News.
Influenza A H1N1 flu: antiviral drugs and vaccines
The Swiss Teratogen Information Service (STIS) commits itself to the follow-up of prospective exposures to antiviral treatments and the CELTURA® vaccine
Efforts aimed at prevention and early treatment of the pandemic flu are of specific concern in pregnant women, considered among those groups presenting an increased risk of developing severe infections from the influenza A H1N1 virus. Healthcare authorities recommend as a priority vaccinating this category of the population, and to contemplate prescribing antiviral drugs in pregnant patients who develop flu symptoms during the pandemic period. But only relatively scarce data are available on the use of these drugs during pregnancy. No data suggests any specific risk for the child from these prescriptions, but the paucity of current observations should urge towards prospective follow-up of pregnancies in order to improve our knowledge and better confirm the safe use of these treatments in pregnant women.
With this aim, the STIS has opened two registries for drug exposures in pregnancy, one for the antiviral drugs
(TAMIFLU® et RELENZA®) and the other for the CELTURA® vaccine. Detailed explanations can be found at the pages devoted to these topics under influenza A H1N1 during pregnancy.
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Mycophenolate mofetil/mycophenolate sodium and congenital malformation.
The FDA has issued an alert regarding mycophenolate mofetil (MFM, CellCept®) and mycophenolate sodium (Myfortic®) following reports on outcomes of pregnancies suggesting an increased risk of pregnancy loss and congenital malformation in association with maternal use of these drugs during pregnancy.
Mycophenolate mofetil and mycophenolate sodium must be considered as associated with an increased risk of pregnancy loss and congenital malformation with regards to attitudes of prescription and information to patients.
Mycophenolate mofetil and mycophenolate sodium are considered contra-indicated during pregnancy. Grounds for this attitude lie on their mechanism of action (inhibition of purine synthesis), as well as animal data (rat, rabbit) showing a teratogenic effect at levels of exposure comparable, or inferior, to those prescribed in humans after an organ transplant (dose/m2).
The FDA has issued an alert regarding mycophenolate mofetil (MFM, CellCept®) and mycophenolate sodium (Myfortic®) following reports on outcomes of pregnancies suggesting an increased risk of pregnancy loss and congenital malformation in association with maternal use of these drugs during pregnancy. Malformations concern principally external/mid ear and facial anomalies (cleft lip/palate), but distal limb (hypoplastic nails, shortened fifth finger), esophagus, kidney (ectopic location) and heart anomalies were reported. Of approximately one hundred registered exposures, pregnancy loss rate was between 30 and 42%, and the rate of structural malformations/ polymalformations was between 18 and 22%. Anomalies of the ear were noted in two thirds to three quarters of these cases.
Links to the FDA safety warning and letters from Roche and Novartis to healthcare professionals are the following:
http://www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2
http://www.fda.gov/medwatch/safety/2007/safety07.htm#Myfortic
Summary of data:
26 exposed pregnancies
11 spontaneous abortions (42%)
4 cases of structural anomalies among 18 live born infants (22%), comprising 3 cases with ear anomaly, and 2 cases of cleft lip/palate
77 exposed pregnancies
25 spontaneous abortions (32%)
14 cases of structural anomalies (18%), among which 6 cases with ear anomaly
The gathering of these observations, generally retrospective, does not allow for an estimation of the incidence of malformations (preferential reporting of pathological outcomes, recall bias, etc.).
Nevertheless, the recurrence of similar patterns of malformation speaks in favor of a causal relation to maternal drug use of mycophenolate mofetil/ mycophenolate sodium, and supports the attitude up to now based on measure of caution and experimental data suggesting a potential risk.
Mycophenolate mofetil and mycophenolate sodium must be considered as associated with an increased risk of pregnancy loss and congenital malformation with regards to attitudes of prescription and information to patients.
Practically, these data will mean little or no change to current attitudes, but the increased risk can be enhanced:
Prescribing mycophenolate mofetil to women of child-baring potential: Rule out an ongoing pregnancy, highly recommend contraception, inform the patient regarding potential risks.
