Primidone (All indications)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Battino (Primidone), 1999	Japan, Italy and Canada 1978 - 1991	Female patient of childbearing age with epilepsy who visited clinics and who consented to be followed throughout their pregnancy. The data from three studies carried out in Canada, Japan and Italy were pooled.	Infants whose epileptic mothers were exposed to primidone in monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Infants whose epileptic mothers were not treated with antiepileptic drugs during pregnancy.	37 / 36	Each country has its own reference standards, then the data from the different countries are pooled. Exposition period deducted from Kaneko 1999.
Battino (Primidone), 1992	Milan 1977 - 1989	Epileptic patients were followed prospectively from the beginning of the pregnancy during the study period in the context of the Milan Collaborative Study on Epilepsy and Pregnancy.	Offspring of epileptic mothers treated with primidone monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Offspring of epileptic mothers with no antiepileptic drugs administered.	31 / 9	The results for the malformations are already available in Canger 1999 (a more recent publication with a larger exposed group) except for minor malformations.
Burja (Primidone) (Controls unexposed, disease free), 2006	Slovenia 1998 - 2002	Newborns and their mothers who gave birth at the Maribor Department of Obstetric and Perinatology during the study period.	Newborn in women diagnosed as having epilepsy who had taken primidone in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Newborn in a randomized sample of pregnant women who had received no prescription at all (with the only diagnosis 'vaginal delivery') in the same period.	1 / 211
Burja (Primidone) (Controls unexposed, sick), 2006	Slovenia 1998 - 2002	Newborns and their mothers who gave birth at the Maribor Department of Obstetric and Perinatology during the study period.	Newborn in women diagnosed as having epilepsy who had taken primidone in monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Newborn in women diagnosed as having epilepsy who didn't take antiepileptic drugs during pregnancy.	1 / 32
Canger (Primidone), 1999	Italy 1977 - 1996	517 women with epilepsy reffered to the study mainly from the Milan metropolitan and suburban areas or other Italian regions. They were followed up during the preconceptional period and/or from the beginning of pregnancy.	Infants of epileptic mothers exposed to primidone monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Infants of epileptic mothers unexposed to antiepileptic drugs during pregnancy.	35 / 25	Only the first pregnancies of each of the 517 women were included in the analysis.
Dean (Primidone), 2002	Scotland 1976 - 2000	Children of mothers taking antiepileptic drugs in pregnancy during the study period were ascertained from hospital obstetric records.	Children whose mothers took primidone monotherapy in pregnancy and continued beyond the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Sibs of exposed cases not exposed to antiepileptic drugs in utero. Either the mothers had epilepsy or the child was born before epilepsy developed.	2 / 38	The data for major congenital malformations include all pregnancies surviving into the second trimester. The vast majority of the mothers were treated for epilepsy.
Kaaja (Primidone), 2003	Finland 1980 - 1998	All women with epilepsy regardless of whether they used antiepileptic drugs during the index pregnancy.	Infants whose epileptic mothers took primidone as monotherapy during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Infants whose epileptic mothers didn't take any antiepileptic drugs during the first trimester.	6 / 239
Källén (Primidone) (Controls exposed to Lamotrigine, sick) (Indications NOS), 2013	Swedish 1996 - 2011	Nearly all births in Sweden during the study period (1,575,847) are registered in The Swedish Medical Birth Register.	Infants whose mothers used primidone in monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Infants whose mothers used lamotrigine in monotherapy in early pregnancy.	9 / 1084	Indications for antiepileptic drugs are not specified. Wide 2004 outcomes' are already included in Källèn et al 2013 or are not compared to an adequate control group. Follow-up period known thanks to author's email reply.
Källén (Primidone) (Controls unexposed, NOS) (Indications NOS), 2013	Swedish 1996 - 2011	Nearly all births in Sweden during the study period (1,575,847) are registered in The Swedish Medical Birth Register.	Infants whose mothers used primidone in monotherapy in early pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Infants in population whose mothers used at least one of a central nervous system active drugs (less than 3%) or weren't exposed in early pregnancy.	9 / 1575847	Indications for antiepileptic drugs are not specified. Follow-up period known thanks to author's email reply.
