A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

Social determinants of antidepressant continuation during pregnancy in the USA: findings from the ABCD cohort study.

PURPOSE: Patients and healthcare professionals overestimate the risks of using antidepressants during pregnancy. According to current literature, approximately half of people stop taking an anti-depressant medication when they become pregnant. Discontinuing antidepressants during pregnancy increases risks of postnatal relapses. Factors like socioeconomic status, education, and planned pregnancies play a role in the decision to continue antidepressant medication, which can worsen disparities in maternal and child health. Our aim was to identify the sociodemographic factors associated with antidepressant continuation after awareness of pregnancy. METHODS: We used representative data from the Adolescent Brain Cognitive Development (ABCD) study that captures maternal medication during pregnancy. We identified women who used antidepressants before awareness of their pregnancy. We calculated crude and adjusted associations between sociodemographic factors and continuation of antidepressant medication during pregnancy. Our model included age, education, ethnicity, first language, household income, living with a partner, having planned the pregnancy, pregnancy duration and smoking during pregnancy. RESULTS: In total, 199 women continued antidepressants and 100 discontinued. The logistic regressions resulted in only one significant factor: first language. Native English speakers were more likely to continue medication than other mothers (adjusted OR = 14.94, 95% CI = [2.40; 291.45], p = .015). CONCLUSIONS: Language differences were associated with continuation of antidepressants. Non-native English speakers were more likely to discontinue antidepressants, which may lead to health inequities. This finding should be taken into account to reinforce information about the limited risks of antidepressants among people with non-English speaking backgrounds in the USA.

[Neonatal Fc receptor : role and implications in maternal fetal medicine]. / Récepteur Fc néonatal : rôle et ­implications en médecine ­fœto-maternelle.

During pregnancy, the mother's IgG immunoglobulins cross the -placenta via the neonatal Fc receptor (FcRn), enabling the fetus to acquire passive immunity. In the presence of maternal allo- or auto-antibodies, placental transfer of these pathogenic antibodies mediated by FcRn can cause diseases in the fetus and/or the newborn. FcRn blockade therefore appears to be a therapeutic strategy in these high-risk pregnancies, firstly by reducing IgG recycling, -thereby reducing its concentration in the maternal circulation, and secondly by blocking placental transfer. The promising results of a recent trial testing nipocalimab, a monoclonal antibody targeting FcRn, in very severe erythrocyte alloimmunisation, has opened the way to new targeted therapeutic approaches for perinatal diseases mediated by maternal IgG.

Durant la grossesse, les immunoglobulines de type G (IgG) de la mère franchissent le placenta via le récepteur Fc néonatal (FcRn), permettant au fœtus d'acquérir une immunité passive. En présence d'allo ou d'autoanticorps maternels, ce passage peut entraîner des pathologies fœtales et/ou néonatales. Ainsi, le blocage du FcRn apparaît comme une stratégie thérapeutique dans ces grossesses à risque, d'une part en diminuant le recyclage des IgG, réduisant ainsi leur concentration dans la circulation maternelle, et d'autre part en bloquant leur transfert placentaire. Les résultats prometteurs d'un essai récent testant le nipocalimab, anticorps monoclonal ciblant le FcRn, dans les allo-immunisations érythrocytaires très sévères, a ouvert la voie à de nouvelles approches thérapeutiques ciblées pour les pathologies périnatales médiées par des IgG maternelles.

Reproductive Safety of Trazodone After Maternal Exposure in Early Pregnancy: A Comparative ENTIS Cohort Study.

PURPOSE/BACKGROUND: Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available. METHODS/PROCEDURES: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021. FINDINGS/RESULTS: The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups. IMPLICATIONS/CONCLUSIONS: This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies.

COVID-19-related medicine utilization study in pregnancy: The COVI-PREG cohort.

AIM: The objective of this study was to describe the use of COVID-19-related medicines during pregnancy and their evolution between the early/late periods of the pandemic. METHODS: Pregnant women who tested positive for SARS-CoV-2 from March 2020 to July 2021 were included using the COVI-PREG registry. Exposure to the following COVID-19-related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti-interleukin-6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID-19 severity level and early/late period of the pandemic (before and after 1 July 2020). FINDINGS: We included 1964 pregnant patients who tested positive for SARS-CoV-2. Overall, 10.4% (205/1964) received at least one COVID-19-related medicine including antibiotics (8.6%; 169/1694), corticosteroids (3.2%; 62/1964), antivirals (2.0%; 39/1964), hydroxychloroquine (1.4%; 27/1964) and anti-interleukin-6 (0.3%; 5/1964). The use of at least one COVID-19-related medicine was 3.1% (12/381) in asymptomatic individuals, 4.2% (52/1233) in outpatients, 19.7% (46/233) in inpatients without oxygen, 72.1% (44/61) in those requiring standard oxygen, 95.7% (22/23) in those requiring high flow oxygen, 96.2% (25/26) in patients who required intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID-19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period. CONCLUSION: Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID-19-related medicines in pregnancy.

