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.

Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences?

The aim of this retrospective cohort study was to investigate the incidence of delayed methotrexate elimination in patients treated with high-dose methotrexate (≥1 g/m2 ) for haematological malignancy and to identify the impact of interacting drugs, especially proton-pump inhibitors (PPIs) and ranitidine. All patients treated with high-dose methotrexate over a 6 year period in the haematology department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) were included. Potential risk factors for delayed methotrexate elimination were tested in a generalized linear model by univariate analysis: patient age, gender, methotrexate dose, administration of PPI or ranitidine, and concomitant nephrotoxic drugs. A total of 412 cycles of methotrexate were administered to 179 patients. Proton-pump inhibitors were co-administered with methotrexate in 127 cycles and ranitidine in 192 cycles. Ninety-three cycles included no antacid drugs. A total of 918 plasma methotrexate assays were performed. Methotrexate concentrations were checked at 24 hours in 92% of cycles. Delayed methotrexate elimination was observed in 20.9% of cycles. A total of 63 cycles with delayed methotrexate elimination were only identified on plasma methotrexate measures at 72 hours: ie, plasma methotrexate was in the normal range at 24 and 48 hour post injection. Use of PPI/ranitidine or no antacid drugs did not increase risk of delayed elimination, with respectively delayed methotrexate elimination in 20.5%, 21.9%, and 19.4% of cycles (P = .89). Impaired baseline creatinine clearance showed significant association in univariate analysis. Fifteen patients showed grade 1 acute kidney injury, 1 grade 2, 2 grade 3, and none grade 4. For half of these cases, delayed methotrexate elimination was observed and the 2 grade 3 events appeared in patients treated with PPIs. This retrospective study suggests that there is no association between concomitant use of proton-pump inhibitors (pantoprazole and esomeprazole) or ranitidine and delayed methotrexate elimination.

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.

Pregnancy outcomes in women exposed to cancer chemotherapy.

PURPOSE: There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database. METHODS: We performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database. RESULTS: In total, 75 questions about "anti-cancer drugs and pregnancy" received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies. CONCLUSION: Pregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs.

Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study.

AIM OF THE STUDY: To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity. METHOD: Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only. RESULTS: From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR=1.36; 95%CI: 0.44-4.20]) nor with major birth defects (5.2% vs. 1.8% [OR=2.96; 95%CI: 0.56-15.64]). The rate of preterm births (22.5% vs. 27.3%, P=0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only). CONCLUSIONS: This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

Nicorandil-induced ulcerations: a 10-year observational study of all cases spontaneously reported to the French pharmacovigilance network.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

[Fibrates and risk of venous thromboembolism: Case/no-case study in French pharmacovigilance database]. / Fibrates et risques thrombo-emboliques veineux : étude cas/non-cas dans la base nationale de pharmacovigilance.

INTRODUCTION: Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates. MATERIALS AND METHODS: Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol). RESULTS: We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR=1.83; 95% CI=[1.53; 2.2]) but not with other fibrates: bézafibrate (ROR=0.44; 95% CI=[0.2; 0.99]), ciprofibrate (ROR=1.15; 95% CI=[0.76; 1.73]) and gemfibrozil (ROR=0.91; 95% CI=[0.45; 1.84]). CONCLUSION: With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

French pharmacovigilance: Missions, organization and perspectives.

Pharmacovigilance aims to identify unknown adverse drug reactions once clinical development is complete, in order to promote improved use of drugs, and thus a reduction in risk for every exposed patient. We describe in this article the missions of French pharmacovigilance system, including French drug agency, Regional Centers of Pharmacovigilance, health professionals, pharmaceutical companies, patients and their associations. We also develop the French pharmacovigilance organization, its perspectives and challenges, both in French and European levels.

Exposure to aripiprazole during embryogenesis: a prospective multicenter cohort study.

