[The new version of the french teratology information service « CRAT ¼ website]. / La nouvelle version du site internet du Centre de Référence sur les Agents Tératogènes et ses fonctionnalités optimisées.

The Centre de Référence sur les Agents Tératogènes (CRAT) is a unique french national reference center involved in the risk assessment of exogenous agents (mainly drugs, but also medical imaging and addictions) on pregnancy, breastfeeding and fertility. To help improve patient care, CRAT makes its expertise available to healthcare professionals via its website (www.lecrat.fr), a free, independent and public online resource regularly updated by its multidisciplinary team. In December 2023, a new version was launched, based on the evolutions desired by the CRAT team and on a satisfaction survey of website's users. A predictive search bar integrated into the home page now enables users to find the specific information they are looking for more quickly. To optimize the access via smartphones, a mobile version is now available.

Post-Conceptional Exposure to Clomiphene Citrate and Congenital Malformations: A Cohort Study.

BACKGROUND: Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies. OBJECTIVES: The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring. METHODS: A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification. RESULTS: Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern. CONCLUSIONS: Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.

[Use of anti-IL-1 drugs during pregnancy]. / État des lieux sur les anti-IL-1 chez la femme enceinte.

Anti-Interleukin-1 (Anti-IL-1) drugs are used to treat some chronic rheumatic diseases that can affect young people, including women of childbearing age. Two anti-IL-1 drugs are available in France: anakinra and canakinumab. Data on their use during pregnancy are still limited. Based on the published literature, we carried out a review of the use of these anti-IL-1 therapies during pregnancy: therapeutic indications, pharmacological profiles and assessment of embryonic, fetal and neonatal risks. Based on this analysis, and given the absence of any reported concern, it is possible to consider the use of these two treatments during pregnancy if the clinical situation so requires and under certain conditions. Based on the data available to date, anakinra should be preferred to canakinumab whenever possible.

[Evaluation of the satisfaction of healthcare professionals using the CRAT website, and launch of a new version]. / Évaluation de la satisfaction des professionnels de santé utilisateurs du site internet du CRAT et lancement d'une nouvelle version.

In preparation for a new version of the CRAT (Centre de référence sur les agents tératogènes) website, an evaluation of user satisfaction was carried out. An invitation to complete an online questionnaire covering the various dimensions of the website (appearance, content, interactivity, ease of use, technical performance) was sent in April 2022 to healthcare professionals who referred to CRAT for clinical expertise over the previous two years. After sending out 3224 individual e-mail invitations, 758 evaluators completed the questionnaire in full (response rate: 23.5%). The evaluation revealed a high-level of overall satisfaction among site users (98.0% very satisfied or satisfied). Satisfaction with the site's appearance was also high, although comments were made about the site's lack of a modern web design. Health professionals recognized in their responses the reliable, relevant and up-to-date nature of the content of this free, public online resource, independent of the pharmaceutical industry. On the basis of these highly favorable assessments, with content that has been widely acclaimed and areas for improvement that have caught the attention of site users (evolution of its appearance, of the search tool, implementation of a mobile site), a new version of www.lecrat.fr was launched in the fall of 2023.

[Varicella vaccination, pregnancy and breastfeeding: The current situation]. / Vaccination contre la varicelle, grossesse et allaitement : un état des lieux.

The varicella vaccine is recommended for women with no history of varicella who are planning to become pregnant, as well as for post-pregnancy women, to prevent the occurrence of this illness and its severe complications, especially an embryopathy, when it occurs in a pregnant woman (congenital varicella syndrome). This live attenuated vaccine should not be administered during pregnancy, nor in the month preceding it. However, when this occurs inadvertently, the data collected on the outcomes of exposed pregnancies, although few in women seronegative at the time of vaccination, allow to reassure the patients to date, as no congenital varicella syndrome has been reported to date following accidental vaccination in early pregnancy. On the other hand, during breastfeeding, a woman may be vaccinated if there is an expected short- or medium-term benefit (varicella exposure, planned pregnancy…).

Congenital Rubella Syndrome Following Rubella Vaccination During Pregnancy.

Rubella vaccine is usually given in combination with measles and mumps vaccines as a measles-mumps-rubella vaccination. Because it contains live attenuated virus, its use is contraindicated during pregnancy. However, since the introduction of rubella vaccine, no cases of congenital rubella syndrome have been reported following vaccination during pregnancy. We report a case of a female infant, born to a woman inadvertently vaccinated with measles-mumps-rubella vaccination early in pregnancy, who manifested a phenotype of cardiac and neurologic defects, neurodevelopmental delay, and lymphocytopenia consistent with congenital rubella syndrome.

[Clinical monitoring of children with in utero exposure to angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers]. / Toxicité fœtale et néonatale des inhibiteurs de l'enzyme de conversion et des sartans : quelle surveillance pour les enfants exposés in utero ?

Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers are widely used to reduce high blood pressure or in other conditions such as congestive heart failure and prevention of diabetic nephropathy. To date, no teratogenic effect has been attributed to them, but in the 2nd and 3rd trimesters of pregnancy, their foetotoxicity is broadly documented: transient oligohydramnios or anamnios, associated to possible neonatal anuria and permanent renal damage, which can lead to intrauterine or neonatal death. Long-term effects among children with in utero exposure are poorly known, but the regression of an oligohydramnios might not always be associated with normal renal function after birth or later in life. This justifies seeking the advice of a pediatric nephrologistto consider the most appropriate monitoring for the child at birth and in the following weeks, and possibly beyond, even in case of normal prenatal ultrasound.

[Centre de référence sur les agents tératogènes (CRAT): a pioneer center]. / Le Centre de référence sur les agents tératogènes (CRAT) : une structure pionnière.

Le Centre de référence sur les agents tératogènes (CRAT), founded in 1975, is the first national and international public organization especially involved in the problem of drugs during pregnancy, and during this period of time has been responsible for many initiatives in this field: health care providers information and counsel service, innovating risk assessment methodology, new method for clinical data collection leading to a database including more than 50 000 exposed pregnancies, innovative free access internet website (http://www.lecrat.org), multidisciplinary expert group in French medicines agencies (Afssaps/ANSM) and foundation of a European network "European network teratology information service" (ENTIS). All these innovations represent consequent advances and contribute to a better management of exposed pregnant women and their newborns, as well as the survey and signal detection during pregnancy. The CRAT is also involved in the field of drugs on fertility and on paternal exposures.

Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study.

Misoprostol during the first trimester of pregnancy is associated with a specific malformative pattern (Moebius sequence and limb defects) whose incidence remains unknown. Data originate mostly from illegal use for abortion and are mainly retrospective. The present prospective controlled study analyses outcomes of first trimester misoprostol exposures after medical prescriptions. Malformation rate was higher among 236 pregnancies exposed before 12 gestational weeks (4%) than in 255 controls (1.8%), although not statistically significant (OR=2.2 [95% CI=0.6-7.7]). Three malformations (2%) in the exposed group were consistent with the misoprostol malformative pattern. This is the largest prospective study on first trimester misoprostol exposure and the first one relying on prescriptions. A trend toward a doubling of the overall rate of malformations was observed and for the first time an estimation of the incidence of misoprostol specific spectrum is proposed (2%). Brainstem injuries including severe trismus might be added to this specific pattern.

Paternal exposure to methotrexate and pregnancy outcomes.

OBJECTIVE: To assess the risk of major malformation in the case of paternal exposure to methotrexate (MTX) at the time of conception. METHODS: Using prospective data of our Teratology Information Service, we analyzed outcomes of paternal MTX exposure at the time of conception or up to 3 months before conception. RESULTS: We report on the outcomes of 42 pregnancies involving 40 men treated with MTX at the time of conception. Twenty-three men were treated for an inflammatory disease (54.8%), 9 for psoriasis (21.4%), and 8 for a malignant disease (19.0%). Weekly dosages varied between 7.5 mg and 30 mg. The pregnancies resulted in 36 live births, 3 spontaneous abortions, and 3 voluntary abortions. No congenital malformation was observed at birth. CONCLUSION: Based on our results and case reports in literature, paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring.

Rheumatology drugs and pregnancy.

Medication exposure during pregnancy, especially in the first trimester, is a common event that causes considerable concern among patients and healthcare professionals alike. Once the pregnancy is known, the response often consists in stopping or substantially diminishing the use of medications. Some medications are teratogenic and/or fetotoxic, requiring effective birth control and prior information of women of childbearing potential. Nevertheless, limiting the use of medications out of a sense of caution is warranted only if no major adverse impact on the mother is expected throughout the 9 months of the pregnancy. Treatment decisions during pregnancy should rest on a careful reappraisal of treatment practices and on an in-depth evaluation of the risk/benefit ratio of each medication. Here, we will discuss the main rheumatology drug classes whose use during pregnancy is most likely to cause concern.

[Immunosuppressants for auto-immune diseases and pregnancy]. / Immunosuppresseurs utilisés dans les maladies systémiques: que faire en cas de grossesse?

Therapeutic stability of a systemic disease is a priority during pregnancy. To stop an effective treatment, to reduce dosages or to switch to less effective treatments might induce some loss of chance for pregnant women, and eventually harmful consequences for fetuses. Due to the teratogenic effects of some immunosuppressants, childbearing susceptible women should use effective contraception and be informed of risks in case of pregnancy. A pre-conceptional consultation is of interest, allowing an adaptation of treatment and advices before pregnancy is ongoing. Mycophenolate is highly suspected to be teratogenic in humans. Mycophenolate should not be prescribed in women of childbearing potential unless some criteria are met. Maternal (even fetal) infectious conditions can occur during immunosuppressive treatments. Therefore, obstetricians and pediatricians should be aware of the maternal treatment in order to allow adequate monitoring of the mother and the neonate.