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Prescription of drugs during pregnancy in France
RESEARCH LETTERS
Research letters
Prescription of drugs during pregnancy in France I Lacroix, C Damase-Michel, M Lapeyre-Mestre, J L Montastruc
See Commentary page 1704 A survey of the records of the French Health Insurance Service of drug prescriptions during pregnancy in 1000 women living in Haute-Garonne, southwest France, showed that 99% of the women received a prescription for at least one drug during pregnancy with a mean of 13·6 medications per woman. 1·6% of women received one or more prescriptions of drugs from the US Food and Drug Administration X category (fetal risk outweighs benefits). 59% of women had a prescription of drugs from the D category (fetal risk but benefits may be acceptable) and 79% of women were exposed to drugs for which information about safety in pregnancy was not available from animal or human studies.
Because pregnant women are excluded from clinical trials, it is impossible to assess the teratogenic potential of drugs in women during the premarketing period. Many women take drugs during pregnancy, but the extent of drug prescription and the types of drugs prescribed are difficult to ascertain.1–3 To collect reliable information about drug prescriptions in pregnant women, we did a retrospective survey of the records of the Caisse Primaire d’Assurance Maladie de la Haute-Garonne, which represents the French Health Insurance System (86% of the population) in this area in southwest France. We examined all the original prescription forms issued throughout the whole pregnancies of 1000 women. To avoid potential seasonal variations, we randomly
selected 500 women who had their babies in May and June, 1996, and 500 who had them in November and December, 1996, in Haute-Garonne. The women gave their consent for us to use prescription records related to their pregnancies. Data were collected directly from the original prescriptions. Subsidised as well as non-subsidised drugs were recorded. The womens’ ages ranged from 17 years to 47 years with a mean age of 29·8 years (SE 4·2). The mean length of gestation was 39·8 weeks (2·4). The rate of delivery before 35 weeks of pregnancy was 4·3%. We examined 8135 prescription forms (mean 8·2 forms per woman) of 18 860 prescribed medications, with a mean of 13·6 (5·8) different prescribed proprietary preparations and 15·8 (5·9) prescribed non-proprietary medicinal substances per woman. Only ten (1%) women had no drug prescription during pregnancy. Six (0·6%) women had more than 50 different prescribed proprietary preparations. The mean number of prescribed drugs per woman was lower in the first trimester of pregnancy (5·2 [3·0]) than in the second (7·1 [3·1]) or the third trimester (6·6 [3·1]). Prescription forms mainly came from family physicians (49%) or gynaecologists (41%). There was no statistical difference in the number of prescribed drugs between the two seasonal periods. When expressed as a percentage of exposed women, the most commonly prescribed classes of drugs were iron (74·9%), gastrointestinal drugs (69·4%), dermatological
Number of exposed women
1 000
800
600
400
200
0
al
al
) s s s s r y cid m ic) ns hics ers ons ugs es ics sic es in al id ug to te r pt t m on tio er ro th rati d dr ra lic a sys stem lge ctiv e a a a n e i O i m t r t a y s p Fo r e i ic s a a y op M Vi in or An i-inf at nt ar at es ho (s co ep ep oe at ul m tro erm t s rr /a r ti oid pr pr c m u s m c n e s i o l s o e a h c D m a a yr H ot Ga ive Ot Rh stem ic ng Th gic infla iov tibi ct m y di lo rd fe n i e s u o t t l a n A t i c s n s C tiex l/o al a Sy ou an l( rv ca l d i a i e a g o ic o ln er gic og ol lo tra ol -st m l o n c n a c e e h e No rc na ht na he Gy Op Gy Ot n
Iro
tin
s te
gic
o ol
Figure 1: Types of drugs prescribed (according to ATC code)
THE LANCET • Vol 356 • 18 November, 2000
1735
For personal use only. Not to be reproduced without permission of The Lancet.
