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.

Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey.

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence.

Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers.

CONTEXT: Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France. OBJECTIVE: To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine. MAIN OUTCOME MEASURES: Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency. RESULTS: Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (>23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P < .001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P < .001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P < .001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment. CONCLUSION: Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Hospitalization for severe bacterial infections in children after exposure to NSAIDs: a prospective adverse drug reaction reporting study.

BACKGROUND: NSAIDs are widely used to treat fever and pain in children, but their possible role in the progression of some bacterial infections is controversial. OBJECTIVE: This study was performed to analyse reported cases of severe bacterial infection associated with NSAID exposure in children admitted for this reason to a general paediatric department. METHODS: This study was based on the reporting system of hospital admissions for severe bacterial infections in children after NSAID exposure, and followed the recommendations of the European Guidelines of Pharmacovigilance for medicines used in a paediatric population. Data were prospectively collected and reported by active daily surveillance in the department from November 2002 to November 2005. RESULTS: Thirty-two cases of severe bacterial infections (cellulitis, soft tissue abscesses, parapneumonic empyema, necrotizing pneumonia, adenophlegmon [fever and a tender, warm and easily compressible neck mass] and lateral or retropharyngeal abscesses) were identified in children who had received NSAIDs, principally ibuprofen, in an exposure window of 15 days before the beginning of the signs of infection. Staphylococcus aureus, group A streptococci and Streptococcus pneumoniae were identified. Seven (22%) children required surgical treatment, and four (13%) were hospitalized in an intensive care unit. CONCLUSIONS: The frequency of hospitalization for severe bacterial infection as a possible adverse effect of NSAID use was 0.6% (95% CI 0.4, 0.9) of all admissions during the study period. The frequency of severe bacterial infections after exposure to NSAIDs was elevated (one case per month) in the department studied. Further work is necessary to confirm these findings, given the potential for recruitment and protopathic biases in our study.

Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors.

CONTEXT: Long-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules. OBJECTIVE: To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers. METHOD: Cancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population. RESULTS: Ten cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990-1999 or 2000-2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3-1.5) and 1.0 (0.5-1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0-7.2] P = 0.05 and 2.4 [0.8-5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine-lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5-73.9)]. CONCLUSION: This study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.

Uncomplicated outcome after an accidental overdose of nevirapine in a newborn.

We report the first case of a massive accidental overdose of nevirapine in a 1-week newborn, due to confusion between nevirapine (Viramune) and nelfinavir (Viracept). The drug was eliminated spontaneously and quickly. We only observed mild neutropenia and hyperlactatemia, which regressed on its own without any clinical complication. Despite the good evolution of this massive overdose, physicians should be aware of confusion risks between some antiretroviral drugs.

Increased incidence of necrotizing enterocolitis in premature infants born to HIV-positive mothers.

OBJECTIVE: To examine if being born to an HIV-positive mother may increase the risk of necrotizing enterocolitis in premature infants. DESIGN: Case-control study. SETTING: Neonatal unit of a level 3 perinatal centre. METHODS: : Over a period of 8.5 years, all cases of necrotizing enterocolitis occurring in premature infants admitted to the neonatal unit were identified. For each case, two controls were retrospectively chosen that matched for postmenstrual age at birth, intrauterine growth and year of birth. Perinatal characteristics were studied in all infants. MAIN RESULTS: There were 79 cases of necrotizing enterocolitis, which were compared with 158 controls. Using multivariate analysis, multiple pregnancy [odds ratio (OR), 2.29; 95% confidence interval (CI), 1.23-4.25; P = 0.009], abnormal umbilical artery velocity (OR, 2.21; 95% CI, 1.08-4.54; P = 0.030), abnormal fetal heart rate (OR, 2.14; 95% CI, 1.05-4.36; P = 0.036) and HIV-positive mother (OR, 6.63; 95% CI, 1.26-34.8; P = 0.025) were significantly more frequent in fetuses who subsequently developed necrotizing enterocolitis. CONCLUSIONS: This preliminary report suggests an association, not previously reported, between maternal HIV-positive status and an increased risk of necrotizing enterocolitis in premature infants. Despite the limitations of this study, we suggest that premature newborn infants of HIV-positive mothers should be monitored very carefully for a possible increased risk of necrotizing enterocolitis.

[Teratogenesis and medication induced fetal toxicity]. / Tératogenèse et foetotoxicité médicamenteuse.

The administration of pharmacological treatments during pregnancy always arouses concerns, shared both by the medical body and the general public. The drama of thalidomide, the main cause, has been followed by a number of efforts to develop some knowledge on the reality, nature and frequency of risk of malformation and foeto-toxicity, in particular from medications. A more rational approach to pharmacotherapy in the pregnant woman has come about following a position that was less supported and more alarmist. The principal idea that emerges consists of defending a more realistic evaluation of the risk:benefit ratio of pharmacotherapy in a sick pregnant woman, against the temptation of not treating or giving a maladaptive treatment. The second notion, essential in chronic pathologies, consists of supporting the efforts of multidisciplinary teams working in the pharmacotherapeutic management of pregnant women, to avoid errors of strategy that may be both medical and human.