What reproductive follow-up for adolescent and young women after cancer? A review.

Fertility capacity has been shown to be one of the main concerns of young cancer survivors. Gonadotoxic treatments may lead to both premature ovarian failure and/or infertility. This review aimed to define which, and when, reproductive indicators should be followed-up to help doctors to counsel patients regarding their fertility and ovarian function, and to determine if a second stage of fertility preservation after the end of cancer treatment is clinically relevant. Longitudinal assessment of anti-Müllerian hormone (AMH) concentrations during cancer treatment indicates the degree of follicular depletion, and allows discrimination between low and high gonadotoxic treatments. Sustained low AMH concentrations after treatment, especially in the case of alkylating protocols, may reduce the duration of the conception window significantly, and expose the patient to the risk of premature ovarian failure. It remains unknown whether this may impact further fertility capacity because of the lack of systematic follow-up of adolescent and young adult (AYA) women after chemo-radiotherapy. It appears that dedicated reproductive follow-up of AYA women under cancer treatment is needed to refine fertility preservation strategies, and to determine if low AMH concentrations after treatment impact the chance of pregnancy in this specific survivor population.

Pregnancy and newborn outcomes after exposure to bisphosphonates: a case-control study.

We analyzed women and newborn outcome after maternal exposure to BPs. BPs have no teratogenic effect on the 36 analyzed pregnancies compared to unexposed controls matched on women underlying diseases (either systemic disease, either "bone" disease) but some outcome differed: neonatal complications rate in systemic diseases and live birth rate in bone diseases). INTRODUCTION: The effect of bisphosphonates (BPs) during pregnancy remains unclear. We aimed to study pregnancy outcomes in women exposed to BPs during pregnancy. METHODS: Data for cases and controls were from the French Reference Centre of Teratogenic Agents. Cases were women who received BPs in the 6 weeks before or during a pregnancy and had systemic or bone diseases. We included two respectively matched control groups: women with systemic diseases not exposed to BPs and healthy women not exposed to BPs or any teratogenic agent. Four controls were assigned to each case. RESULTS: Thirty-six women were exposed to BPs including 5 just before pregnancy and 30 during the first trimester; 23 had systemic diseases (systemic lupus erythematosus, n = 5; rheumatoid arthritis, n = 5; other, n = 13) and 13 had bone diseases. Rate of observed congenital malformations did not differ in women with a systemic or a bone disease compared to their respective controls (respectively 2/23 [8.7%] vs 2/92 [2.2%], p = 0.178 and 0/13 [0%] vs 0/52 [0%], p = 1.00). Among women with systemic diseases, non-specific neonatal complications were more frequent for cases (4/16 [25.0%] vs 4/64 [6.3%], p = 0.027). Among women with bone disorders, the live birth rate was lower for cases than healthy controls (8/10 [80%] vs 50/50 [100%], p = 0.025). CONCLUSION: We found no major teratogenic effects of BPs, but rates of neonatal complications were increased for women with systemic diseases, as were spontaneous abortions for women with bone diseases likely linked to the severity of the underlying diseases and concomitant medications.

Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect often presenting with neonatal jaundice and/or hemolytic anemia. G6PD hemolytic events are linked with exposure to a pro-oxidant agent. We here report three cases of initial G6PD crises in breastfed children secondary to maternal consumption of a tonic drink which contains quinine. Quinine was found in breast milk of one of the mothers after she consumed tonic water. CONCLUSION: The amount of quinine that is transmitted through breast milk appears to be sufficient to induce G6PD crises in breastfed children. We hence recommend that consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency. What is Known: • G6PD hemolytic events are linked with exposure to a pro-oxidant agent. • Ingestion of fava beans by a mother who was breastfeeding has been reported to induce a neonatal G6PD crisis. What is New: • Maternal consumption of tonic drink which contains quinine appears to be sufficient to induce G6PD crises in breastfed children. • Maternal consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency.

Continuation of pregnancy after first-trimester exposure to mifepristone: an observational prospective study.

OBJECTIVE: To report the follow-up of continuing pregnancies after first-trimester exposure to mifepristone. DESIGN: Observational prospective study. SETTING: France. SAMPLE: Patients exposed to mifepristone during the first 12 weeks of pregnancy. METHODS: Women were included in the study when they or their doctors asked a French pharmacovigilance centre or the Paris Teratogen Information Service about the risk of mifepristone exposure in early pregnancy. Exclusion criteria were requests received after 22 weeks of gestation or subsequent elective termination of pregnancy without a pathological examination of the fetus. Data on maternal history and drug exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. MAIN OUTCOME MEASURES: Rate of major congenital malformations. RESULTS: A total of 105 pregnancies were included, with 46 exposed to mifepristone alone, and 59 exposed to both mifepristone and misoprostol. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI 1.2-10.4%), with two cases among 38 patients exposed to mifepristone alone, and two cases among 57 patients exposed to both mifepristone and misoprostol. CONCLUSIONS: This first prospective study found that the rate of major malformations after first-trimester exposure to mifepristone is only slightly higher than the expected 2-3% rate in the general population. Such findings provide reassuring data for risk evaluation for continuation of pregnancy after mifepristone exposure.

