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.

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.

[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.

[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.

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.

[Transplacental or breast milk intoxication to clonidine: a case of neonatal hypotonia and drowsiness]. / Intoxication transplacentaire ou par lait maternel à la clonidine : un cas de somnolence et d'hypotonie néonatale.

We report a case of clonidine poisoning in a breastfed newborn. At 2 days of life, this boy presented a consciousness deficit with drowsiness, hypotonia, and suspected generalized seizures. There were no cardiorespiratory problems outside of progressive central apneas beginning the 5th day. Further initial investigations were normal (extensive biological exams, cranial ultrasonography and transfontanellar Doppler, electroencephalography, and brain MRI study), excluding the main causes of neonatal hypotonia (encephalitis, infection, metabolic disorder). However, new medical questioning revealed maternal daily intake of 0.15 mg clonidine for hypertension during and after pregnancy. Since it was impossible to quantify clonidine quantification in newborn serum and breast milk, a weaning test was performed the 9th day. Twenty-four hours after cessation of breastfeeding, complete regression of symptoms was obtained. Poisoning by clonidine after fetal and neonatal exposure through breast milk is rare but severe enough to simulate a neurological disease. Diagnosis is based on the search for drug use and the cessation of breastfeeding if doubt persists. Recovery of normal examination results is then rapid and complete.

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.

[Neonatal seizures, buprenorphine abstinence syndrome, and substitutive treatment with morphine]. / Convulsions néonatales, syndrome de sevrage à la buprénorphine et traitement morphinique substitutif.

We report the case of a hypotrophic twin who presented neonatal abstinence syndrome to buprenorphine and developed neonatal seizures when the substitutive treatment by morphine was stopped. The other eutrophic twin did not develop withdrawal symptoms. This case demonstrates the unpredictable nature of transplacental transfer of buprenorphine. It also shows that neonatal abstinence syndrome can be potentially severe and that morphine treatment is not without risk.

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.

[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.

[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.

[Medication and pregnancy counseling, an incomfortable role for the retail pharmacists]. / Un rôle difficile pour le pharmacien d'officine, le conseil en matière de médicament et grossesse.

Tragedies subsequent to use of medication at the beginning of pregnancy have given rise to extreme distrust, placing the retail pharmacist in an uncomfortable situation. A survey of pharmacists in France has revealed that pregnant women ask for more information than any other patients, particularly when it comes to continuing medication started before pregnancy. In such cases, 57% of the polled pharmacists recommended discontinuation of the medication. Ninety percent thought they were sufficiently informed and massively recommended a prudent attitude. Their wish was to have an independent high-performance information tool available. There is such a tool: the Teratogenic Agent Information Center, rarely used by pharmacists. With the support of such a structure, 80% would be eager to take on more responsibilities in counseling patients and preventing teratogenic risks, in relation with other healthcare workers, thus guaranteeing high-quality medication counseling.

[Cancer and pregnancy: risks of exposure to cancer chemotherapy during pregnancy]. / Risques des médicaments.

Animal studies reveal that almost all antineoplastic agents are teratogenic. But extrapolation to human beings is not simple because of species differences. Few human data are available, most are sporadic case reports. Other toxic effects for the fetus and neonate (intrauterine exposure during second and third trimester) must be taken in consideration when prescribing chemotherapy for pregnant women. Adverse effects observed in adult and children are helpful if data during fetal life are lacking. Long-term studies are needed to evaluate the transplacental effects of chemotherapy during pregnancy; these studies should assess the child's mental and physical development, infertility and the occurrence of second malignancies.

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.