If a pregnancy is planned: Give preference to another immunosuppressant, whenever possible, at least during the first trimester of pregnancy. If no alternative can be considered and treatment is mandatory, inform the patient regarding potential risks and ensure an adapted follow-up (see below).
Pregnancy occurring during treatment: Inform the patient regarding potential risks and assess whether continuation of mycophenolate mofetil is mandatory (especially during the first trimester of pregnancy).
If exposure occurred during the first trimester, prenatal screening centered on the described malformations should be carried out (high level ultrasound in a specialized unit).
Other than risk of spontaneous abortion and malformations, an increased risk of infections should be taken into account with these treatments.
Pediatricians in charge for the child should be advised of maternal exposure to these drugs.
All serious or unexpected adverse effects must be reported to a pharmacovigilance center (such as spontaneous abortion, malformation, premature birth). Recording of exposures and their prospective follow-up should be carried out, as is gathering of uneventful outcomes of fortuitously exposed pregnancies, in order to add to our knowledge regarding these substances, and to minimize bias in the interpretation of exposure data (contact for the Swiss Teratology Information Service: 021 314 42 67).
References:
1. Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006;82:1698–702.
2. Schoner K, Steinhard J, Figiel J, Rehder H. Severe Facial Clefts in Acrofacial Dysostosis: A Consequence of Prenatal Exposure to Mycophenolate Mofetil? Obstet Gynecol. 2008 Feb;111(2):483-486
3. Velinov M, Zellers N. The fetal mycophenolate mofetil syndrome. Clin Dysmorphol 2008;17:77–8.
4. Tjeertes IF, Bastiaans DE, van Ganzewinkel CJ, Zegers SH. Neonatal anemia and hydrops fetalis after maternal mycophenolate mofetil use. J Perinatol 2007;27:62–4.
5 Perez-Aytes A, Ledo A, Boso V, Sàenz P, Roma E, Poveda JL, Vento M. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A. 2008 Jan 1;146(1):1-7
6. Le Ray C, Coulomb A, Elefant E, Frydman R, Audibert F. Mycophenolate Mofetil in Pregnancy after renal transplantation: a case of major fetal malformations. Obstet Gynecol 2004;103:1091–4.
Laura Rothuizen, Françoise Livio, Jérôme Biollaz 21-02-2008
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NSAIDs and Pregnancy: new elements to prefer paracetamol.
Two studies suggest an increased risk of miscarriage after nonsteroidal anti-inflammatory drugs (NSAID) use during the first trimester of pregnancy.
The NSAID exposure during the first trimester of pregnancy could also be related to an increased risk in congenital anomalies (specifically cardiac defects). However, this teratogenic potential remains uncertain.
In practice, a benefit/risk evaluation on a case-by-case basis should always be undertaken before prescribing NSAIDs during the first trimester of pregnancy and paracetamol should, whenever possible, be used instead.