[Potential teratogenicity of modafinil - Conflicting evidence, need for research]. / Tératogénicité potentielle du modafinil ­ des données contradictoires, un besoin de recherche.

Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil.

French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

[Methotrexate: How long between administration and conception?] / Méthotrexate : quel délai entre l'administration et une conception ?

In women of childbearing age, methotrexate is prescribed in many indications other than cancer, either chronically (psoriasis, rheumatoid arthritis, IBD, etc.) or occasionally (ectopic pregnancies). The time given to these patients to consider pregnancy is currently subject to great variability depending on the sources. Analysis of the available objective evidence suggests that it is not justified to unnecessarily lengthen this period, and that conceiving the menstrual cycle following stopping methotrexate is quite possible.

Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database.

BACKGROUND: Because of the limited data concerning drug risks in pregnancy, health professionals are often deprived of relevant and sufficient information related to prescribing or dispensing during pregnancy. However, previous studies have emphasised the widespread French prescription of several drugs (sometimes "typically French") which have not been assessed in pregnant women. OBJECTIVES: The aim of the present study was to create the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies. METHODS: This feasibility study concerns pregnant women who gave birth to a baby between 1 July 2004 to 30 June 2005 in Haute-Garonne and who are registered in the French Health Insurance Service. Data sources include (1) the French Health Insurance Database (drugs prescribed during pregnancy), (2) the Mother and Child Protection Centre Database (newborn health at birth and 9 months after) and (3) the Antenatal Diagnostic Centre Database (medical pregnancy interruptions). RESULTS: The database is composed of 10,174 "mother-outcome" pairs. The prevalence rate of congenital anomalies was 2.2%. Pregnant women were prescribed 11.3 +/- 8.2 different drugs. Among the 20 most frequently prescribed drugs, around half of them have not been evaluated in pregnant women. CONCLUSIONS: The first results of this study show that implementation of a French database on prescription of drugs and pregnancy outcomes is feasible. Compared with several databases available in other countries, EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the baby 9 months after birth. Recording these data would make it possible to assess the risk of malformations due to a greater number of drugs and would contribute to international drug evaluation studies.

[Maternal cigarette smoking during pregnancy and malformations]. / Quels sont les risques d'embryo-foetopathie liés à l'exposition au tabagisme pendant la grossesse?

While cigarette smoking continues to increase among women, the influence of maternal smoking during pregnancy on the prevalence of malformations has been widely investigated over the past 30 years. Although many women discontinue smoking during pregnancy, the fetus is still often exposed during first weeks of gestation, including embryological development, raising questions about the teratogenic effect of smoking. We review the literature on this topic highlighting methodological issues. The overall prevalence of malformations does not seem to be increased among offspring of women who smoked during pregnancy. A mild but significant association was found between several specific malformations (oral cleft, gastroschisis and craniosynostosis) and maternal smoking. Though the odds ratios were very low for these associations, the change in absolute number, especially for facial clefts, is important due to high prevalence of smoking during pregnancy. These findings should be taken into account in preconceptional counselling.

[Isotretinoin: compliance with recommendations in childbearing women]. / Isotrétinoïne: suivi de l'application des recommandations des prescriptions chez les femmes en âge de procréer.

