Patterns of Pregnancy Exposure to Prescription FDA C, D and X Drugs in a Canadian Population

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Journal of Perinatology (2008) 28, 324–329 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp ORIGINAL ARTICLE Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population

{ { SW Wen1,2,3,4,5, T Yang1,2,4,5, D Krewski3,5,6, Q Yang1,2, C Nimrod , P Garner , W Fraser7, O Olatunbosun8 and MC Walker1,2 1OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, ON, Canada; 2Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, ON, Canada; 3Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada; 4School of Public Health, Central South University, Changsha, Hunan, China; 5McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; 6Risk Sciences International, Ottawa, ON, Canada; 7Department of Obstetrics and Gynecology, University of Montreal Faculty of Medicine, Montreal, QC, Canada and 8Department of Obstetrics and Gynecology, University of Saskatchewan Faculty of Medicine, Saskatoon, SK, Canada

thalidomide in human pregnancy in 1960s.1,2 Information on the Objective: To examine prescription Food and Drug Administration (FDA) safety of marketed drugs for pregnant women is limited. Clinical C, D and X drugs in general obstetric population. trials of drugs normally excluded pregnant women because of Study Design: Historical cohort study. ethical and legal concerns. To guide safe drug use during pregnancy, the Food and Drug Administration (FDA) of the United Result: A total of 18 575 women who gave a birth in Saskatchewan States has developed a scheme to rate the potential fetal risk of between January 1997 and December 2000 were included. Among them, drugs that are classified into one of five major categories A, B, C, D 3604 (19.4%) received FDA C, D or X drugs at least once during and X.3 Most drugs are classified into category C, which includes a pregnancy. The pregnancy exposure rates were 15.8, 5.2 and 3.9%, statement that the drug should be given only if potential benefits respectively, for category C, D and X drugs, and were 11.2, 7.3 and 8.2%, outweigh potential risks to the fetus. Categories D and X indicate respectively, in the first, second and third trimesters. Salbutamol evidence of risk in pregnancy. (albuterol), trimethoprim/sulfamethoxazole (co-trimoxazole), ibuprofen, The objective of the present study was to examine the patterns of naproxen and oral contraceptives were the most common C, D, X drugs pregnancy exposure to FDA category C, D and X drugs, using the used during pregnancy. population-based health services databases in the Canadian Conclusion: About one in every five women uses FDA C, D and X drugs province of Saskatchewan. at least once during pregnancy, and the most common prescription drugs in pregnancy are antiasthmatic, antibiotics, nonsteroid anti-inflammation drugs, antianxiety or antidepressants and oral contraceptives. Journal of Perinatology (2008) 28, 324–329; doi:10.1038/jp.2008.6; Methods published online 21 February 2008 Study population Keywords: pregnancy; prescription drug; FDA pregnancy risk classifi- This study was based on the linked maternal-infant database from cation; antibiotics; antidepressants; oral contraceptives the Canadian province of Saskatchewan. Details of the dataset have been described elsewhere.4 About 18% of Saskatchewan infants who were born to mothers with registered Indian status were excluded Introduction from the study because drug information was not available for The use of prescription drugs during pregnancy has become a them, and women with less than 1 year of Saskatchewan Health concern since the discovery of birth defects resulting from coverage were also excluded. All live births and stillbirths born to Saskatchewan residents between 1 January 1997 and 31 December Correspondence: Dr SW Wen, OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Ottawa, 501 Smyth Road, Box 241, Ottawa, 2000 were identified. Women with one or more infants born during ON K1H 8L6, Canada. the study period were assigned index dates corresponding to the E-mail: [email protected] birth date of each qualifying infant. A random sample (by mother’s {Deceased. Received 9 August 2007; revised 26 November 2007; accepted 27 December 2007; published provincial health-care number) of approximately 50% of the online 21 February 2008 eligible women during the period of interest was selected. Patterns of prescription drugs in pregnancy SW Wen et al 325

