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…).

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.

[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.

Overuse of antenatal visits and ultrasounds in low-risk women: A national population-based study.

BACKGROUND: A better understanding of the overuse of antenatal care is needed to improve its organisation to deal with limited medical resources and doctor shortages. OBJECTIVES: To assess the proportion of women who overuse antenatal care and the associations of overuse with maternal characteristics and the qualifications of healthcare providers. METHODS: We used the 2016 National Perinatal Survey, a cross-sectional population-based survey, performed in all maternity units in France, including 13,132 women. Based on the French national guidelines, 6-8 antenatal visits were defined as adequate, 9-11 as high use, and ≥12 as overuse, while 3 ultrasounds were considered adequate, 4-5 as high use, and ≥6 as overuse. We performed binary modified Poisson regressions-with adequate care as the reference-including maternal social and medical characteristics and the healthcare professionals' qualifications. RESULTS: After women with inadequate care were excluded, 19.2% of low-risk women had at least 12 visits and 30.5% at least 6 ultrasounds. Overuse of visits was associated with primiparity, average to high income, less than good psychological well-being, and care by an obstetrician. The risks of overuse of ultrasounds were higher among primiparous, women with average to high income and those receiving care from a public-sector obstetrician (adjusted relative risk 1.17, 95% CI, 1.13, 1.21) or private obstetrician (adjusted relative risk 1.12, 95% CI, 1.07, 1.16), compared with a public-sector midwife. CONCLUSIONS: Antenatal care overuse is very common in France and associated with some maternal characteristics and also the qualification of care provider. Antenatal care should be customised according to women's needs, in particular for primiparae and those with poor well-being, and available medical resources.

Potential avoidability of planned cesarean sections in a French national database.

OBJECTIVE: To study the frequency and determinants of potentially avoidable planned cesarean sections, with a classification based on their indications, maternal obstetric history, and information about the current pregnancy. DESIGN: Cross-sectional population-based study. SETTING: All maternity units in France (n = 535). POPULATION: A total of 14,681 women from the 2010 French National Perinatal Survey, a routine survey of a representative sample of births. METHODS: Planned cesareans were classified in two groups: potentially avoidable and unavoidable. The classification was based on the French national guidelines and used data from medical records. We used logistic regression analyses to compare characteristics of the mothers with potentially avoidable cesareans with those of women who had a trial of labor. Analyses were performed separately in primiparas and multiparas. MAIN OUTCOME MEASURE: Rate of potentially avoidable planned cesarean sections. RESULTS: The overall planned cesarean rate was 10.9%; 28% of these cesareans were found to be potentially avoidable. Breech presentation and history of one previous cesarean accounted for 83% of them. Determinants of potential avoidability were maternal age >35 years, intensive surveillance during pregnancy, and private status of the unit [adjusted odds ratio (OR) 1.9, 95% CI 1.2-3.2 among primiparas; adjusted OR 2.5, 95% CI 1.5-4.3 among multiparas]. Obesity was also a significant determinant but only among multiparas (adjusted OR 2.7, 95% CI 1.9-3.8). No association was found with maternal social characteristics. CONCLUSION: Our results suggest a high proportion of potentially avoidable cesareans and highlight the associated obstetric situations. They can help to target policies aimed at reducing cesarean rates.

Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003.

OBJECTIVE: To assess the efficiency of the French national screening program for 21-hydroxylase deficiency (21-OHD). Neonatal screening for congenital adrenal hyperplasia due to 21-OHD is mainly intended to prevent death due to salt wasting but remains controversial because of the number of false-positive results and the ease with which most female cases can be identified by virilized genitalia at birth. DESIGN: Population-based study. SETTING: National neonatal screening program, pediatric endocrinologists nationwide, and reference center for genotyping. PARTICIPANTS: All neonates screened for 21-OHD in mainland France between January 1, 1996, and December 31, 2003. OUTCOME MEASURES: Screening efficiency indicators, disease severity, contribution of screening to early diagnosis, and disease-specific mortality before and during the study period. RESULTS: A total of 6,012,798 neonates were screened; results in 15,407 were considered positive for 21-OHD. Three hundred eighty-three cases were identified, giving a prevalence of 1 for every 15,699 births. The positive predictive value of screening was 2.3% (95% CI, 2.1%-2.6%), with a sensitivity of 93.5% (90.9%-95.9%) and a specificity of 99.7% (99.7%-99.7%). The false-positive rate was particularly high in preterm infants, for which the positive predictive value was 0.4% (95% CI, 0.2%-0.5%). Screening allowed clinical diagnosis in 162 of 383 cases (42.3%), with the others being detected clinically or through family history. There was a trend toward declining neonatal mortality due to 21-OHD. CONCLUSIONS: In this large population-based study, the efficiency of routine 21-OHD screening was moderate in neonates born at term and very low in preterm neonates. We recommend the discontinuation of screening, as currently performed in France, in preterm neonates.

Obstetric interventions for low-risk pregnant women in France: do maternity unit characteristics make a difference?

BACKGROUND: In many countries the closure of small maternity units has raised concerns about how the concentration of low-risk pregnancies in large specialized units might affect the management of childbirth. We aimed to assess the role of maternity unit characteristics on obstetric intervention rates among low-risk women in France. METHODS: Data on low-risk deliveries came from the 2010 French National Perinatal Survey of a representative sample of births (n = 9,530). The maternity unit characteristics studied were size, level of care, and private or public status; the interventions included induction of labor; cesarean section; operative vaginal delivery (forceps, spatulas or vacuum); and episiotomy. Multilevel logistic regression analyses were adjusted for maternal confounding factors, gestational age, and infant birthweight. RESULTS: The rates of induction, cesarean section, operative delivery, and episiotomy in this low-risk population were 23.9 percent, 10.1 percent, 15.2 percent, and 19.6 percent, respectively, and 52.0 percent of deliveries included at least one of them. Unit size was unrelated to any intervention except operative delivery (adjusted odds ratio [aOR] = 1.47 (95% CI, 1.10-1.96) for units with >3,000 deliveries per year vs units with <1,000). The rate of every intervention was higher in private units, and the aOR for any intervention was 1.82 (95% CI, 1.59-2.08). After adjustment for maternal characteristics and facility size and status, significant variations in the use of interventions remained between units, especially for episiotomies. Results for level of care were similar to those for unit size. CONCLUSIONS: The concentration of births in large maternity units in France is not associated with higher rates of interventions for low-risk births. The situation in private units could be explained by differences in the organization of care. Additional research should explore the differences in practices between maternity units with similar characteristics.