INTRODUCTION: The aim of this survey is to ascertain if the incidence of isotretinoin exposed pregnancies was reduced by the late recommendations of prescription and issue (AMM modification on 06/08/2001 and 25/09/2001). METHODS: All isotretinoin exposed pregnancies registered by the French Regional Drug Monitoring Centres, the Information Centre for Teratogenic Agents and Roche (Roaccutane), Pierre Fabre (Curacné Gé) and Expanscience (Procuta Gé) laboratories, from January 1st, 1999 to December 31st, 2002, were analysed. Enforcement of the strengthening of isotretinoin prescription recommendations was analysed on a sample of 68 prescriptions from 45 pharmacies throughout France. RESULTS: In 4 years, 103 isotretinoin exposed pregnancies (Roaccutane 97 p. 100, Curacné(R) Gé 3 p. 100) during teratogenic risk period, were registered. Pregnancy started less than one month after isotretinoin stopping (37 p. 100), during the treatment (43 p. 100), or was in progress when the treatment was initiated (20 p. 100). The reason of the 22 lacking contraception was known 12 times, i.e. an absence of prescription (6 times), a refusal to take a prescribed contraception (3 times) and a self-medication (3 times). Among the 71 pregnancies whose contraceptive status is known, 48 p. 100 could had been avoided if recommendations had been followed (pregnancies due to a premature stopping or an absence of contraception). The issue of pregnancies is a voluntary termination in 60 cases (87 p. 100). Malformations frequency is 25 p. 100. Incidence of isotretinoin exposed pregnancies remained stable, 0.26/1000 treated women (vs 0.34 after 2001's AMM modifications). Of 68 prescriptions studied, 23 (24 p. 100) carried all the legal warnings, which is close to the previous survey's results. Contraception was in accordance with the recommendations in 78 p. 100 of cases and women learned and applied information given in 38 p. 100 of cases. At last, only 6 patients (9 p. 100) have both a correctly written prescription, a contraception and a time between the pregnancy test date and prescription and issue dates, in accordance with the licence and have had a correct information and understood it. Regarding the previous survey, pregnancy test before treatment was more often prescribed (96 p. 100 vs 88 p. 100). On the other hand, less women knew the necessity to keep on taking contraception one month after isotretinoin stopping (82 p. 100 vs 93 p. 100). CONCLUSION: Despite 3 successive isotretinoin prescription and issue recommendations strengthening in childbearing women, pregnancies can't be totally avoided. Bad compliance concerns the prescription and/or an incomplete or not understood information by the patient who does not scrupulously apply the care and contraception agreement. However, this study does not allow to assess the proportion of issued prescriptions despite their non-accordance with the licence criteria. The National Commission of Pharmacovigilance did not like to limit isotretinoin prescription to dermatologists only. It estimates that the administrative authority must intensify information by dermatologists, general practitioners and pharmacists, about measures to take to avoid an exposure to isotretinoin during pregnancy.

Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules.

BACKGROUND: Little information is available about the safety of high doses of mesalazine during pregnancy. AIM: To study the fate of pregnancy and foetal outcome in women taking 1-4 g/day of mesalazine microgranules for inflammatory bowel disease. PATIENTS AND METHODS: Case reports were collected from the Pharmacovigilance Department of Ferring SA, France, from a survey conducted in three gastroenterology units, and from a teratology information service. The evolution of pregnancy and foetal outcome were assessed by questionnaire. RESULTS: The study covered a total of 123 pregnancies (126 foetuses). Ninety-six women took mesalazine during the first trimester, 85 during the second and 83 during the third. The mean daily dose was 2.1+/-0.8 g; 86 women received <3 g/day (low-dose group), 37 women received > or =3 g/day (high-dose group). The following abnormalities were observed in the low-dose and high-dose groups, respectively: ectopic pregnancy (1/0), spontaneous abortions (1/1), foetal death (0/1), premature deliveries (3/5, P < 0.05), congenital malformations (3/1) and one case of lethal oxalosis. Abnormalities were not considered to be related to mesalazine. CONCLUSIONS: The use of oral mesalazine microgranules during pregnancy is safe at doses < or =2 g/day, and probably also at a dose of 3 g/day.

Association of microwaves and ionizing radiation: potentiation of teratogenic effects in the rat.

Pregnant Wistar rats were exposed to either microwave-induced hyperthermia or gamma radiation or a combination of both. In microwave-induced hyperthermia, a core temperature of 42 degrees C was slightly teratogenic and a core temperature greater than or equal to 43 degrees C was highly teratogenic. Gamma radiation at 40 cGy was subteratogenic, while a dose of 75 cGy was highly teratogenic. A combination of microwave-induced hyperthermia up to 42 degrees C with 40 cGy of gamma radiation was highly teratogenic, indicating a mutual potentiation of the embryotoxic action of these two teratogens.

Administration of a gonadotropin-releasing hormone agonist during pregnancy: follow-up of 28 pregnancies exposed to triptoreline.

OBJECTIVE: To evaluate the teratogenic or fetal risk of a long-acting GnRH agonist (GnRH-a) triptoreline acetate (Decapeptyl; Ipsen-Biotech, Inc., Paris, France), inadvertently administrated in the first weeks of pregnancy. DESIGN: Prospective follow-up of exposed pregnancies and case reports. SETTING: Teratology information service of a public hospital and pharmacovigilance department of the firm. PATIENTS: Inadvertent pregnant women receiving a treatment, mainly for endometriosis or IVF. INTERVENTIONS: Case by case, individual estimations of the risks have been provided. MAIN OUTCOME MEASURE: Each pregnancy issue has been analyzed. RESULTS: No teratogenic or fetal toxic effect has been noted. CONCLUSION: No specific hazard has been observed among newborns after inadvertent exposures to a GnRH-a during the first 20 weeks of pregnancy.

Hierarchization of animal teratology findings for improving the human risk evaluation of drugs.

