DOI: 10.1111/1471-0528.12617

Maternal medicine

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Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database A-B Beau,a C Hurault-Delarue,a T Vial,b J-L Montastruc,a C Damase-Michel,a I Lacroixa a Service de Pharmacologie Me´dicale, CHU Toulouse, Universite´ de Toulouse, INSERM 1027, Toulouse, France b Centre Re´gional de PharmacoVigilance, Hospices Civils de Lyon, Lyon, France Correspondence: A-B Beau, Service de Pharmacologie Me´dicale, Faculte´ de Me´decine, 37 Alle´es Jules-Guesde, 31000 Toulouse, France. Email [email protected]

Accepted 26 November 2013. Published Online 11 February 2014.

Objective To compare pregnancy outcome between women

Main outcome measures Pregnancy loss for any cause, preterm

exposed and unexposed to oseltamivir during pregnancy.

delivery, low birthweight, neonatal pathology, and congenital malformation.

Design A comparative observational cohort study of women

exposed to oseltamivir during pregnancy. Setting A French prescription database (EFEMERIS) that includes

data for pregnant women was used. EFEMERIS records prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes in Haute-Garonne, South West France. Population Women who delivered from 1 July 2004 to 31

December 2010. Methods The study compared exposed and unexposed pregnant women. Two women unexposed to oseltamivir were individually matched, by maternal age, month, and year of delivery, with one women exposed to oseltamivir. Multivariable conditional logistic regression and multivariable Cox proportional hazards regression were used to evaluate associations between each outcome and exposure to oseltamivir during pregnancy.

Results A cohort of 337 (0.58% of women included in EFEMERIS) women exposed to oseltamivir were compared with 674 unexposed women. The risk for pregnancy loss (HR 1.52; 95 % CI 0.80–2.91), for preterm birth (adjusted OR 0.64; 95% CI 0.31–1.27), and for neonatal pathology (adjusted OR 0.62; 95% CI 0.23–1.54) did not differ between exposed and unexposed groups. When exposure during organogenesis was considered, one case of congenital anomaly (2.0%) among 49 exposed women and one case (1.0%) among 99 unexposed women were observed (crude OR 2.00; 95% CI 0.13–32.00). Conclusions There was no significant association between adverse

pregnancy outcomes and exposure to oseltamivir during pregnancy. Keywords Adverse pregnancy outcomes, EFEMERIS, influenza A (H1N1), oseltamivir, pregnancy.

Please cite this paper as: Beau A-B, Hurault-Delarue C, Vial T, Montastruc J-L, Damase-Michel C, Lacroix I. Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database. BJOG 2014;121:895–900.

Introduction Pregnant women are at increased risk for severe illness, hospitalisation, and complications as a result of influenza, especially during the second and third trimesters. An increased risk for miscarriage, stillbirth, and preterm birth has also been reported in pregnant women with influenza infection.1–5 Oseltamivir (Tamiflu; F. Hoffman-La Roche Ltd., Basel, Switzerland) and zanamivir (Relenza; GlaxoSmithKline Inc., Ontario, Canada) are neuraminidase inhibitors recommended for the treatment and prophylaxis of influenza types A and B.6,7 They have been used to treat influenza

ª 2014 Royal College of Obstetricians and Gynaecologists

since 2006, and their use has increased with the spread of the influenza A (H1N1) pandemic in 2009. Data suggest a moderate benefit: treatment with antivirals, if taken within 48 hours of the onset of symptoms, reduced the duration of the illness by ~1 day only.7–9 Even if there are limited safety data, it was assumed that the moderate maternal benefit justified their use during pregnancy. Current French health authority guidelines recommend the use of neuraminidase inhibitors for the treatment and prophylaxis of influenza in women at any time of pregnancy. Recently, a few studies have investigated the potential adverse effects of the use of neuraminidase inhibitors during pregnancy on the fetus.10–14 These studies found no

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increased risk for small for gestational age (SGA), low birthweight, preterm delivery, congenital malformation, and stillbirth; however, considering the relatively low number of women exposed to antiviral drugs, more comparative studies are needed to confirm the safety of their use during pregnancy. This study was designed to evaluate the potential effects of oseltamivir used in prophylaxis and treatment of influenza in women on pregnancy outcomes.

Methods This observational cohort study compared two groups of pregnant women: one group exposed to oseltamivir during pregnancy and one group unexposed to this drug. The study was based on EFEMERIS, a French prescription database that includes records for pregnant women.15 EFEMERIS is a French database holding data on prescriptions in the general population, and can be used to evaluate drug risks during pregnancy. Data come from three different sources. Firstly, the French Health Insurance System (Caisse Primaire d’Assurance Maladie, CPAM) from Haute-Garonne (in South West France) records the reimbursed drugs prescribed and dispensed to patients under general state coverage (80% of the Haute-Garonne population). Secondly, the Mother and Child Protection Centre (Protection Maternelle et Infantile, PMI) records data from the children’s certificates that are filled out during compulsory medical examinations at 8 days, 9 months, and 2 years. These health certificates contain data for both the mother (maternal characteristics, some pathologies during pregnancy) and the child (child characteristics, neonatal pathology, congenital malformation). Thirdly, the Antenatal Diagnosis Centre (Centre de Diagnostic Antenatal, CDA) centralises all occurrences of major and minor malformations in the maternities of the region if a therapeutic termination has been considered. The mother and her outcome (newborn or pregnancy loss) are linked with an anonymous irreversible code. More details on the design of EFEMERIS were published previously.15 All drugs are classified according to the World Health Organization’s Anatomical Therapeutic Chemical classification. The EuroCAT (European Network for Surveillance of Congenital Anomalies) classification system is used to classify all congenital malformations (major and minor). The date of conception is transmitted by the CPAM (all expecting mothers have to declare their pregnancy). The date of birth is given by the CPAM and the CDA. The timing of exposure was calculated with the date of conception and the date of medicine dispensation. At the time of the study, 58,034 mother–outcome pairs with women who delivered in Haute-Garonne between 1 July 2004 and 31 December 2010 were recorded in EFEME-

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RIS. The study was approved by the French Data protection Agency (Commission Nationale des Informations et Libertes, CNIL). Any mother–outcome pair who received at least one prescription of oseltamivir during pregnancy were assigned to the ‘exposed’ group. The single woman receiving a prescription of zanamivir was not included in the study. Two ‘unexposed’ women for each ‘exposed’ woman were randomly selected from the individuals in the study population who did not receive a prescription of oseltamivir during pregnancy. ‘Unexposed’ women were individually matched with the ‘exposed’ women by maternal age, and month and year of the end of the pregnancy. Maternal characteristics considered as potential confounding factors were multiple births, the presence of a long-term adverse health condition, pre-eclampsia, gestational diabetes, pregnancy-induced hypertension, a number of different active substances prescribed during pregnancy, the use of folic acid during organogenesis, the use of teratogens (retinoids, antiepileptics, vitamin K antagonists) during organogenesis (exposure between days 1 and 56 of gestation, which is the period of high susceptibility to teratogens). We examined the relationship between oseltamivir exposure during pregnancy and pregnancy outcomes, including pregnancy loss for any cause (legal or therapeutic termination, miscarriage, stillbirth, and ectopic pregnancy), the occurrence of congenital malformation (major and minor congenital malformations could be identified on the 8-day and 9-month child health certificates, or from the CDA in the case of a therapeutic termination), preterm birth (

Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database.

To compare pregnancy outcome between women exposed and unexposed to oseltamivir during pregnancy...
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