RESEARCH LETTERS
We thank C Chaluleau and J Bes of the Caisse Primaire d’Assurance Maladie for allowing us to consult the records from the medical insurance system, and to M Grau for her participation. This study was supported by a grant from the Soutien à la Recherche Clinique, Direction de la Recherche Clinique, Centre Hospitalier Universitaire de Toulouse.
100
Exposed women (%)
80
1
60 2
40 3
20
0
4
A
B
C
D
X
U
FDA risk classification Figure 2: Percentage of women exposed in relation to fetal risk
drugs (63·0%), and analgesics (62·3%; figure 1). We used the US Food and Drug Administration (FDA) risk classification: category A, controlled studies in women do not show risk to the fetus in the first trimester; B, animalreproduction studies do not show risk to the fetus but there are no controlled studies in pregnant women; C, studies in animals show adverse effects on the fetus but there are no controlled studies in women; D, there is positive evidence of human fetal risk, but benefits from use in pregnant women may be acceptable despite the risk; X, studies in animals or human beings show fetal abnormalities and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit (figure 2).4 1·6% of women received one or more prescriptions from the higher-risk category (X)—for example, misoprostol (one), clomifene (three), topical or oral oestradiol or oestriol (nine). 59·3% of women used drugs from the D category: phenobarbital as a sedative (seven), high doses of aspirin or non-steroidal antiinflammatory drugs during the third trimester (27), quinine for the treatment of cramps (three), angiotensin-convertingenzyme inhibitors during the second and the third trimester (two), tetracyclines (seven), aminoglycosides (four), ergot derivatives (eight), benzodiazepines (51), bromide salts (three), and buprenorphine in high doses (three). We added a U category (U for unknown) for drugs for which evidence of safety in pregnancy was not available from studies in human beings or in animals (no FDA code, absence of published data), and 78·9% of women were exposed to drugs in the U category. If homoeopathic drugs are excluded, 77·5% of women were exposed to U-category drugs. Women were exposed to several U-category herbal drugs including Valeriana officinalis (122), Ballota nigra (106), Crataegus oxyacantha (39), and Passiflora incarnata (12). 138 women were exposed to helicidine, 147 to hexamidine, 126 to tuaminoheptane, 96 to osseinehydroxyapatite, and 93 to muramidase. The method of data collection that we used in this study allowed us to obtain reliable information on all drug prescriptions during the whole of pregnancy and to study a representative sample of French pregnant women. Our findings emphasise that French pregnant women are too frequently exposed to drugs, the known risks of which outweigh their benefits or for which there are no available data about their use in pregnancy. Drug use in French pregnant women should be continuously monitored and physicians and women should be more aware of the potential risks to the fetus.
1736
Olesen C, Hald Steffensen F, Lauge Nielsen G, de Jong-van den Berg L, Olsen J, Toft Sorensen H, The Euromap group. Drug use in first pregnancy and lactation: a population-based survey among Danish women. Eur J Clin Pharmacol 1999; 55: 139–44. Damase-Michel C, Lapeyre-Mestre M, Moly C, Fournié A, Montastruc JL. drug use during pregnancy: survey in 250 women consulting at a university hospital center. J Gynecol Obstet Biol Reprod (Paris) 2000; 29: 77–85. Irl C, Haasford J, Pegasus study group. The PEGASUS project: a prospective cohort study for the investigation of drug use in pregnancy. Int J Clin Pharmacol Ther 1997; 35: 572–76. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk, 4th edn. Baltimore: Williams and Wilkins, 1994: 975.
Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 31073 Toulouse, France (I Lacroix PharmD, C Damase-Michel PharmD, M Lapeyre-Mestre MD, J L Montastruc MD) Correspondence to: Dr C Damase-Michel (e-mail: [email protected])
Clonal culture of fetal cells from maternal blood B Tutschek, J Reinhard, G Kögler, P Wernet, D Niederacher Successful isolation and genetic testing of fetal cells obtained from maternal blood could eliminate the risks associated with invasive prenatal testing. We used clonal in-vitro expansion of fetal haemopoietic cells and micromanipulation and fluorescent PCR of single colonies to obtain pure fetal colonies from peripheral blood of 12 healthy pregnant women. Of 2966 randomly selected colonies, 42 contained fetal and other cells and, for four women, two to four colonies each contained purely fetal cells. Detection of fetal cells has been hampered by rarity in maternal blood, but with our approach many cells are available for analysis.