Ascertainment of pregnancy drug exposure and according to the dispense date, the exposure was further Ascertainment of prescription FDA CDX drugs during pregnancy divided into three trimesters based on the estimated gestational age was determined using information in the outpatient prescription at the time of dispensing (first trimester: 0–12 weeks of gestation; drug database. FDA CDX drugs were assigned by comparing the second trimester: 13–26 weeks of gestation; third trimester: 27 FDA list with the available Saskatchewan Formulary for the study weeks of gestation to delivery). Information on maternal and period. Pregnant women with at least one prescription FDA CDX neonatal characteristics such as age, plurality (that is, number of drugs dispensed during pregnancy were considered as exposed. The fetuses of this pregnancy), parity (based on numbers of live births pregnancy period of drug exposure was calculated based on the and stillbirths) and social assistance plan status were obtained combination of gestational age, date of delivery and drug dispense from the provincial population registry and birth registration files. date. Only FDA CDX drugs dispensed during pregnancy was counted Chronic disease status was based on a chronic disease score calculated using outpatient prescription drug data in the year prior to the index date following previously established methods.5 Table 1 Characteristics of pregnant women in Saskatchewan, 1997–2000 Statistical analysis (n ¼ 18 575) We first described the maternal and fetal characteristics of the study Characteristic Number Rate (%) population. We then calculated the rates and 95% confidence Maternal age intervals (CIs) of exposure to FDA CDX drugs during the entire <20 1477 7.95 pregnancy and in each trimester of the pregnancy. We finally listed 20–24 4310 23.20 the top 10 FDA CDX drugs used during pregnancy. All analyses 25–29 6223 33.50 were performed by SAS 9.1.3(SAS Institute Inc., Cary NC, USA). 30–34 4477 24.10 35+ 2088 11.24 Results Saskatchewan assistance plan A total of 18 575 pregnant women were included in the final No special coverage 16 347 88.01 analysis. Majority of pregnant women were 25 years of age or older Saskatchewan assistance plan 2228 11.99 with no chronic health problem and were not on provincial social Chronic disease score assistance plan (Table 1). 0 16 518 88.93 Of the 18 575 women studied, 3604 (19.4%) were dispensed FDA X1 2057 11.07 CDX drugs at least once during pregnancy, and the rate of exposure was higher in the first trimester (11.2%) than those in the Parity second (7.3%) and third trimesters (8.2%). The rate of pregnancy 1 7282 39.20 exposure was higher for category C (15.8%) than those in category 2 6429 34.61 D (5.2%) or category X drugs (3.9%), with similar CDX distribution X3 4864 26.19 pattern for trimester-specific exposures (Table 2). The most commonly dispensed category C drugs were Plurality salbutamol (or albuterol, 4.2%), trimethoprim/sulfamethoxazole Single 17 949 96.63 (or co-trimoxazole, 3.2%), fluticasone (2.4%), codeine (2.3%) and Multiple 626 3.37 beclomethasone (1.6%) (Table 3). The most commonly dispensed

Table 2 Prevalence of FDA drug categories C, D and X used among pregnant women by pregnancy period in Saskatchewan, 1997–2000 (n ¼ 18 575)

Period of gestation Category CDXa Category C Category D Category X

Numbers % (95% CI)b Numbers % (95% CI) Numbers % (95% CI) Numbers % (95% CI)

Throughout gestation 3604 19.4 (18.8, 20.0) 2938 15.8 (15.3, 16.3) 973 5.2 (4.9, 5.5) 729 3.9 (3.6, 4.2) First trimester 2077 11.2 (10.7, 11.7) 1556 8.4 (8.0, 8.8) 693 3.7 (3.4, 4.0) 549 3.0 (2.8, 3.2) Second trimester 1351 7.3 (6.9, 7.7) 1210 6.5 (6.1, 6.9) 380 2.1 (1.9, 2.3) 204 1.1 (0.9, 1.3) Third trimester 1519 8.2 (7.8, 8.6) 1385 7.5 (7.1, 7.9) 384 2.1 (1.9, 2.3) 202 1.1 (0.9, 1.3)

Abbreviations: CI, conﬁdence intervals; FDA, Food and Drug Administration. aOne or more category C or D or X. b95% CI

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category D drugs included ibuprofen (0.8%), naproxen (0.7%), lorazepam(0.6%), amitriptyline(0.6%) and doxycycline(0.6%) (Table 4). The most frequently dispensed category X drugs were 193 1.1 oral contraceptives such as ethinyl estradiol/norgestrel (1.5%), ethinyl estradiol/norgestimate (0.6%) and medroxyprogester (0.5%) (Table 5).

