (n = 6,224; 4.4%; aOR [95% CI] = 1.89 [1.13-3.18]).Conclusion: This study indicated an increased risk of HDP in women treated with SNRIs versus women treated with SSRIs.

Prevalence of polypharmacy in pregnancy: a systematic review.

OBJECTIVES: The use of medications among pregnant women has been rising over the past few decades but the reporting of polypharmacy has been sporadic. The objective of this review is to identify literature reporting the prevalence of polypharmacy among pregnant women, the prevalence of multimorbidity in women taking multiple medications in pregnancy and associated effects on maternal and offspring outcomes. DESIGN: MEDLINE and Embase were searched from their inception to 14 September 2021 for interventional trials, observational studies and systematic reviews reporting on the prevalence of polypharmacy or the use of multiple medications in pregnancy were included.Data on prevalence of polypharmacy, prevalence of multimorbidity, combinations of medications and pregnancy and offspring outcomes were extracted. A descriptive analysis was performed. RESULTS: Fourteen studies met the review criteria. The prevalence of women being prescribed two or more medications during pregnancy ranged from 4.9% (4.3%-5.5%) to 62.4% (61.3%-63.5%), with a median of 22.5%. For the first trimester, prevalence ranged from 4.9% (4.7%-5.14%) to 33.7% (32.2%-35.1%). No study reported on the prevalence of multimorbidity, or associated pregnancy outcomes in women exposed to polypharmacy. CONCLUSION: There is a significant burden of polypharmacy among pregnant women. There is a need for evidence on the combinations of medications prescribed in pregnancy, how this specifically affects women with multiple long-term conditions and the associated benefits and harms. TWEETABLE ABSTRACT: Our systematic review shows significant burden of polypharmacy in pregnancy but outcomes for women and offspring are unknown. PROSPERO REGISTRATION NUMBER: CRD42021223966.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

Adverse perinatal outcomes associated with prenatal exposure to protease-inhibitor-based versus non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations in pregnant women with HIV infection: a systematic review and meta-analysis.

BACKGROUND: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. METHODS: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. RESULTS: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. CONCLUSIONS: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO NUMBER: CRD42022306896.

Adverse drug reactions in pregnant women: Do they differ from those in non-pregnant women of childbearing age?

Pharmacoepidemiological research in pregnant women has focused on adverse drug reactions for the course of pregnancy or for the unborn child, but little is known on the risks for the mother. We reported the results of a study that compared adverse drug reactions in pregnant women with non-pregnant women of childbearing age, and investigated whether which types of adverse reactions were more often reported in pregnant women and which drugs were more often involved. This study was carried out in the French pharmacovigilance database (BNPV). We compared adverse drug reactions reported between 1 January 2010 and 31 December 2019 in pregnant women with those reported in of non-pregnant women of childbearing age. We cross-matched each pregnant woman with three non-pregnant women of childbearing age according to geographic area, age and year the adverse reaction was reported. Data analysis revealed that serious adverse reactions were more frequently reported in pregnant women, including anaphylactic reactions. Other adverse reactions including tachycardia, hypotension and hepatic injury were also more frequent in pregnant women than in non-pregnant women of the same age. This could be explained by physiological changes in pregnancy that lead to greater sensitivity to certain adverse reactions. Some drugs, such as phloroglucinol, metoclopramide, iron, atosiban and nifedipine, were more frequently involved in adverse reactions in pregnant women. These drugs are specifically used during pregnancy, which may explain why they are over-represented in adverse reactions. This is the first comparative descriptive study on drug adverse reactions in pregnant women. Specific epidemiological and pharmacokinetic studies are necessary to confirm these results and better understand the differences observed to improve the monitoring of pregnant women exposed to certain drugs.

Trends and regional variations in prescriptions dispensed to stimulate uterine contractions at the end of pregnancy in Belgium: A community-based study from 2003 to 2018.