The prospect of isolating fetal cells from maternal blood for prenatal genetic testing has prompted different approaches, mostly based on sorting fetal cells.1 The possibility of increasing their number through expansion by culturing has been explored.2–4 We report the use of clonal in-vitro expansion combined with micromanipulation and fluorescent PCR with polymorphic markers to detect and analyse pure colonies grown from viable fetal cells present in the peripheral blood of healthy pregnant women. We recruited 14 women with normal pregnancies of between 14 and 20 weeks’ gestation, presenting for amniocentesis because of maternal age. After obtaining informed consent, we took peripheral blood samples before any other procedure was done. We separated mononuclear cells by single-step density gradient centrifugation (Ficoll, Pharmacia) and 5⫻105 nucleated cells were placed in two different semisolid media to promote clonal colony formation. The two media were: granulocyte-erythroid-macrophagemegakaryocyte colony-forming unit (CFU-GEMM) semisolid medium, containing 0·3% methylcellulose, 5 U/mL human interleukin 3, 30 U/mL human interleukin 6, 10 U/mL human granulocyte-colony-stimulating factor, 3 U/mL erythropoietin, and 15 ng/mL human stem-cell factor (StemBio 2a, StemGEM-CNRS); and 1% methylcellulose, 30% fetal bovine serum, 1% bovine serum albumin, 3 U/mL erythropoietin, and 2 mmol/L L-glutamine in Iscove’s modified Dulbecco medium (Methocult HC4330, CellSystems).
THE LANCET • Vol 356 • 18 November, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Research letters
Prescription of drugs during pregnancy in France I Lacroix, C Damase-Michel, M Lapeyre-Mestre, J L Montastruc
See Commentary page 1704 A survey of the records of the French Health Insurance Service of drug prescriptions during pregnancy in 1000 women living in Haute-Garonne, southwest France, showed that 99% of the women received a prescription for at least one drug during pregnancy with a mean of 13·6 medications per woman. 1·6% of women received one or more prescriptions of drugs from the US Food and Drug Administration X category (fetal risk outweighs benefits). 59% of women had a prescription of drugs from the D category (fetal risk but benefits may be acceptable) and 79% of women were exposed to drugs for which information about safety in pregnancy was not available from animal or human studies.
Because pregnant women are excluded from clinical trials, it is impossible to assess the teratogenic potential of drugs in women during the premarketing period. Many women take drugs during pregnancy, but the extent of drug prescription and the types of drugs prescribed are difficult to ascertain.1–3 To collect reliable information about drug prescriptions in pregnant women, we did a retrospective survey of the records of the Caisse Primaire d’Assurance Maladie de la Haute-Garonne, which represents the French Health Insurance System (86% of the population) in this area in southwest France. We examined all the original prescription forms issued throughout the whole pregnancies of 1000 women. To avoid potential seasonal variations, we randomly
selected 500 women who had their babies in May and June, 1996, and 500 who had them in November and December, 1996, in Haute-Garonne. The women gave their consent for us to use prescription records related to their pregnancies. Data were collected directly from the original prescriptions. Subsidised as well as non-subsidised drugs were recorded. The womens’ ages ranged from 17 years to 47 years with a mean age of 29·8 years (SE 4·2). The mean length of gestation was 39·8 weeks (2·4). The rate of delivery before 35 weeks of pregnancy was 4·3%. We examined 8135 prescription forms (mean 8·2 forms per woman) of 18 860 prescribed medications, with a mean of 13·6 (5·8) different prescribed proprietary preparations and 15·8 (5·9) prescribed non-proprietary medicinal substances per woman. Only ten (1%) women had no drug prescription during pregnancy. Six (0·6%) women had more than 50 different prescribed proprietary preparations. The mean number of prescribed drugs per woman was lower in the first trimester of pregnancy (5·2 [3·0]) than in the second (7·1 [3·1]) or the third trimester (6·6 [3·1]). Prescription forms mainly came from family physicians (49%) or gynaecologists (41%). There was no statistical difference in the number of prescribed drugs between the two seasonal periods. When expressed as a percentage of exposed women, the most commonly prescribed classes of drugs were iron (74·9%), gastrointestinal drugs (69·4%), dermatological