A cohort study evaluating the risk factors associated with miscarriages highlighted an increase in the events after the use of NSAID during the first trimester of pregnancy (1' 055 pregnant women identified in a medical care program in the United States, 53 of them had taken NSAID). After adjustment for potential confounders (maternal age, gestity, parity, tobacco, alcohol, fever, diabetes, hypertension, acid folic), the relative risk (RR) for miscarriage was 1,8 (95% confidence interval (IC95%) 1 to 3.2). Statistical association was stronger if the use of AINS lasted more than a week (RR: 8.1; IC95% 2.8 to 23.4) or if the initial NSAID use occurred around the time of conception (RR: 5.6; IC95% 2.3 to 13.7). No association was found after Paracetamol used by 172 women [1]. A Danish case control study also highlighted an increased risk in miscarriage associated with the dispensation of NSAIDS (1599 women who had miscarriage of whom 45 had received a NSAID prescription; controls: 15' 990 women who had a live birth). The association was reinforced when the prescriptions occurred in the week before the date of miscarriage [2].Four studies looking for a possible teratogen potential after NSAID use in early pregnancy didn’t allow a precise evaluation of the risks [3]. A cohort study conducted by the same Danish group didn’t highlight any increase in congenital malformations in newborn of mothers having used AINS (RR: 1.0; IC95% 0.8 to 1.7) [4]. A Swedish cohort study including 279’734 pregnancy of whom 2' 557 used NSAID in early pregnancy did not show any increase for any congenital anomaly (RR: 1.0; IC95% 0.8 to 1.3). However, the relative risk for cardiac defects was increased (RR: 1.9; IC95% 1.3 to 2.6) as well as for cleft palate (RR: 2.61; IC95% 1.01 to 6.78; only 6 cases) [5]. A Swedish case control study evaluated the maternal drug use of 5' 015 infant with cardiovascular defect in comparison with 577' 730 controls. The list of the 10 maternal used drugs, which were more often associated with cardiac defect in the newborn contained naproxene [6]. Another case control study conducted in Canada included 93 new-born babies having a congenital malformation who were born from 1' 056 women who received a prescription of NAISD during the first trimester and 2 ' 478 new-born without anomaly and whom mother didn’t received a prescription of NAIDS. The relative risk for any anomalies was among 2.2 (IC95% 1.7-2.9), and rose to 3.3 (IC95% 1.9-6.0) for anomalies related to cardiac septum defect, and 9.6 (IC95% 3.1-29.6) for anomalies of the respiratory system [7].
At the moment, data are still missing to formally confirm an increased risk of miscarriage associated with the use of NSAIDS during the first trimester of pregnancy or before conception. The results should however be considered as a signal. The possible increased risk in cardiac defects associated to the NAIDS remains difficult to evaluate, as the number of cases observed is too low, and potential confounders couldn’t be excluded. However, while waiting for a confirmation or an invalidation of these results with new observations, a benefit/risk evaluation on a case-by-case basis before prescribing NAIDS to pregnant women in the first trimester of pregnancy is recommended. When an antalgic effect is required, paracetamol should, whenever possible, be used instead. At present, this molecule suffers from no limitation during the three trimesters of pregnancy. Finally, it seems not necessary to worry patients that have accidentally been exposed to NAIDS during the first trimester of pregnancy.
1. Li DK et al. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage. BMJ 2003;327:368.
2. Nielsen GL et al. Danish group reanalyses miscarriage in NSAID users. BMJ 2004;328:109.
3. No NSAIDs during pregnancy. Prescrire Int. 2007;16(87):232.
4. Nielsen GL et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001;322:266-270.
5. Ericson A et al. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxico 2001;15(4):371-375.
6. Källén BA et al. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxico 2003;17(3):255-261.
7. Ofori B et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs : a nested case-control study. Birth Defect Res 2006;77:268-279.