The risk assessment of drugs in pregnancy can be improved through better knowledge and interpretation of significant experimental findings. Embryo-fetal effects can be considered as the endpoint of importance, after excluding that their occurrence is related to maternal toxicity. If embryo-fetal toxic effects occur in the presence of maternal toxicity, the dam influence should be clearly assessed, and can be taken into account in the determination of a safety margin. A determination of the lowest developmental toxic dose, if any, apart from any maternal toxicity, should be made. With positive animal developmental findings, interpretation should take into account various parameters including the incidence and the severity of the embryo-fetal insult, interspecies reproducibility, the level of exposure, metabolic pathways, and the results of possible mechanistic investigations. Hierarchization of the experimental findings should take into account all these parameters together to provide support for the risk assessment in humans.

The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS).

The European Network of the Teratology Information Services (ENTIS) has collected and evaluated data on 689 pregnancies in which exposure to tricyclic and nontricyclic antidepressants occurred. Data were collected prospectively from the time of in utero exposure and all the cases were followed up to the first few weeks of postnatal life using standardized procedures. In most cases, no longer term follow-up data were available. Approximately two-thirds of the mothers were on multidrug therapy, and of those, half took a benzodiazepine. About 95% of the patients were exposed during the first trimester. The most striking feature of the pregnancy outcomes is that 97% of live-born babies were morphologically normal. The incidence of spontaneous abortion and late fetal/neonatal deaths were within the normal range. Fourteen live-born babies and one fetus had either major or minor malformations, and six had minor anomalies. However, there was no increase in either a particular type of malformation or a specific pattern of defects. Another 31 infants without malformations had neonatal problems; these were usually associated with chronic multidrug therapy, especially near term. Elective termination of pregnancy occurred more frequently in the multidrug groups (86 out of 488) than in the monotherapy groups (20 out of 201), but data concerning the condition of the fetus are not available in the majority of the cases. Overall, no causal relationship could be established between in utero exposure to antidepressants and adverse pregnancy outcome.

Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: To study potential teratogenic effects of quinolone exposure during pregnancy. STUDY DESIGN: Prospective follow-up study. Subjects are pregnant women who contacted a teratology information center for risk information on quinolone treatment. A total of 549 pregnancies was collected by the European Network of Teratology Information Services between 1986 and 1994. In addition 116 prospectively documented pregnancies and 25 retrospective case reports on malformed children from other databases were analyzed. RESULTS: The malformation rate among the live-born babies in the prospective ENTIS cohort was approximately 4.8%. No specific patterns of congenital abnormalities were found. The results do not suggest an elevated risk for spontaneous abortion, prematurity, intrauterine growth retardation and postnatal disorders. CONCLUSION: The present study does not reveal any clear adverse reactions (fetal and neonatal toxicity, including birth defects) due to the in utero exposure to quinolones. Hence, termination of pregnancy because of such exposure is not indicated. However, considering the limitations of this study and the fact that diseases urgently requiring quinolone treatment are rare, it appears advisable to prefer penicillin, cephalosporins and erythromycin as antibiotics of choice.

[Pregnancy outcome in inflammatory bowel diseases]. / Pronostic de la grossesse au cours des maladies inflammatoires intestinales.

OBJECTIVE: To assess pregnancy outcome in relation to disease activity and maintenance therapy in patients with inflammatory bowel disease. METHODS: A postal questionnaire was sent to every woman of child-bearing age followed for inflammatory bowel disease in three referral centers (Rothschild, Saint-Lazare, Saint-Louis). Response rate was 65%. RESULTS: One hundred and forty-four pregnancies (153 fetuses) in 138 women (122 had Crohn's disease) were reported. Outcome of pregnancy was normal (baby > 2500 g, without malformation) in 115 cases (77%). There were 17 cases of preterm birth (11.5%), 3 cases of hypotrophy, and 14 pregnancy losses (9 miscarriages (6%), 4 therapeutic abortions for major malformation (2.8%)). Percentages of normal pregnancy outcome were not different between patients who continued maintenance therapy and those who stopped: respective percentages were 75 vs 73% in patients receiving mesalamine or olsalazine (n = 30), and 60 vs 75% in patients receiving azathioprine (n = 22). CONCLUSION: In a selected series of women with inflammatory bowel disease, pregnancy outcome is approaching that observed in a normal population, except for an elevated rate of preterm births. There is no need to stop maintenance therapy with 5-aminosalicylates or azathioprine during pregnancy.

[Evaluation of medication risk in pregnant women: methodology of evaluation and risk management]. / Evaluation du risque médicamenteux chez la femme enceinte: méthodologie d'évaluation et gestion du risque.

This round table discussion was devoted to the description of the tools currently available for the evaluation of drug risks and management during pregnancy. Five topics were submitted for discussion: pre-clinical data, methodological tools, benefit/risk ratio before prescription, teratogenic or fetal risk evaluation, legal comments.