Kaneko (Primidone), 1999	Japan, Italy and Canada. 1978 - 1991	Female patient of childbearing age with epilepsy who visited clinics and who consented to be followed throughout their pregnancy. The data from three studies carried out in Canada, Japan and Italy were pooled.	Offspring whose epileptic mothers were under primidone monotherapy until term. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Offspring from epileptic mothers without antiepileptic drug exposure until term.	35 / 98	Details about the design were completed thanks to Battino et al., 1999 publication. Kaneko 1999 overlapped with Kaneko 1988, Canger 1999 and Battino 1992.
Katz (Primidone), 2001	USA 1990 - 2000	The clinical histories of women with epilepsy cared for at the center, contributing 103 newborns during the study period.	Newborn of women with epilepsy exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Newborn of women with epilepsy exposed to lamotrigine monotherapy during pregnancy.	2 / 3	The analysis of developmental delay excluded the 20 pregnancies occurring within 1 year of chart review because of insufficient time to evaluate developmental milestones.
Kilic (Primidone) (Controls exposed to Lamotrigine, sick) (Mixed indications), 2014	Denmark 1997 - 2008	All singleton live-born children in Denmark during the study period.	Children whose mothers have been exposed to primidone in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Children whose mothers have been exposed to lamotrigine in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth.	20 / 880	Less than 90% of women are epileptic.
Kilic (Primidone) (Controls unexposed NOS) (Mixed indications), 2014	Denmark 1997 - 2008	All singleton live-born children in Denmark during the study period.	Children whose mothers have been exposed to primidone in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children whose mothers haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth.	20 / 676834	Less than 90% of women are epileptic.
Kilic (Primidone) (Controls unexposed, sick) (Mixed indications), 2014	Denmark 1997 - 2008	All singleton live-born children in Denmark during the study period.	Children whose mothers have been exposed to primidone in monotherapy during the exposure window defined from 30 days before the estimated day of conception to the day prior to birth. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Children whose mothers have an epilepsy diagnosis and haven't been exposed to antiepileptic drugs 30 days before the estimated day of conception to the day of birth.	20 / 5296	Less than 90% of women are epileptic.
Kini (Primidone) (Controls exposed to Lamotrigine, sick), 2006	UK 1989 - 1999	375 children aged between 6 months and 16 years from 219 mothers with epilepsy exposed and not exposed to antiepileptic drugs during pregnancy attending epilepsy clinics or antenatal care between the study period.	Children exposed to primidone monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Children exposed to lamotrigine monotherapy during pregnancy and with epileptic mothers.	2 / 9	Because we don't know the exact number of children exposed to lamotrigine and analyzed for malformations, this outcome cannot be reported here.
Kini (Primidone) (Controls unexposed, sick), 2006	UK 1989 - 1999	375 children aged between 6 months and 16 years from 219 mothers with epilepsy exposed and not exposed to antiepileptic drugs during pregnancy attending epilepsy clinics or antenatal care between the study period.	Children exposed to primidone monotherapy during pregnancy and with epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Children not exposed to antiepileptic drugs during pregnancy and with epileptic mothers.	2 / 101	Because we don't know the exact number of children exposed to primidone and analyzed for malformations, this outcome cannot be reported here.
Koch (Primidone), 1996	Germany 1976 - 1983	Children born to epileptic women who had been treated during pregnancy with antiepileptic drug monotherapy of either primidone/phenobarbitone, phenytoin or valproic acid were studied in detail. The mothers were randomly recruited during their pregnancy from five obstetric departments within the city of Berlin.	Children born to epilepic mothers who had been exposed to primidone during fetal life. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Children born to mothers randomly recruited during their pregnancy from the same obstetric departments.	14 / 65	Primidone and phenobarbitone are regarded as the same drug for the authors. Study design partly completed with cited source [13].