Alice Panchaud and Thierry Buclin, 05-04-2007
----------------------------------------------------------------------------------------- Association of lamotrigine with an increased risk of non-syndromic oral clefts. New data from the North American Antiepilectic Drug Pregnancy Registry (NAAED) suggest a possible association between exposure to lamotrigine monotherapy during the first trimester of pregnancy and cleft lip and/or cleft palate. New data from the North American Antiepilectic Drug Pregnancy Registry (NAAED) suggest a possible association between exposure to lamotrigine monotherapy during the first trimester of pregnancy and cleft lip and/or cleft palate. In the NAAED registry, 2 cases of non-syndromic isolated cleft lip and 3 cases of isolated cleft palate occurred among 564 pregnant women treated with lamotrigine montherapy during the first trimester of pregnancy. The prevalence rate was 8.9 per 1000, which exceeded the 0.37 per 1000 rate observed in the control group (non epileptic) used in the study. Other pregnancy registries of similar size have not confirmed this observation. Following these data, Swissmedic has decided to update the product information for all lamotrigine products: Subsequent to these statements, it appears important to address some factts in order to allow for an overall perception of the context in which lamotrigine is prescribed during pregnancy. 1. Morrow J et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-198. 2. Holmes LB et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy (abstract). Birth Defects Research Part A: Clinical and Molecular Teratology. 2006; 76(5): 318. ----------------------------------------------------------------------------------------- ACEI could be associated to an increase risk of congenital malformations. Exposure to ACEI during the first trimester of pregnancy could be associated with an increase in the risk of congenital anomalies among newborns. According to data available until recently, angiotensin converting enzyme inhibitors (ACEI), as welle as angiotensin II antagonists, were associated with fetal complications of vascular (hypotension) and renal systems (disgenesia, oligoanuria, oligohydramnios, etc) after exposure during 2nd and 3rd trimesters of pregnancy. One of the consequences of this fetotoxicity, oligohydramnios, potentialy involved secondary fetal complications such as limb deformations, pulmonary hypoplasia, or anomalies of the skull hypocalvania. In contrast, fetopathy was not reported among women who took ACEI only during the first trimester pf pregnancy. The Food and Drug Administration (FDA) emitted a safety alert following this publication. However, the label of pregnancy category of this drug class was not modified to this date following these results (C during 1st trimester and D during 2nd and 3rd trimester). Swissmedic will closely follow the developments regarding this potential drug-related risk and will introduce, if necessary, new modifications in the products information to reinforce safety issues concerning use of these drugs in pregnancy. Meanwhile, so long as further observations enabling confirmation or refutation of these results are not available, it seems appropriate to avoid, when possible, the prescription of all the classes of substances acting on the renin-angiotensin system during all three trimesters of pregnancy. At present, these molecules cannot be considered as completely devoid of risk in the 1st trimester anymore, and should be replaced by another class of antihypertensive agent as soon as the pregnancy is discovered. In order to acquire knowledge in the field, exposures to ACEI and antagonists of angiotensin during pregnancy should be reported to one of the regional Swiss centers of pharmacovigilance or to the Swiss center of teratovigilance (STIS), which will inquire about the follow-up of the pregnancy. [1] William O. Cooper, M.D., M.P.H., Sonia Hernandez-Diaz, M.D., Dr.P.H., Patrick G. Arbogast, Ph.D., Judith A. Dudley, B.S., Shannon Dyer, B.S., Patricia S. Gideon, R.N., Kathi Hall, B.S., and Wayne A. Ray, Ph.D. Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors. NEJM 2006;354:2443-2451.
Alice Panchaud and Thierry Buclin, 13-06-2006
----------------------------------------------------------------------------------------- Paroxetine associated with congenital cardiovascular malformations. Publication STIS.
« The post-marketing data from several prospective registries include more than 2000 women having received lamotrigine in monotherapy during the first trimester of their pregnancy. Although these data do not show an obvious increase in the overal risk of major congenital malformations associated with lamotrigine, a registry did however report an increase risk of non syndromic cleft palate and/or cleft lip. A complete analysis of 6 other pregnancy registries has not confirmed this observation. »
However, the results of a study published recently in the New England Journal of Medicine [1] seem to cast doubt on ACEI drug safety during the 1st trimester of pregnancy. These new data suggest an increase in the risk of congenital anomalies among new-born whose mothers were exposed to ACEI during the 1st trimester, as compared to unexposed newborns with a risk ratio (RR) of 2.7 (95% confidence interval (IC): 1.7-4.3). The increases was chiefly attributable to cardiovascular (RR: 3.72; IC, 1.9-7.3) and nervous system malformations (RR: 4.4; IC, 1.4-14.0).
This was an exploratory study that included 29'507 births, data was collected from an American insurance system database (Medicaid) providing maternal medical history and medication through records of filled prescriptions, as well as infants medical and vital records. Among these births, 411 had been exposed to antihypertensive treatments during the 1st trimester of pregnancy, of which 209 specifically to an ACEI substance. The rate of congenital malformations was 7.1% after exposure to an ACEI, against 2.6% in the unexposed group to an antihypertensive treatment. This would represent a little more than a doubling in the basal risk of congenital malformations, or a number needed to harm of 23 (of 23 exposures on average would appear one malformation assignable to the treatment).
