Prescriptions in pregnancy test the competence of pharmacovigilance
Three recent pieces and one previous commendable piece in the BMJ about epilepsy and valproate in pregnancy (1-4) miss a vital point: that international regulatory agencies should have acted earlier. The first report of congenital malformation due to valproate was made by a French team in 1982. (5) Despite many meetings and reports, there was no action until 2015, when a legal case went public thanks to a mother whose two children, one after the other, were damaged. She created the Association of Parents of Children with Anticonvulsant Syndrome (6) which enduringly lobbied for improvements. In France in 2015 this led to a restriction of prescription of valproate and its by-products in women of childbearing age to specialists who must obtain signed consent. The association also called for, and saw implemented in October 2017, pictograms on packaging which are not restricted to valproate. In France, 5000 drugs now have packaging with (danger or forbidden) pictograms and messages. (7)
Drug safety during pregnancy is a major problem. Pregnant women and children are vulnerable populations, not helped by the absence of data to ascertain the benefit:harm ratio or guide dosing. Even when available, data are often overlooked by prescribers. (8) For example, antidepressants are unduly promoted during pregnancy, ignoring: a) that first-line should be cognitive behavioural therapy (9); b) fluoxetine is teratogenic and increases the risk of cardiac anomalies; c) serotonin-norepinephrine reuptake inhibitors increase the risk of postpartum haemorrhage. (10)
There are real and present dangers to faster and faster drug approval, use of surrogate benefits, and forgetting the history of drug safety. The late withdrawal or restriction of drugs in the face of evidence of harm is unconscionable. (11) Worse, the long delay before banning valproate in women of childbearing age means an opportunity has been lost to ask if the system itself could be broken. (2) Databases and artificial intelligence allow prescribers to minimize prescription errors by sending red flags. Professional organizations and authorities in charge of quality of care or Continuous Medical Education remain half asleep at the wheel.
1 Wieck A, Jones S. Dangers of valproate in pregnancy. BMJ 2018;361:k1609.
2 Iacobucci G. MHRA bans valproate prescribing for women not in pregnancy prevention programme. BMJ 2018;361:k1823.
3 Angus-Leppan H, Liu RSN. Weighing the risks of valproate in women who could become pregnant. BMJ 2018;361:k1596.
4 Kinney MO, Morrow J. Epilepsy in pregnancy. BMJ 2016;353:i2880.
5 Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:937.
8 Charlton R, Garne E, Wang H, et al. Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions. Pharmacoepidemiol Drug Saf 2015;24:1144-54
9 Braillon A, Bewley S. Paucity of data on the safety of drugs for treating depression in pregnancy BMJ 2016;353:i2582.
10 Braillon A, Bewley S. Postpartum hemorrhage and use of serotonin reuptake inhibitor antidepressants in pregnancy. Obstet Gynecol 2016;128:405-6
11 Braillon A, Menkes DB. Balancing accelerated approval for drugs with accelerated withdrawal. JAMA Intern Med 2016;176:566-7.
Competing interests:
AB is an expert for several taskforces at the French Drug Agency (Agence Nationale de Sécurité des Médicaments et des produits de santé), none related to the topic. SB declares no interests
11 May 2018
alain braillon
senior consultant
Susan Bewley (Women’s Health Academic Centre, King’s College London, London, UK)
Rapid Response:
Prescriptions in pregnancy test the competence of pharmacovigilance
Three recent pieces and one previous commendable piece in the BMJ about epilepsy and valproate in pregnancy (1-4) miss a vital point: that international regulatory agencies should have acted earlier. The first report of congenital malformation due to valproate was made by a French team in 1982. (5) Despite many meetings and reports, there was no action until 2015, when a legal case went public thanks to a mother whose two children, one after the other, were damaged. She created the Association of Parents of Children with Anticonvulsant Syndrome (6) which enduringly lobbied for improvements. In France in 2015 this led to a restriction of prescription of valproate and its by-products in women of childbearing age to specialists who must obtain signed consent. The association also called for, and saw implemented in October 2017, pictograms on packaging which are not restricted to valproate. In France, 5000 drugs now have packaging with (danger or forbidden) pictograms and messages. (7)
Drug safety during pregnancy is a major problem. Pregnant women and children are vulnerable populations, not helped by the absence of data to ascertain the benefit:harm ratio or guide dosing. Even when available, data are often overlooked by prescribers. (8) For example, antidepressants are unduly promoted during pregnancy, ignoring: a) that first-line should be cognitive behavioural therapy (9); b) fluoxetine is teratogenic and increases the risk of cardiac anomalies; c) serotonin-norepinephrine reuptake inhibitors increase the risk of postpartum haemorrhage. (10)
There are real and present dangers to faster and faster drug approval, use of surrogate benefits, and forgetting the history of drug safety. The late withdrawal or restriction of drugs in the face of evidence of harm is unconscionable. (11) Worse, the long delay before banning valproate in women of childbearing age means an opportunity has been lost to ask if the system itself could be broken. (2) Databases and artificial intelligence allow prescribers to minimize prescription errors by sending red flags. Professional organizations and authorities in charge of quality of care or Continuous Medical Education remain half asleep at the wheel.
1 Wieck A, Jones S. Dangers of valproate in pregnancy. BMJ 2018;361:k1609.
2 Iacobucci G. MHRA bans valproate prescribing for women not in pregnancy prevention programme. BMJ 2018;361:k1823.
3 Angus-Leppan H, Liu RSN. Weighing the risks of valproate in women who could become pregnant. BMJ 2018;361:k1596.
4 Kinney MO, Morrow J. Epilepsy in pregnancy. BMJ 2016;353:i2880.
5 Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:937.
6 https://www.oacscharity.org/apesac
7 http://solidarites-sante.gouv.fr/actualites/presse/communiques-de-presse...
8 Charlton R, Garne E, Wang H, et al. Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions. Pharmacoepidemiol Drug Saf 2015;24:1144-54
9 Braillon A, Bewley S. Paucity of data on the safety of drugs for treating depression in pregnancy BMJ 2016;353:i2582.
10 Braillon A, Bewley S. Postpartum hemorrhage and use of serotonin reuptake inhibitor antidepressants in pregnancy. Obstet Gynecol 2016;128:405-6
11 Braillon A, Menkes DB. Balancing accelerated approval for drugs with accelerated withdrawal. JAMA Intern Med 2016;176:566-7.
Competing interests: AB is an expert for several taskforces at the French Drug Agency (Agence Nationale de Sécurité des Médicaments et des produits de santé), none related to the topic. SB declares no interests