Comment Our population-based study found that about one in every ﬁve pregnant women was dispensed one or more FDA category C, D or X drugs during pregnancy. The exposure was higher in the ﬁrst

acetaminophen/codeine trimester (11.2%) than those in the second (7.3%) and third trimesters (8.2%). We also found that exposure to category C drugs (15.8%) was higher as compared to categories D (5.2%) or X drugs (3.9%), with similar CDX distribution pattern for trimester-speciﬁc

174 0.9 Codeine including exposures. The most frequent category C drugs used in pregnancy were 18 575)

¼ antiasthmatic (for example, salbutamol, ﬂuticasone, n beclomethasone), antibiotics (for example, trimethoprim/ sulfamethoxazole) and pain killers (for example, codeine). The most commonly dispensed category D drugs during pregnancy were nonsteroid anti-inﬂammation drugs (for example, ibuprofen and naproxen), antianxiety (for example, lorazepam), antidepressants (for example, amitriptyline) and antibiotics (for example,

codeine doxycycline). The most frequently dispensed category X drugs during pregnancy were oral contraceptives such as ethinyl estradiol/norgestrel, ethinyl estradiol/norgestimate and medroxyprogesterone. Previous studies reported a great deal of variation in the rates of 222 1.2 Codeine including acetaminophen/ pregnancy exposure to prescription drugs with potential fetal risk.6–16 Major differences in study design, study population, time period, drug exposure ascertainment method and drug classification systems (some used FDA system while others used European or Australian or ‘ad hoc’ system) make it difficult to reconcile rates observed in different studies. For studies used similar methodology, the results were quite similar to ours. For example, by linking three nationwide registration databases in Finland, Malm et al.10 found that 20.4% women used at least one acetaminophen/codeine prescription drug during pregnancy with potential fetal risk and 3.4% used at least one clearly harmful drug by FDA criterion. Andrade et al.7 reported that 1.1% of women received a category X drug after the initial prenatal care visit, and 3.3% of women 432 2.3 Codeine including received FDA category D or X during the pregnancy period,8 using data from a Health Maintenance Organization. Olesen et al.15 found 0.9% of Danish pregnant women filled prescriptions for drugs associated with human malformations in a population-based study. Using a survey of the record of the French Health Insurance Throughout pregnancy First trimesterService Second trimester of drug prescriptions, Lacroix et Third trimester al.11 reported that 1.6% of Prevalence and top 10 of FDA drug category C used by pregnant women during pregnancy period in Saskatchewan, 1997–2000 ( women received one or more prescriptions of drugs from FDA category X during pregnancy. Hardy et al.14 found that 0.6%

Table 3 DrugTotalSalbutamol (albuterol)Trimethoprim/sulfamethoxazoleFluticasone 596Codeine including acetaminophen/codeine 784 Numbers 3.2Beclomethasone Trimethoprim/sulfamethoxazole % 4.2Nystatin, vaginal tablet Salbutamol Drug 2938 (albuterol)Niconazole 389Fluconazole 15.8 443Hydroxyzine Total 2.1Paroxetine 293 2.4 297 Fluticasone 434 FluticasoneAbbreviation: FDA, Food 1.6 and Drug 1.6 Administration. Nystatin vaginal Beclomethasone 2.3 tablet 182 Numberswomen Salbutamol 165 (albuterol) 103 0.9 % 0.8 Niconazole were 88 Fluconazole 0.6 Drug 1556 136 267 Paroxetine 251 prescribed 0.5 188 464 8.4 1.4 Mefenamic 0.7 acid 1.4 Fluticasone 2.5 Total Nystatin 1.0 vaginal tablet Trimethoprim/sulfamethoxazolewith Salbutamol (albuterol) Beclomethasone one 95 208 88 or Numbers 73more 466 1.1 0.5 132 65 % 0.4 Trimethoprim/sulfamethoxazole 2.5 242 Niconazole category Fluconazole 0.4 0.7 195 0.3 173 1.3 Nystatin, Paroxetine vaginal 1210 tablet 1.1 Hydroxyzine X 0.9 Drugprescriptions 6.5 Beclomethasone Total 154 0.8 81 Num 60 % 0.4 175 41 0.3 34 Niconazole Fluconazole 0.9 0.2 0.1 Hydroxyzine 1385 Paroxetine 7.5 91 77 0.5 0.4 66 46 0.3 0.2

Journal of Perinatology Patterns of prescription drugs in pregnancy SW Wen et al 327

Table 4 Prevalence and top 10 of FDA drug category D used by pregnant women during pregnancy period in Saskatchewan, 1997–2000 (n ¼ 18 575)