PURPOSE: To investigate trends and regional variations in uterotonics dispensed around birth between 2003 and 2018 in Belgium. METHODS: Data, including outpatient and inpatient prescriptions were extracted from a nationally representative prescription database. The prevalence of uterotonics dispensed during a period including the 7 days before birth, the delivery day and the 7 days after birth was computed over three 4-year-long study periods from 2003 to 2018. The trends between periods and associations between the use of at least one uterotonic and maternal age, region of residence, delivery type and social status were assessed using logistic regression. RESULTS: In total, 31 675 pregnancies were included in the study. The proportion of pregnancies exposed to at least one uterotonic decreased significantly from 92.9% (95%CI, 92.3-93.4) in 2003-2006 to 91.4% (95%CI, 90.7-92.0) in 2015-2018 for vaginal births and from 95.5% (95%CI, 94.5-96.4) to 93.7% (95%CI, 92.6-94.7) for caesarean sections. However, for vaginal births, the proportion of oxytocin increased from 84.5% (95%CI, 83.7-85.2) to 89% (95%CI 88.3-89.7). A significant association was found between uterotonic agent use and maternal age, region of residence, and delivery type. The dispensation of some uterotonic agents differed significantly between the regions. CONCLUSIONS: The proportion of pregnancies exposed to at least one uterotonic was high across the study period but decreased slightly between 2003 and 2018. Important variations in uterotonic use between regions highlight the need for improved national guidance.

First trimester pregnancy exposure to fosfomycin and risk of major congenital anomaly: a comparative study in the EFEMERIS database.

PURPOSE: Fosfomycin trometamol has been recommended as first-line bactericidal antibiotic for urinary tract infections in pregnant women since 2015 in France. However, studies assessing fosfomycin safety in pregnancy are sparse. This study aimed to assess the risk of major Congenital Anomaly (CA) after fosfomycin exposure during the first trimester of pregnancy. METHODS: We performed a comparative study in EFEMERIS, the French database including expecting mothers covered by the French Health Insurance System of Haute-Garonne from July 1st, 2004 to December 31th, 2018. EFEMERIS contains prescribed and dispensed reimbursed medications during pregnancy and pregnancy outcomes. Logistic regressions have been conducted to compare three groups: (1) pregnancies exposed at least once to fosfomycin; (2) pregnancies exposed at least once to nitrofurantoin; and (3) pregnancies exposed neither to fosfomycin nor to nitrofurantoin, another antibiotic prescribed for urinary infections, before and during pregnancy. RESULTS: A total of 2724 (2.0%) pregnant women received at least one fosfomycin prescription during the first trimester, 650 (0.5%) received nitrofurantoin during the first trimester, and 133,502 (97.5%) pregnant women were not exposed to fosfomycin nor to nitrofurantoin. First trimester pregnancy exposure to fosfomycin was not associated with an increased risk of major CA, compared to first trimester exposure to nitrofurantoin (2.0% versus 2.5%; ORa = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; ORa = 0.97 [0.73-1.30]). CONCLUSION: This is the first large comparative study assessing fosfomycin safety in pregnancy. It does not exhibit an increased risk of major CA after fosfomycin exposure during the first trimester of pregnancy.

Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert.

BACKGROUND: The pharmacoepidemiology of the long-term benefits and harms of medicines in pregnancy and breastfeeding has received little attention. The impact of maternal medicines on children is increasingly recognised as a source of avoidable harm. The focus of attention has expanded from congenital anomalies to include less visible, but equally important, outcomes, including cognition, neurodevelopmental disorders, educational performance, and childhood ill-health. Breastfeeding, whether as a source of medicine exposure, a mitigator of adverse effects or as an outcome, has been all but ignored in pharmacoepidemiology and pharmacovigilance: a significant 'blind spot'. WHOLE-POPULATION DATA ON BREASTFEEDING: WHY WE NEED THEM: Optimal child development and maternal health necessitate breastfeeding, yet little information exists to guide families regarding the safety of medicine use during lactation. Breastfeeding initiation or success may be altered by medicine use, and breastfeeding may obscure the true relationship between medicine exposure during pregnancy and developmental outcomes. Absent or poorly standardised recording of breastfeeding in most population databases hampers analysis and understanding of the complex relationships between medicine, pregnancy, breastfeeding and infant and maternal health. The purpose of this paper is to present the arguments for breastfeeding to be included alongside medicine use and neurodevelopmental outcomes in whole-population database investigations of the harms and benefits of medicines during pregnancy, the puerperium and postnatal period. We review: 1) the current situation, 2) how these complexities might be accommodated in pharmacoepidemiological models, using antidepressants and antiepileptics as examples; 3) the challenges in obtaining comprehensive data. CONCLUSIONS: The scarcity of whole-population data and the complexities of the inter-relationships between breastfeeding, medicines, co-exposures and infant outcomes are significant barriers to full characterisation of the benefits and harms of medicines during pregnancy and breastfeeding. This makes it difficult to answer the questions: 'is it safe to breastfeed whilst taking this medicine', and 'will this medicine interfere with breastfeeding and/ or infants' development'?