PURPOSE: The main purpose of this study was to evaluate the risk of major malformations after aripiprazole exposure during the embryonic period. The secondary purposes were to assess the risk of miscarriage, prematurity, fetal growth retardation and maternal complications and to describe possible neonatal adverse effects. METHODS: We conducted a cohort study using data prospectively collected by the French Pharmacovigilance Centres participating to the Terappel program and the Centre de Référence sur les Agents Tératogènes between 2004 and 2011. The exposed group consisted of pregnant women exposed to aripiprazole during embryogenesis, and the unexposed group consisted of pregnant women without exposure or exposed to non-teratogenic agents. Two unexposed patients, matched for age and gestational age at call, were randomly selected for each exposed patient. RESULTS: Eighty-six patients were included in the exposed group and 172 in the unexposed group. Exposure to aripiprazole was not significantly associated with an increased rate of major malformations (OR 2.30, 95%CI 0.32-16.7) or miscarriage (1.66, 0.63-4.38) or gestational diabetes (1.15, 0.33-4.04) compared to non-exposure. The study revealed significantly increased rates of prematurity (OR 2.57, 95%CI 1.06-6.27) and fetal growth retardation (2.97, 1.23-7.16) in exposed newborns, difficult to interpret because of the short duration of maternal exposure. Two cases of neonatal complications were reported among the 19 newborns exposed to aripiprazole near delivery. CONCLUSION: This study failed to demonstrate a significant association between aripiprazole exposure during the embryonic period and major malformations. More powerful prospective studies are required to clarify the reproductive safety profile of aripiprazole.

[Proton Pump Inhibitor and High-dose Methotrexate: Two Cases Reports]. / Inhibiteurs de pompe à proton et méthotrexate haute dose : à propos de deux cas.

Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20 mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.

[Terappel: description of a computerised database and examples of studies]. / Terappel : description et exemple(s) d'exploitation.

Risk assessment and recommendations regarding the use of medicines during pregnancy or in women of childbearing age is an important task of pharmacovigilance. As a drug information resource, the network of French regional pharmacovigilance centres is involved in providing a personalized risk assessment and individualized counselling during pregnancy. It must also ensure systematic follow-up of exposed pregnancies for which it has been contacted. To ensure harmonized data collection and follow-up, a dedicated database was set-up in 1984 by the Lyon pharmacovigilance centre, which was later made available to 18 other centres. Prospective data from this database is regularly used by the network for descriptive or comparative collaborative studies at the national level or by participating to studies initiated by the European Network of Teratology Information Services in order to provide information on the safety profile of drug exposure in pregnant women. The characteristics of this database and examples of utilization are described in this article.

Imiquimod and pulmonary embolism: a case report.

Bilateral pulmonary embolism possibly related due to topically applied imiquimod is reported in a 47-year-old male patient with no evidence of risk factors.

[Balancing drug regulation and health democracy: The role of patient and healthcare professional advisors at the ANSM]. / Concilier régulation du médicament et démocratie sanitaire : rôle des conseillers patient ou professionnel de santé à l'ANSM.

The French National Agency for Health Products (ANSM) is a regulatory and public health agency. Its regulatory, health policing and public health protection activities require a perfect fit with the field and the various people involved in the use of health products. Since 2019, the ANSM has adapted its organisation, procedures and processes to encourage and improve interaction with its stakeholders, as part of its policy of openness towards civil society. To accompany this ambitious change and to support its staff, the Agency has recruited advisors corresponding to the main users of health products: prescribers (doctor's hospital and outpatient), pharmacists and patients. Working as a group or individually, they provide a "lived" user perspective on health products at each stage of the evaluation process. They may be involved in the assessment of dossiers, signals or applications received by the Agency, in the internal validation of reports or in discussions with stakeholders. They are particularly involved when the analysis requires expertise that goes beyond the technical, scientific or regulatory aspects. They may also work with ANSM staff to explain certain processes and difficulties in the field. Advisors help to ensure that regulatory and/or scientific expertise is clear and consistent with user experience. In addition to their scientific and therapeutic aspects, medicines are also economic, social and political issues. Their regulation is therefore particularly affected by the need for health democracy. This requires the active participation of health professionals, patients and, more broadly, civil society in the decision-making process. Civil society is a space occupied by a wide range of actors who exert pressure from different ideological positions to influence the regulation of health products. In this context, taking into account a plurality of viewpoints in the regulation of health products is necessary and complex, but its operation can be facilitated by the collective efforts of the actors and the adaptation of organisations, such as the integration of advisors.

Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs.

AIMS: The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs. METHODS: Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared. RESULTS: Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 ± 21 vs. 69.4 ± 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 ± 0.9 mmol l(-1) in the DXP group compared with 2.5 ± 1 mmol l(-1) in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8). CONCLUSIONS: Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP.

Lacosamide use during breastfeeding: A case report and a literature review.