Throughout pregnancy First trimester Second trimester Third trimester

Drug Numbers % Drug Numbers % Drug Numbers % Drug Numbers %

Total 973 5.2 Total 693 3.7 Total 380 2.1 Total 384 2.1 Ibuprofen 147 0.8 Ibuprofen 110 0.6 Lorazepam 54 0.3 Lorazepam 74 0.4 Naproxen 132 0.7 Amitriptyline 101 0.5 Amitriptyline 54 0.3 Amitriptyline 50 0.3 Lorazepam 123 0.6 Naproxen 98 0.5 Ibuprofen 46 0.2 Indomethacin 40 0.2 Amitriptyline 122 0.6 Doxycycline 93 0.5 Naproxen 42 0.2 Ibuprofen 39 0.2 Doxycycline 117 0.6 Lorazepam 76 0.4 Indomethacin 42 0.2 Naproxen 36 0.2 Indomethacin 100 0.5 Indomethacin 50 0.3 Meperidine 28 0.1 Atenolol 30 0.1 Tetracycline 52 0.3 Tetracycline 46 0.3 Propylthiouracil 27 0.1 Doxycycline 25 0.1 Meperidine 50 0.3 Carbamazepine 30 0.2 Doxycycline 24 0.1 Meperidine 25 0.1 Diazepam 38 0.2 Meperidine 25 0.1 Atenolol 24 0.1 Propylthiouracil 22 0.1 Propylthiouracil 36 0.2 Diazepam 25 0.1 Carbamazepine 24 0.1 Carbamazepine 22 0.1

Abbreviation: FDA, Food and Drug Administration. in an approximately early pregnancy using the UK General direct, objective evidence of harm based on these exposures. Practice Research Database. Riley et al.13 reported that 4% of Moreover, since the cohort was identified based on live births or women were prescribed a category D or X drugs and the most stillbirths, by definition any pregnancies that were terminated due common classes of medications prescribed were antibiotics (62%), to fetal anomalies were excluded. Therefore, the pregnancies that analgesics (18%), asthma medications (18%) and antiemetics continued were those with the less likelihood of harm based on (17%). Garriguet analyzed several national databases in Canada, these drug exposures. including the 1994/1995 through 2002/2003 National Longitudinal Our study findings, based on a 50% random sample of the Survey of Children and Youth, the 2003 Canadian Community entire population in a Canadian province, suggested that one in Health Survey and the 1996/1997 National Population Health every five pregnant women was exposed to prescription drugs with Survey, and estimated that 27% of Canadian women were taking real or potential fetal risk. Many of these drugs used may be prescription medications while in pregnancy.16 However, in this needed, because the mother’s condition may be deteriorated if left Canadian study, the author did not attempt to classify prescription untreated, and because the outcomes in infants born to mothers drugs by fetal risk. with untreated maternal diseases may be worse. However, under Our study has several strengths as compared with previous many other circumstances, the use of prescription drugs with real studies that have examined the issue. Since our study was based on or potential fetal risk could be avoided or reduced. For example, a 50% random sample of the population eligible for drug benefits our study found that trimethoprim/sulfamethoxazole is the most in the Canadian province of Saskatchewan, no selection bias could frequently used antibiotics in pregnancy. While antibiotics during occur. Drug exposure information was abstracted from the pregnancy are often needed (for example, for urinary tract outpatient prescription drug database instead of relying on infection),18 the use of trimethoprim/sulfamethoxazole could be women’s recall, thereby avoiding recall bias. Finally, in our study, avoided because it is not the only choice of antibiotics for urinary drug exposure time was determined by actual gestation period at tract infection; there are alternative antibiotics with equal effects.19 the date of drug dispensing, so that the exposure time can be Trimethoprim/sulfamethoxazole is a folic acid antagonist that may estimated precisely. cause birth defects and other adverse outcomes in the infants.20,21 Our study also has several limitations. We used administrative Antiasthmatic drugs (category C drugs) were also frequently used. data and this type of data is prone to certain degree of coding Previous studies have demonstrated that asthmatic pregnant errors.17 We have no compliance information in Saskatchewan’s women with asthma were at substantially increased risk for many prescription drug file. Some patients who got prescription drugs adverse pregnancy outcomes.22,23 Pharmacological therapy for from the pharmacy but did not actually consume them could be asthma is often necessary during pregnancy. However, an increase misclassified as exposed, and thus the exposure could be in the risk of congenital malformation associated with the use of overestimated. We have not been able to take measures to deal with certain antiasthmatic drugs such as salbutamol during pregnancy the potential problems caused by coding errors and has been observed,24 suggesting the need to choose less toxic noncompliance. The interpretation of the results is based on the antiasthmatic drugs even if pharmacological therapy for asthmatic opinion of the medical necessity of these drugs, rather than any mother is indicated. Antidepressants in pregnancy such as selective