Prenatal Drug Exposure in Children With a History of Neuropsychiatric Care: A Nested Case-Control Study.

Background and Objectives: Neuropsychiatric disorders in childhood after prenatal drug exposure raises concerns. Most of the published studies focused on psychotropic medications. This study investigated which prenatal medication exposure was associated with neuropsychiatric disorders in childhood. Methods: A case-control study, nested in the French POMME cohort, was conducted to compare prenatal medication exposure between children with a history of neuropsychiatric care (ages 0-8 years) and children in a control group. POMME included children born in Haute-Garonne to women covered by the general Health Insurance System, between 2010 and 2011 (N = 8,372). Cases were identified through: (1) reimbursement for neuropsychiatric care; (2) psychomotor development abnormalities specified on health certificates; and (3) reimbursement for methylphenidate or neuroleptics. Controls had none of these criteria. Prenatal exposure to each of the major "Anatomical Therapeutic Chemical" classes was compared between the groups. Class(es) for which there was a statistically significant difference (after Bonferroni adjustment, i.e., p < 0.0033) was(were) compared using logistic regression. Results: A total of 723 (8.6%) cases and 4,924 (58.8%) controls were identified. This study showed a statistically significant difference in prenatal exposure to nervous system drugs (excluding analgesics) between the groups [ORa: 2.12 (1.55; 2.90)]. Differences (not statistically significant at the 0.0033 threshold) were also observed for the ATC classes: Musculoskeletal, Genito-urinary System and Sex Hormones, Alimentary Tract and Anti-infectives. Conclusion: Through identification of children with neuropsychiatric disorders and of their prenatal medication exposure, this study provides guidance for the assessment of long-term neuropsychiatric effects after prenatal medication exposure, without focusing on psychotropic medications.

COVID-19 in pregnancy-what study designs can we use to assess the risk of congenital anomalies in relation to COVID-19 disease, treatment and vaccination?

BACKGROUND: The COVID-19 pandemic has accelerated pregnancy outcome research, but little attention has been given specifically to the risk of congenital anomalies (CA) and first trimester exposures. OBJECTIVES: We reviewed the main data sources and study designs used internationally, particularly in Europe, for CA research, and their strengths and limitations for investigating COVID-19 disease, medications and vaccines. POPULATION: We classify research designs based on four data sources: a) spontaneous adverse event reporting, where study subjects are positive for both exposure and outcome, b) pregnancy exposure registries, where study subjects are positive for exposure, c) congenital anomaly registries, where study subjects are positive for outcome and d) population healthcare data where the entire population of births is included, irrespective of exposure and outcome. STUDY DESIGN: Each data source allows different study designs, including case series, exposed pregnancy cohorts (with external comparator), ecological studies, case-control studies and population cohort studies (with internal comparator). METHODS: The quality of data sources for CA studies is reviewed in relation to criteria including diagnostic accuracy of CA data, size of study population, inclusion of terminations of pregnancy for foetal anomaly, inclusion of first trimester COVID-19-related exposures and use of an internal comparator group. Multinational collaboration models are reviewed. RESULTS: Pregnancy exposure registries have been the main design for COVID-19 pregnancy studies, but lack detail regarding first trimester exposures relevant to CA, or a suitable comparator group. CA registries present opportunities for improving diagnostic accuracy in COVID-19 research, especially when linked to other data sources. Availability of inpatient hospital medication use in population healthcare data is limited. More use of ongoing mother-baby linkage systems would improve research efficiency. Multinational collaboration delivers statistical power. CONCLUSIONS: Challenges and opportunities exist to improve research on CA in relation to the COVID-19 pandemic and future pandemics.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Topical sertaconazole during pregnancy and risk of adverse pregnancy outcome and major congenital anomalies: Comparative study in the EFEMERIS database.