The size of the group exposed to the ACEI (N=209) appears low with regards to the background noise induced by the selected data source. Because the Medicaid database is above all aimed at financial management, its coding system is perhaps not adapted for a study of this type and notably due to limited information on possible confounding factors (ex: pre-diabetes, alcohol, drugs, drugs on free sale, industrial polluting agent). This can unfortunately be regarded as a potential source of bias in this work. However, in spite of these brought up imperfections, the results of this study cannot be ignored and should be regarded as a signal. Other studies remain necessary to confirm these results.
Swissmedic and the concerned companies have changed the product information. It contains from now on the new following recommendations regarding the risk of congenital malformations associated with the use of paroxetine, updated to current observations:
- Paroxetine should not be newly prescribed in women who anticipate a pregnancy or are already pregnant.
- The physician will have to consider the option of an alternative treatment in pregnant women already treated with paroxetine, and should continue to prescribe paroxetine only if it is absolutely necessary. Sudden discontinuation of the treatment should also be avoided during pregnancy.
- Read more on www.swissmedic.ch
- A. Panchaud, L.E. Rothuizen, T.Buclin. Malformations cardiaques congénitales sous paroxétine. Journal Suisse de Pharmacie 2006; 8:292-295. (French)
- A. Panchaud, L.E. Rothuizen, T.Buclin. Attitude de prescription chez la femme enceinte: exemple de prise en charge d'un état dépressif. Forum Médical Suisse 2006; 6:961-964.
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«Médicaments, grossesse et lactation». 
Release of the new edition of «Médicaments, grossesse et lactation» 3rd edition, J-f. Delaloye, P. Rousso, T Buclin, P. De Grandi, Y. Vial, P. Hohlfeld. Editions Médicine et Hygiène, 2006.
Prescription Guide, this third edition of «Médicaments, grossesse et lactation» offers to the health provider a decision-making aid. While the multiplication of the nuances, going through “the authorization to a formal contra-indication”, passing by a “not advisable administration without being formally prohibited”, or being “allowed but subject to caution” is common in the literature, this guide provides once again the only two alternatives of Yes- allowed or No- prohibited.
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«Drugs during pregnancy and lactation». 
Release of the new edition of «Drugs during pregnancy and lactation» 2nd edition, Christof Schaefer, Paul W.J. Peters, Richard K Miller. Editions Hardbound, 2007.
The latest edition is the resource for any practicing OB/GYN, family physician, midwife, or pharmacist who prescribes medicinal products to or evaluates environmental or occupational exposures in women who are or may become pregnant. Based on the highly successful seven German editions of this reference, the up-to-date drug listings have been revised into a handy pocket guide color tabbed for quick access to important information. Easy to reference each drug is listed discussing the side effects, general impact on organ systems, potential toxicity, and risks before offering dosage recommendations. It is the only book of its kind to provide conclusive information on treatments for diseases during pregnancy and lactation and actions to be taken after (inadvertant) exposure to drugs suspected to be developmentaly toxic. Unlike other dosage guides, this edition is an affordable, compact compendium of knowledge on the very latest drugs and their effects on pregnant/lactating women.
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37th Annual Conference of the European Teratology Society.
September 6 to 10, 2009
Arles, France
http://www.etsoc.com
On this side:
News:
NSAIDs and Pregnancy: new elements to prefer paracetamol.
Association of lamotrigine with an increased risk of non-syndromic oral clefts.
ACEI could be associated with congenital malformations.
Paroxetine associated with congenital cardiovascular malformations.
Books:
«Médicaments, grossesse et lactation».
Release of the new edition of «Drugs during pregnancy and lactation»
Congress:
37th Annual Conference of the European Teratology Society.