Journal of Perinatology Patterns of prescription drugs in pregnancy SW Wen et al 328

serotonin reuptake inhibitors (SSRIs) are other examples. Our recent study found that pregnancy use of SSRIs was associated with several adverse outcomes in infants, including low birth weight, 9 0.05 4 0.1 75 0.4 preterm birth, fetal death and seizures in newborns.4 Although SSRIs for severe depression is needed, its use in pregnancy may have been too liberal that may have included mild depression cases or for other indications. imate 36 0.2 We found that the most frequently dispensed X drugs during pregnancy were oral contraceptives such as ethinyl estradiol/ norgestrel. Most of these drug used occurred in the ﬁrst trimester, likely the results of unintended pregnancy/failed contraceptives,25,26 although data error and uses for other indications may account for

either isomer acetate a few cases recorded in the second and third trimesters. Oral contraceptive drug is the most commonly used method of contraception in North America and failure of oral contraceptive 26

72 0.4 Ethinyl estradiol/norgestrel (both or pills contributes for a large proportion of unintended pregnancy. Measures aimed at reducing failure of oral contraception and 18 575)

¼ monitoring outcomes in pregnancies as the result of failed oral n contraception should be implemented, particularly in teenagers, women with low socioeconomic status and women in unstable sexual relationships.27 Detailed description of the patterns of pregnancy exposure to prescription drugs with real or potential fetal risk, including rate of exposure during different periods of gestation and speciﬁc drugs or drug groups, such as the one in the current study, can increase the

either isomer awareness of physicians and new mothers, so that appropriate measures such as better pregnancy planning and improved communication between physician and women at reproductive age, can be employed. Further efforts directed to develop data on the

205 1.1 Ethinyl estradiol/norgestrel (both or safety of drugs during pregnancy are needed. The current study implies that drug use in pregnant women should be monitored and health-care providers and women must be made aware of the medications on the real or potential risks to the fetus.

Acknowledgments This study was supported, in part, by a grant from Physicians Services Incorporated (grant no. PSI 02-23), a Research Allowance from The Canadian

either isomer Institutes for Health Research (SWW) and Ontario Premier’s Award for Research Excellence (SWW). Drs SW Wen and MC Walker are recipients of New Investigator’s Award from the Canadian Institute of Health Research. Dr D Krewski is the NSERC/SSHRC/McLaughlin Research Chair in Population Health Risk 24 0.1 Misoprostol/diclofenac 17 0.1 Misoprostol/diclofenac 9 0.05 Ethinyl estradiol/norethindrone 271 1.5 Ethinyl estradiol/norgestrel (both or Assessment. This study was based on nonidentiﬁable data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health. Throughout pregnancy First trimester Second trimester Third trimester

Prevalence and top 10 of FDA drug category X used by pregnant women during pregnancy period in Saskatchewan, 1997–2000 ( References 1 Rajkumar SV. Thalidomide: tragic past and promising future. Mayo Clin Proc 2004; Table 5 Abbreviation: FDA, Food and Drug Administration. DrugTotalEthinyl estradiol/norgestrel (both or either isomer Ethinyl estradiol/norgestimateMedroxyprogesterone 119Ethinyl Numbers estradiol/norethindroneEthinyl % estradiol/desogestrel 0.6 Drug 80Temazepam Ethinyl estradiol/norgestimate 729Ethinyl 96 estradiol/norethindrone 0.4 49acetate Ethinyl 3.9 estradiol/norethindrone 0.5 Total 0.3 Medroxyprogesterone 91 Ethinyl estradiol/desogestrel 62 0.5 33 Ethinyl estradiol/norgestimate 0.3 0.2 Numbers Medroxyprogesterone 37 Ethinyl estradiol/norethindrone acetate 80 % 0.2 18 31 Drug 0.4 Temazepam 0.2 Ethinyl 0.1 549 estradiol/norethindrone Ethinyl estradiol/norgest Ethinyl estradiol/norethindrone acetate 3.0 23 Total 10 24 0.1 Temazepam 0.1 0.1 Ethinyl estradiol/desogestrel Ethinyl estradiol/norethindrone 15 Numbers % 0.1 22 Drug 1 Medroxyprogesterone 0.1 22 204 0.1 1.1 Total 18 0.1 Numbers % 202 1.1 Misoprostol/diclofenacConjugated estrogenEstradiol 21 0.1 21 Temazepam79 0.1:899–903. Estradiol 16 0.1 Conjugated estrogen 16 0.1 16 Ethinyl estradiol/desogestrel 9 0.1 Conjugated 0.05 estrogen Norethindrone 7 0.03 Misoprostol/diclofenac 6 0.03 Conjugated estrogen 6 6 0.03 Norethindrone 0.03 3 0.01 2 0.01

Journal of Perinatology Patterns of prescription drugs in pregnancy SW Wen et al 329

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