[Risk assessment of drugs during breastfeeding]. / Évaluation des risques liés aux médicaments pendant l'allaitement.

Medication intake during the postpartum period is common with discontinuation of breastfeeding sometimes unnecessarily recommended for fear of adverse effects in the breastfed infant, while exposure through human milk is generally low. The assessment of risks associated with medication intake during breastfeeding is based, among other things, on the little clinical evidence available in specialized sources of information, and on pharmacokinetic principles. A decision-making support is presented to facilitate communication with mothers, foster medication adherence and prevent unnecessary interruption of breastfeeding.

La prise de médicaments pendant la période postnatale est courante et associée à un arrêt de l'allaitement parfois recommandé à tort par crainte d'effets indésirables chez l'enfant allaité, alors que l'exposition à travers le lait maternel est généralement faible. L'évaluation des risques d'utilisation de médicaments pendant l'allaitement repose, entre autres, sur le peu de preuves cliniques disponibles, documentées dans des sources d'information spécialisées, et sur les principes pharmacocinétiques. Un algorithme d'aide à la décision est proposé pour faciliter la communication avec les mères, renforcer l'adhésion thérapeutique et éviter une interruption inutile de l'allaitement.

Monkeypox in pregnancy: virology, clinical presentation, and obstetric management.

The 2022 monkeypox outbreak, caused by the zoonotic monkeypox virus, has spread across 6 World Health Organization regions (the Americas, Africa, Europe, Eastern Mediterranean, Western Pacific, and South-East Asia) and was declared a public health emergency of international concern on July 23, 2022. The global situation is especially concerning given the atypically high rate of person-to-person transmission, which suggests viral evolution to an established human pathogen. Pregnant women are at heightened risk of vertical transmission of the monkeypox virus because of immune vulnerability and natural depletion of population immunity to smallpox among reproductive-age women, and because orthopoxviral cell entry mechanisms can overcome the typically viral-resistant syncytiotrophoblast barrier within the placenta. Data on pregnancy outcomes following monkeypox infection are scarce but include reports of miscarriage, intrauterine demise, preterm birth, and congenital infection. This article forecasts the issues that maternity units might face and proposes guidelines to protect the health of pregnant women and fetuses exposed to the monkeypox virus. We review the pathophysiology and clinical features of monkeypox infection and discuss the obstetrical implications of the unusually high prevalence of anogenital lesions. We describe the use of real-time polymerase chain reaction tests from mucocutaneous and oropharyngeal sites to confirm infection, and share an algorithm for the antenatal management of pregnant women with monkeypox virus exposure. On the basis of the best available knowledge from prenatal orthopoxvirus infections, we discuss the sonographic features of congenital monkeypox and the role of invasive testing in establishing fetal infection. We suggest a protocol for cesarean delivery to avoid the horizontal transmission of the monkeypox virus at birth and address the controversy of mother-infant separation in the postpartum period. Obstetrical concerns related to antiviral therapy with tecovirimat and vaccinia immune globulin are highlighted, including the risks of heart rate-corrected QT-interval prolongation, inaccuracies in blood glucose monitoring, and the predisposition to iatrogenic venous thromboembolism. The possibility of monkeypox vaccine hesitancy during pregnancy is discussed, and strategies are offered to mitigate these risks. Finally, we conclude with a research proposal to address knowledge gaps related to the impact of monkeypox infection on maternal, fetal, and neonatal health.

Prolonged Maternal Zika Viremia as a Marker of Adverse Perinatal Outcomes.

Whether prolonged maternal viremia after Zika virus infection represents a risk factor for maternal-fetal transmission and subsequent adverse outcomes remains unclear. In this prospective cohort study in French Guiana, we enrolled Zika virus-infected pregnant women with a positive PCR result at inclusion and noninfected pregnant women; both groups underwent serologic testing in each trimester and at delivery during January-July 2016. Prolonged viremia was defined as ongoing virus detection >30 days postinfection. Adverse outcomes (fetal loss or neurologic anomalies) were more common in fetuses and neonates from mothers with prolonged viremia (40.0%) compared with those from infected mothers without prolonged viremia (5.3%, adjusted relative risk [aRR] 7.2 [95% CI 0.9-57.6]) or those from noninfected mothers (6.6%, aRR 6.7 [95% CI 3.0-15.1]). Congenital infections were confirmed more often in fetuses and neonates from mothers with prolonged viremia compared with the other 2 groups (60.0% vs. 26.3% vs. 0.0%, aRR 2.3 [95% CI 0.9-5.5]).