Number of exposed women
1 000
800
600
400
200
0
al
al
) s s s s r y cid m ic) ns hics ers ons ugs es ics sic es in al id ug to te r pt t m on tio er ro th rati d dr ra lic a sys stem lge ctiv e a a a n e i O i m t r t a y s p Fo r e i ic s a a y op M Vi in or An i-inf at nt ar at es ho (s co ep ep oe at ul m tro erm t s rr /a r ti oid pr pr c m u s m c n e s i o l s o e a h c D m a a yr H ot Ga ive Ot Rh stem ic ng Th gic infla iov tibi ct m y di lo rd fe n i e s u o t t l a n A t i c s n s C tiex l/o al a Sy ou an l( rv ca l d i a i e a g o ic o ln er gic og ol lo tra ol -st m l o n c n a c e e h e No rc na ht na he Gy Op Gy Ot n
Iro
tin
s te
gic
o ol
Figure 1: Types of drugs prescribed (according to ATC code)
THE LANCET • Vol 356 • 18 November, 2000
1735
For personal use only. Not to be reproduced without permission of The Lancet.
RESEARCH LETTERS
We thank C Chaluleau and J Bes of the Caisse Primaire d’Assurance Maladie for allowing us to consult the records from the medical insurance system, and to M Grau for her participation. This study was supported by a grant from the Soutien à la Recherche Clinique, Direction de la Recherche Clinique, Centre Hospitalier Universitaire de Toulouse.
100
Exposed women (%)
80
1
60 2
40 3
20
0
4
A
B
C
D
X
U
FDA risk classification Figure 2: Percentage of women exposed in relation to fetal risk
drugs (63·0%), and analgesics (62·3%; figure 1). We used the US Food and Drug Administration (FDA) risk classification: category A, controlled studies in women do not show risk to the fetus in the first trimester; B, animalreproduction studies do not show risk to the fetus but there are no controlled studies in pregnant women; C, studies in animals show adverse effects on the fetus but there are no controlled studies in women; D, there is positive evidence of human fetal risk, but benefits from use in pregnant women may be acceptable despite the risk; X, studies in animals or human beings show fetal abnormalities and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit (figure 2).4 1·6% of women received one or more prescriptions from the higher-risk category (X)—for example, misoprostol (one), clomifene (three), topical or oral oestradiol or oestriol (nine). 59·3% of women used drugs from the D category: phenobarbital as a sedative (seven), high doses of aspirin or non-steroidal antiinflammatory drugs during the third trimester (27), quinine for the treatment of cramps (three), angiotensin-convertingenzyme inhibitors during the second and the third trimester (two), tetracyclines (seven), aminoglycosides (four), ergot derivatives (eight), benzodiazepines (51), bromide salts (three), and buprenorphine in high doses (three). We added a U category (U for unknown) for drugs for which evidence of safety in pregnancy was not available from studies in human beings or in animals (no FDA code, absence of published data), and 78·9% of women were exposed to drugs in the U category. If homoeopathic drugs are excluded, 77·5% of women were exposed to U-category drugs. Women were exposed to several U-category herbal drugs including Valeriana officinalis (122), Ballota nigra (106), Crataegus oxyacantha (39), and Passiflora incarnata (12). 138 women were exposed to helicidine, 147 to hexamidine, 126 to tuaminoheptane, 96 to osseinehydroxyapatite, and 93 to muramidase. The method of data collection that we used in this study allowed us to obtain reliable information on all drug prescriptions during the whole of pregnancy and to study a representative sample of French pregnant women. Our findings emphasise that French pregnant women are too frequently exposed to drugs, the known risks of which outweigh their benefits or for which there are no available data about their use in pregnancy. Drug use in French pregnant women should be continuously monitored and physicians and women should be more aware of the potential risks to the fetus.