INTRODUCTION: Topical sertaconazole is indicated in the treatment of vaginal or mucocutaneous fungal infections due to Candida and dermatophytosis. To our knowledge, there is no data available in the literature on the potential effects of sertaconazole during pregnancy. The aim of this study was to evaluate the potential risks of topical sertaconazole use during pregnancy for the foetus and pregnancy. MATERIALS AND METHODS: The EFEMERIS database was used, which contained medications prescribed and dispensed to pregnant women in the Haute-Garonne region whose pregnancy ended between July 2004 and December 2018. We compared pregnant women exposed to sertaconazole at least once during pregnancy to unexposed. Crude and adjusted odds ratios (OR) of major congenital anomalies and small gestational age at birth were estimated using logistic regression models. For other outcomes, hazard ratios (HR) were estimated by Cox regression models. RESULTS: The study included 16,222 pregnant women (15.0%) who were given sertaconazole and 91,976 who were not. Exposure to sertaconazole during pregnancy was not associated with increased risks of any of the investigated outcomes, including natural pregnancy termination (HRa  = 0.92 [0.78-1.08]), preterm birth (HRa  = 1.06 [0.95-1.17]) and small for gestational age at birth (ORa  = 0.78 [0.66-0.92]). No association between risk of major congenital anomalies overall and maternal exposure to sertaconazole during the first trimester was observed (ORa  = 1.01 [0.84-1.21]). DISCUSSION: This is the first study involving a large number of pregnant women to assess the potential risks of sertaconazole during pregnancy. This study does not indicate an increased risk of adverse pregnancy outcome and major congenital anomalies from exposure to topical sertaconazole.

Longitudinal Methods for Modeling Exposures in Pharmacoepidemiologic Studies in Pregnancy.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as "ever exposed" versus "never exposed" within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins' generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

Initial data on the safety of metopimazine during pregnancy and the risk of major birth defects and pregnancy loss - An observational study using the EFEMERIS database.

INTRODUCTION: Metopimazine is an anti-emetic drug used to treat nausea and vomiting of pregnancy. However, no animal or clinical data are available regarding its safety in pregnant women. The aim of this study was, therefore, to assess the risk of birth defects and pregnancy loss associated with the use of metopimazine during pregnancy in a population-based cohort study. METHODS: The study focused on the EFEMERIS database including the prescription and dispensation of drugs for pregnant women in Haute-Garonne, France, between July 2004 and December 2017. This was an observational, retrospective, comparative study. Pregnancy loss and major birth defects were compared between women exposed to metopimazine during pregnancy and those with no exposure using multivariate logistic regression and Cox proportional risk models. RESULTS: Among 135,574 pregnant women, 11,402 (8.2%) were exposed to metopimazine during pregnancy, mostly in the first trimester (more than 70% of women). No association was found between major birth defects and exposure to metopimazine in the first trimester of pregnancy (ORa=[95% CI]=1.06 [0.92-1.23]). Pregnancy loss was negatively associated with metopimazine use during pregnancy (HRa [95% CI]=0.80 [0.72-0.88]), taking into account major potential confounders. Comparable rates were recorded between women exposed to metopimazine and those unexposed to the drug in terms of prematurity (6.7% vs. 6.4%), low birth weight (6.2% vs. 6.2%) and small for gestational age (1.2% vs. 1.4%). CONCLUSION: This study illustrates the wide use of metopimazine during pregnancy in France although no studies on efficacy or safety in pregnant women are available. The results of this study do not indicate any teratogenic effect or an increased risk of pregnancy loss of metopimazine.

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding.

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population.