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study.

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-ß-exposed pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-ß group (odds ratio, 2.2; 95% confidence interval, 0.2-24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-ß-exposed pregnancies was 0.6 (95% confidence interval, 0.2-1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.

Ability to detect potentially inappropriate prescribing in older patients: comparative analysis between PIM-Check and STOPP/STARTv2.

PURPOSE: Potentially inappropriate prescribing (PIP) is a source of preventable adverse drug events. The objective of this study was a comparative analysis (quantitative and qualitative) between two tools used to detect PIP, PIM-Check and STOPP/START. METHODS: First, a qualitative analysis (QAC) was conducted to evaluate the concordance between the criteria, which constitute PIM-Check and the gold standard STOPP/START. Second, a retrospective comparative and observational study was performed on the list of treatment at the admission of 50 older patients hospitalized in an acute geriatric ward of a university hospital in Switzerland in 2016 using both tools. RESULTS: The QAC has shown that 50% (57 criteria) of STOPP/START criteria are fully or partially concordant with those of PIM-Check. The retrospective study was performed on 50 patients aged 87 years, suffering from 5 co-morbidities (min-max 1-11) and treated by of 8 drugs (min-max 2-16), as medians. The prevalence of the detected PIP was 80% by PIM-Check and 90% by STOPP/START. Medication review shows that 4.2 PIP per patient were detected by PIM-Check and 3.5 PIP by STOPP/START among which 1.9 PIP was commonly detected by both tools, as means. PIM-Check detected more PIP related to cardiology, angiology, nephrology, and endocrinology in older patients but missed the PIP related to geriatric syndromes (e.g., fall, dementia, Alzheimer) detected by STOPP/START. CONCLUSIONS: By using PIM-Check in geriatric settings, some PIP will not be detected. It is considered as a limitation for this tool in this frail population but brings a certain complementarity in other areas of therapy not covered by STOPP/START.

Mental health status of pregnant and breastfeeding women during the COVID-19 pandemic-A multinational cross-sectional study.

INTRODUCTION: Evidence on perinatal mental health during the coronavirus disease 2019 (COVID-19) pandemic and its potential determinants is limited. Therefore, this multinational study aimed to assess the mental health status of pregnant and breastfeeding women during the pandemic, and to explore potential associations between depressive symptoms, anxiety, and stress and women's sociodemographic, health, and reproductive characteristics. MATERIAL AND METHODS: A cross-sectional, web-based study was performed in Ireland, Norway, Switzerland, the Netherlands, and the UK between 16 June and 14 July 2020. Pregnant and breastfeeding women up to 3 months postpartum who were older than 18 years of age were eligible. The online, anonymous survey was promoted through social media and hospital websites. The Edinburgh Depression Scale (EDS), the Generalized Anxiety Disorder seven-item scale (GAD-7), and the Perceived Stress Scale (PSS) were used to assess mental health status. Regression model analysis was used to identify factors associated with poor mental health status. RESULTS: In total, 9041 women participated (including 3907 pregnant and 5134 breastfeeding women). The prevalence of major depressive symptoms (EDS ≥ 13) was 15% in the pregnancy cohort and and 13% the breastfeeding cohort. Moderate to severe generalized anxiety symptoms (GAD ≥ 10) were found among 11% and 10% of the pregnant and breastfeeding women. The mean (±SD) PSS scores for pregnant and breastfeeding women were 14.1 ± 6.6 and 13.7 ± 6.6, respectively. Risk factors associated with poor mental health included having a chronic mental illness, a chronic somatic illness in the postpartum period, smoking, having an unplanned pregnancy, professional status, and living in the UK or Ireland. CONCLUSIONS: This multinational study found high levels of depressive symptoms and generalized anxiety among pregnant and breastfeeding women during the COVID-19 outbreak. The study findings underline the importance of monitoring perinatal mental health during pandemics and other societal crises to safeguard maternal and infant mental health.