1736
Olesen C, Hald Steffensen F, Lauge Nielsen G, de Jong-van den Berg L, Olsen J, Toft Sorensen H, The Euromap group. Drug use in first pregnancy and lactation: a population-based survey among Danish women. Eur J Clin Pharmacol 1999; 55: 139–44. Damase-Michel C, Lapeyre-Mestre M, Moly C, Fournié A, Montastruc JL. drug use during pregnancy: survey in 250 women consulting at a university hospital center. J Gynecol Obstet Biol Reprod (Paris) 2000; 29: 77–85. Irl C, Haasford J, Pegasus study group. The PEGASUS project: a prospective cohort study for the investigation of drug use in pregnancy. Int J Clin Pharmacol Ther 1997; 35: 572–76. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk, 4th edn. Baltimore: Williams and Wilkins, 1994: 975.
Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 31073 Toulouse, France (I Lacroix PharmD, C Damase-Michel PharmD, M Lapeyre-Mestre MD, J L Montastruc MD) Correspondence to: Dr C Damase-Michel (e-mail: [email protected])
Clonal culture of fetal cells from maternal blood B Tutschek, J Reinhard, G Kögler, P Wernet, D Niederacher Successful isolation and genetic testing of fetal cells obtained from maternal blood could eliminate the risks associated with invasive prenatal testing. We used clonal in-vitro expansion of fetal haemopoietic cells and micromanipulation and fluorescent PCR of single colonies to obtain pure fetal colonies from peripheral blood of 12 healthy pregnant women. Of 2966 randomly selected colonies, 42 contained fetal and other cells and, for four women, two to four colonies each contained purely fetal cells. Detection of fetal cells has been hampered by rarity in maternal blood, but with our approach many cells are available for analysis.
The prospect of isolating fetal cells from maternal blood for prenatal genetic testing has prompted different approaches, mostly based on sorting fetal cells.1 The possibility of increasing their number through expansion by culturing has been explored.2–4 We report the use of clonal in-vitro expansion combined with micromanipulation and fluorescent PCR with polymorphic markers to detect and analyse pure colonies grown from viable fetal cells present in the peripheral blood of healthy pregnant women. We recruited 14 women with normal pregnancies of between 14 and 20 weeks’ gestation, presenting for amniocentesis because of maternal age. After obtaining informed consent, we took peripheral blood samples before any other procedure was done. We separated mononuclear cells by single-step density gradient centrifugation (Ficoll, Pharmacia) and 5⫻105 nucleated cells were placed in two different semisolid media to promote clonal colony formation. The two media were: granulocyte-erythroid-macrophagemegakaryocyte colony-forming unit (CFU-GEMM) semisolid medium, containing 0·3% methylcellulose, 5 U/mL human interleukin 3, 30 U/mL human interleukin 6, 10 U/mL human granulocyte-colony-stimulating factor, 3 U/mL erythropoietin, and 15 ng/mL human stem-cell factor (StemBio 2a, StemGEM-CNRS); and 1% methylcellulose, 30% fetal bovine serum, 1% bovine serum albumin, 3 U/mL erythropoietin, and 2 mmol/L L-glutamine in Iscove’s modified Dulbecco medium (Methocult HC4330, CellSystems).
THE LANCET • Vol 356 • 18 November, 2000
For personal use only. Not to be reproduced without permission of The Lancet.