Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-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. DESIGN: This 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. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This 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. RESULTS: Exposure 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. CONCLUSIONS: This 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.

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy.

In March 2022, the Summary of Product Characteristics for the Lyrica brand of pregabalin was updated with warnings regarding malformation risks. This literature review and critical appraisal aims to explore whether these Summary of Product Characteristics updates are justified and provide clarity on the risk-benefit balance for pregabalin use in early pregnancy. A literature review was conducted in May 2022 to identify English language comparative studies of any design providing data about first trimester maternal pregabalin use and malformation risk. Five observational comparative cohort studies using data from 9 distinct datasets were located. Collectively these studies described at least 5300 unique pregabalin exposed pregnancies, with 4900 exposed in at least the first trimester. Three studies investigated overall major malformation risks, and 4 investigated specific malformation risks. The available evidence was found to be conflicting and generally of low quality, probably influenced by bias and data confounding, with no clear pattern of specific malformations observed. Findings from the largest study suggested absolute risks of major malformation of 4.8-5.6%, relative to a background risk of approximately 4%. Due to study methodology limitations, the available data were judged to only provide low quality evidence suggestive of a possible and unconfirmed small increased risk that cannot be solely attributed to foetal pregabalin exposure. This literature review and critical appraisal indicates that the Lyrica product literature updates are insufficiently substantiated and could result in confusion and misinformed clinical risk-benefit decision making.

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.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) During Pregnancy and the Risk for Autism spectrum disorder (ASD) and Attention deficit hyperactivity disorder (ADHD) in the Offspring: A True Effect or a Bias? A Systematic Review & Meta-Analysis.

BACKGROUND AND OBJECTIVE: An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis. METHODS: Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random- effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study. RESULTS: Eighteen studies were included in the meta-analysis. We found an association between SSRIs/ SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23-1.65, I2=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I2=0%) in the Offspring, although they were not exposed to those medications in utero. CONCLUSIONS: Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.

Pregnancy outcome after first trimester exposure to vortioxetine: A case series.

BACKGROUND: The objective of this study was to collect outcome after vortioxetine exposure during the first trimester of pregnancy in a case series. METHODS: Callers who were counseled by the Israeli Teratology Information Service (TIS) regarding vortioxetine exposure during pregnancy were prospectively collected and followed-up by telephone using a structured questionnaire. Outcomes were confirmed by a pediatrician with medical records in the neonatal period. RESULTS: Between 2016 and 2019, a total of 19 women were included in the TIS database after first trimester exposure to vortioxetine. Seventeen pregnancy follow-ups were obtained, while two pregnancies were lost to follow-up. Eleven pregnancies resulted in 12 live births with no malformations including one set of twins; there were three miscarriages, two terminations, and one stillbirth in week 22. One termination was performed due to prenatal diagnosis of acrania (the woman also took carbamazepine, folic acid and dipyrone), and the second due to fear of abnormalities after cystic hygroma was suspected at week 12 with nuchal translucency of 8.1 mm and no further cytogenetic testing. The twins were born in week 35. Two women continued using the medication until delivery; one of these women reported nursing her baby from birth to up to 1 year, while she continued taking vortioxetine. DISCUSSION: This case series provides preliminary outcome data on vortioxetine exposure in pregnancy. However, the small sample size calls for caution in the interpretation of results. Denominator-based studies are needed before conclusions can be drawn.

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.

Pregnancy outcome following in-utero exposure to ondansetron: A prospective comparative observational study.

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10-0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08-0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Cutaneous Leishmaniasis: Case Series on Pregnancy Outcome.

We report the pregnancy outcomes of 6 women with cutaneous leishmaniasis; 5 of these women received topical antileishmenial therapy during gestation with paromomycin plus methylbenzethonium chloride combination ointment and/or sodium stibogluconate intralesional injections. No teratogenic effects were reported. Furthermore, no vertical transmission was observed.

Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study.

OBJECTIVE: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin-angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. METHODS: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. RESULTS: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. CONCLUSION: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I.