Lacosamide, a voltage-gated sodium channel inhibitor, is an anti-seizure medication (ASM) from the age of 4. We report on the case of a woman treated with lacosamide for pharmacoresistant epilepsy who breastfed her infant for more than 6 months after birth. The infant's blood concentrations of lacosamide were 2.4 mg/L on Day 1 and less than 1 mg/L on Day 10 (reference values are 1-10 mg/L). No adverse drug reactions (ADRs) were reported for the infant. Eight cases of breastfeeding by mothers receiving lacosamide are described in the literature. These data confirm that a significant amount of lacosamide seems to pass into breast milk, with a relative infant dose (RID) above 20% in two cases but a low RID (1.8%) in another case. Nevertheless, blood tests, performed in two breastfed infants, revealed low concentrations of lacosamide. No ADRs were reported in eight of the breastfed infants; however, one infant, whose mother was also treated with levetiracetam, presented poor feeding and sleepiness at Day 15 of life. Given the well-known benefits of breastfeeding for both mothers and their infants, as well as the above reassuring data, breastfeeding of healthy full-term infants could be possible for mothers on lacosamide monotherapy. Nonetheless, relatives should be warned that data concerning the safety of lacosamide during breastfeeding are scarce and that long-term neurodevelopment outcomes in breastfed children are unknown. Clinical monitoring of breastfed infants for drowsiness, adequate weight gain, or cutaneous rash is recommended. Additionally, the infants' serum levels should be measured in case of an unexplained adverse reaction.

Vaccines and Bell's palsy: A narrative review.

The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results.

Prevention and management of health products shortages by the French national agency (ANSM), 10 years of experience.

Shortages of drugs and medical devices have tended to increase in France and worldwide, with consequences for patients and healthcare professionals. Preventing shortages of health products has become a priority for regulatory authorities, including the French National Agency for Medicines and Health Products Safety (ANSM). To highlight perspectives for a better prevention, we described and analyzed the management of shortages in the availability of health products in France over the last 10 years. The supply chain was mapped to identify the main causes of shortages and stakeholders involved in managing shortages throughout the supply chain. National and European initiatives and regulatory measures were reviewed. A retrospective nationwide data analysis from the French reporting system of health product shortage reports was conducted over 10 years for drugs (2013-2022) and over an 18-month period for medical devices, from 1st March 2022 to 31st August 2023. An increase in drug shortage reports was observed, rising from 404 in 2013 to 3,761 in 2022 for drugs, with a relatively constant distribution of affected therapeutic classes. In 2022, the main reported causes of drug shortage risk were insufficient production capacity (27.1%), increased sales volume (21.5%), or lack of supply (13.6%). Over half of the reports on medical devices (55.4%) were objectified as indispensable, and their causes were mainly due to a lack of supply (48.2%), discontinuation of marketing (14.9%), increased sales volume (13.2%), and regulatory reasons (9.6%). ANSM and French authorities have engaged a public health policy for prevention and management of health product shortages including financial penalties, minimum safety stocks for Major Therapeutic Interest drugs, and a shortage management plan. Based on 10 years of experience, four priority measures have been identified to anticipate the risk of heath products shortages based: the importance of a national coordination from raw materials to local market, the implementation of new prevention and management actions in the supply chain, strengthening European cooperation and regulation including the establishment of a list of critical drugs, and promoting transparency and information.

Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services.

After maternal exposure to mycophenolate in pregnancy a high number of fetal losses and a specific pattern of birth defects consisting of microtia, cleft lip, and other anomalies have been reported. However, so far, prospective data on pregnancy outcome allowing quantitative risk assessment are missing. We report on 57 prospectively ascertained pregnancies after maternal therapy with mycophenolate (mycophenolate mofetil or mycophenolate sodium) identified by European Teratology Information Services (ETIS) through their risk consultation process. The outcome of these prospective pregnancies was as follows: 16 spontaneous abortions, 12 elective terminations of pregnancy (ETOP) (including two late terminations for multiple malformations consistent with mycophenolate embryopathy), and 29 liveborn infants. The probability of spontaneous abortion was about 45% (95% CI 29 to 66%) estimated using survival analysis technique. Six out of 29 live born infants had major congenital defects: Two with external auditory canal atresia (EACA) (with and without microtia), one with tracheo-esophageal atresia, one with severe hydronephrosis, one with an atrial septal defect (ASD) and one with a myelomeningocele. Thus, at least four fetuses/infants of our prospective case series had a clinical phenotype consistent with mycophenolate embryopathy. Our results confirm a high incidence of major malformations (26%) after first trimester exposure to mycophenolate. Apart from exposure to mycophenololate, the underlying maternal disease and concomitant medication may also have contributed to the other poor pregnancy outcomes such as a high rate of spontaneous abortions, prematurity (62%), and low birth weight (31%).