Clinical and economic impacts of explicit tools detecting prescribing errors: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Many explicit tools have been developed to reduce prescribing errors and ensure patients' safety. The impact of explicit tools is not well studied. The objective of this study was (a) to conduct a systematic review of systematic reviews listing explicit tools developed to detect prescribing errors and (b) to assess their impact on clinical and economic outcomes. METHODS: This project includes two related parts. First, a systematic review of systematic reviews listing explicit tools dedicated to geriatrics or internal medicine was performed to develop an exhaustive list of explicit tools. Then, using the list compiled in the first step, a systematic review of randomized controlled trials (RCT) assessing clinical or economic impacts of tools was performed to evaluate their usefulness. RESULTS AND DISCUSSION: The systematic review of systematic reviews identified 49 explicit tools. The systematic review of RCT, using one or more of the 49 explicit tools, identified 5 RCT using explicit tools as intervention (3 STOPP/START and 2 FORTA RCT). The 5 studies evaluated clinical impacts with 3 RCT identifying significant clinical impacts (falls, activities of daily living and/or adverse drug reactions) and 2 STOPP/START RCT identifying significant economic impacts. WHAT IS NEW AND CONCLUSION: The systematic review of RCT showed that explicit tools can have some effect in improving patients' safety. Further studies are warranted to better characterize their clinical and economic impact.

Impact of Pharmaceutical Interventions in Hospitalized Patients: A Comparative Study Between Clinical Pharmacists and an Explicit Criteria-Based Tool.

BACKGROUND: It has been well recognized that pharmaceutical interventions (PIs) can prevent patient harm related to prescribing errors. Various tools have been developed to facilitate the detection and the reduction of inappropriate prescriptions and some have shown benefit on clinical outcomes. OBJECTIVE: The objective of this study was to evaluate the clinical, economical, and organizational impact of interventions generated by clinical pharmacists in hospitalized patients, and to evaluate the performance of an explicit tool, the Potentially Inappropriate Medication Checklist for Patients in Internal Medicine (PIM-Check), in detecting each pharmacist's intervention. METHODS: A cohort retrospective study was conducted on hospitalized patients. The impact of PIs based on pharmacists' standard examination was evaluated using the Clinical, Economic, and Organizational (CLEO) tool. The performance of PIM-Check in detecting each intervention was assessed by conducting a retrospective medication review based on available information collected from patients' records. A qualitative analysis was also conducted to identify the types of PIs that PIM-Check failed to detect. RESULTS: The study was performed on 162 patients with a median age of 68 years (interquartile range = 46-77 years) and a median hospital stay of 5 days (interquartile range = 4-7 days). The pharmacists generated 1.9 PIs per patient (n = 304) of which 31% were detected by PIM-Check. The acceptance rate of the interventions by physicians was 84% (n = 255). Among the accepted interventions, 53% (n = 136) had a clinical impact graded CL ≥ 2C (moderate or major), whereas the majority of them were not detected by PIM-Check (63%; 86 out of 136). In addition, 46% of accepted interventions (n = 117) were associated with a cost decrease, among which 62% were not detected by PIM-Check (73 out of 117). The qualitative analysis shows that PIM-Check mostly failed to detect PIs related to dose adjustment, overprescribing, and therapy monitoring. CONCLUSIONS: According to the CLEO tool evaluation of PIs, our results show that clinical pharmacists' interventions are associated with improved clinical outcomes. In comparison with pharmacists' interventions, PIM-Check failed in detecting the majority of interventions associated with a moderate or major impact.

A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk.

BACKGROUND AND OBJECTIVES: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed. METHODS: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation. RESULTS: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average. CONCLUSION: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.

SARS-CoV-2 in the context of past coronaviruses epidemics: Consideration for prenatal care.

Since December 2019, the novel SARS-CoV-2 outbreak has resulted in millions of cases and more than 200 000 deaths worldwide. The clinical course among nonpregnant women has been described, but data about potential risks for women and their fetus remain scarce. The SARS and MERS epidemics were responsible for miscarriages, adverse fetal and neonatal outcomes, and maternal deaths. For COVID-19 infection, only nine cases of maternal death have been reported as of 22 April 2020, and pregnant women seem to develop the same clinical presentation as the general population. However, severe maternal cases, as well as prematurity, fetal distress, and stillbirth among newborns have been reported. The SARS-CoV-2 pandemic greatly impacts prenatal management and surveillance and raise the need for clear unanimous guidelines. In this narrative review, we describe the current knowledge about coronaviruses (SARS, MERS, and SARS-CoV-2) risks and consequences on pregnancies, and we summarize available current candidate therapeutic options for pregnant women. Finally, we compare current guidance proposed by The Royal College of Obstetricians and Gynaecologists, The American College of Obstetricians and Gynecologists, and the World Health Organization to give an overview of prenatal management which should be utilized until future data appear.

Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance.

PURPOSE: The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. METHODS: Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. RESULTS: We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. CONCLUSIONS: Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.