Lowe (Primidone) (Controls unexposed, disease free), 1973	UK (Wales) 1965 - 1971	All the infants (31,877) born to women domiciled in Cardiff during the study period.	Infants born to women who gave a history of having had an epileptic seizure at any time in their lives and exposed to primidone alone during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Infants born to women living in Cardiff who didn't gave a history of having had an epileptic seizure at any time in their lives.	4 / 31632
Lowe (Primidone) (Controls unexposed, sick), 1973	UK (Wales) 1965 - 1971	All the infants (31,877) born to women domiciled in Cardiff during the study period.	Infants born to women who gave a history of having had an epileptic seizure at any time in their lives and exposed to primidone alone during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Infants of mothers with a history of epilepsy but not on anticonvulsants.	4 / 111
Samrén (Primidone), 1999	Netherlands 1972 - 1994	Offspring of women with epilepsy, with or without antiepileptic drug use during pregnancy, born during the study period.	Children born to mothers with epilepsy and using primidone monotherapy at least during the first trimester of pregnancy	unexposed, disease free Children born to nonepileptic nonexposed women.	18 / 2000
Steegers-Theunissen (Primidone), 1994	Netherlands Not specified	Epileptic and healthy control women visiting the outpatient departments were recruited before conception and just one singleton pregnancy per woman is studied.	Singleton of epileptic women exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Singleton of healthy women unexposed during pregnancy.	1 / 106	Women could only participate if they or any first-degree relative had no genetic disorder known to cause major congenital malformations, and if they were not under treatment for infectious, metabolic, endocrine or malignant diseases.
Titze (Primidone) (Controls unexposed, disease free), 2008	Germany 1976 - 1984	Adolescents born during the study period from mothers randomly recruited during their pregnancy, were asked to participate if they had been followed up to 6 years of age.	Adolescents whose epileptic mothers were exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, disease free Adolescents from non-affected mothers.	9 / 49
Titze (Primidone) (Controls unexposed, sick), 2008	Germany 1976 - 1984	Adolescents born during the study period from mothers randomly recruited during their pregnancy, were asked to participate if they had been followed up to 6 years of age.	Adolescents whose epileptic mothers were exposed to primidone monotherapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Adolescents whose epileptic mothers weren't exposed to any antiepileptic drugs during pregnancy.	9 / 13
Tomson (Primidone), 2018	42 countries 1999 - 2016	Pregnancies registered in the database during the study period who had been exposed to antiepileptic drug monotherapy and had complete follow-up data up to 1 year. They were enrolled within gestation week 16 and before fetal outcome is known.	Offspring exposed in utero to primidone monotherapy during the first trimester and born from epileptic mothers. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Offspring exposed in utero to lamotrigine monotherapy during the first trimester and born from epileptic mothers.	40 / 2514	This study is an update of Tomson's 2011 publication. They excluded from the current analysis pregnancies occurring in women without epilepsy. EURAP registry: potential overlap.
Vajda (Primidone) (Controls exposed to Lamotrigine, sick), 2019	Australia 1999 - 2018	Pregnant women taking antiepileptic drugs for any indications or not treated with antiepileptic drugs in at least the first half of pregnancy.	Offsprings born from women nearly always with epilepsy exposed to primidone in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Offsprings born from women nearly always with epilepsy exposed to lamotrigine in monotherapy in at least the first trimester of pregnancy.	2 / 406	Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2013 and 2014. Study design partly completed with Vajda 2013.
Vajda (Primidone) (Controls unexposed, sick), 2019	Australia 1999 - 2018	Pregnant women taking antiepileptic drugs for any indications or not treated with antiepileptic drugs in at least the first half of pregnancy.	Offsprings born from women nearly always with epilepsy exposed to primidone in monotherapy in at least the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study).	unexposed, sick Offsprings born from women nearly always with epilepsy not treated with antiepileptic drugs in at least the first half of pregnancy.	2 / 176	Women with epilepsy accounted for 98.3%. Completely overlap Vajda 2013 and 2014. Study design partly completed with Vajda 2013.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Bànhidy (Primidone), 2011	Hungary 1980 - 1996	Children affected with congenital abnormalities and who had mothers with medically recorded epilepsy.	Newborn infants without congenital abnormality and who had mothers with medically recorded epilepsy.	95 / 90	Congenital abnormalities syndromes caused by major mutant genes or chromosomal aberrations with preconceptional origin were excluded. Exposure period completed with Czeizel 1992.
Czeizel (Primidone), 1992	Hungary 1980 - 1987	Children affected with congenital abnormalities born from treated or untreated mothers.	Children without congenital abnormalities born from treated or untreated mothers.	100 / 54	Only one women was treated with primidone for eclampsia. The study design was partly completed thanks to the reference [6] cited in the publication. All congenital abnormalities except spina bifida are overlapped by the publication of Bànhidy 2011.

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