In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: A prospective comparative observational study.

OBJECTIVE: To evaluate the rate of major anomalies after first trimester (T1)-metformin exposure. DESIGN: Comparative, observational cohort study done at the Israeli Teratology Information Service between 2000 and 2013. RESULTS: 170 T1-metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE) pregnancies. The differences in the rate of major anomalies excluding genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5% (2/80) - insulin, and 1.7% (9/519) - NTE; ORadj metformin/NTE 1.77; 95% CI 0.45-7.01; ORadj insulin/NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) groups compared with the NTE group [138/503 (27.4%)]. CONCLUSION: Metformin-T1-exposure per se is not associated with an increased risk of major anomalies.

Is it safe to use lamotrigine during pregnancy? A prospective comparative observational study.

BACKGROUND: Lamotrigine is a second-generation antiepileptic drug, also used as a mood stabilizer. Published data on its use in human pregnancy are largely derived from pregnancy registries. Pregnancy experience in most studies has been reassuring. However, data from the North American Antiepileptic Drug Pregnancy Registry suggested an increased risk for oral clefts. The primary objective of the study was to evaluate the rate of major anomalies after lamotrigine exposure during pregnancy compared with pregnancies of women counseled for nonteratogenic exposure (NTE). METHODS: Callers who contacted the Israeli Teratology Information Service regarding lamotrigine treatment or NTE during pregnancy between 1997 and 2008 were prospectively followed-up. RESULTS: The rate of major congenital anomalies was similar between 218 lamotrigine exposed pregnancies (208 in the first trimester) and 865 NTE-pregnancies. There was no case of oral cleft in the lamotrigine-exposed group. The median lamotrigine dose in the beginning of pregnancy was 200 mg/d. The dose was increased during pregnancy in 29%. The majority of women in the cohort (82%) were treated for neurologic indications, while 18% for psychiatric disorders. Monotherapy was taken by 72%. CONCLUSION: The data available, thus far, on lamotrigine monotherpy-exposed pregnancies are encouraging. However, further studies are needed to determine with greater certainty the overall risk for major anomalies, as well as the specific risk for oral clefts. Based on the current and previously published data, lamotrigine, seems a reasonable alternative for pregnant women when clinically indicated. Birth Defects Research 109:1196-1203, 2017. © 2017 Wiley Periodicals, Inc.

Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study.

INTRODUCTION: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications. METHODS: In a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact. RESULTS: 382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001). CONCLUSIONS: The present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages.

Pregnancy outcome after in utero exposure to local anesthetics as part of dental treatment: A prospective comparative cohort study.

BACKGROUND: Dental treatment and use of local anesthetics during pregnancy generally are considered harmless because of lack of evidence of adverse pregnancy effects. Data on the safety of dental treatment and local anesthetics during pregnancy are scant. Dental care is often a reason for concern both among women and their health care providers. The primary objective of this study was to evaluate the rate of major anomalies after exposure to local anesthetics as part of dental care during pregnancy. METHODS: The authors performed a prospective, comparative observational study at the Israeli Teratology Information Services between 1999 and 2005. RESULTS: The authors followed 210 pregnancies exposed to dental local anesthetics (112 [53%] in the first trimester) and compared them with 794 pregnancies not exposed to teratogens. The rate of major anomalies was not significantly different between the groups (4.8% versus 3.3%, P = .300). There was no difference in the rate of miscarriages, gestational age at delivery, or birth weight. The most common types of dental treatment were endodontic treatment (43%), tooth extraction (31%), and tooth restoration (21%). Most women (63%) were not exposed to additional medications. Approximately one-half (51%) of the women were not exposed to dental radiography, and 44% were exposed to radiation, mostly bite-wing radiography. CONCLUSIONS: This study's results suggest that use of dental local anesthetics, as well as dental treatment during pregnancy, do not represent a major teratogenic risk. PRACTICAL IMPLICATIONS: There seems to be no reason to prevent pregnant women from receiving dental treatment and local anesthetics during pregnancy.