Surveillance of adverse fetal effects of medications (SAFE-Med): Findings from the International Clearinghouse of Birth Defects Surveillance and Research

Reproductive Toxicology 29 (2010) 433–442

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Surveillance of adverse fetal effects of medications (SAFE-Med): Findings from the International Clearinghouse of Birth Defects Surveillance and Research Alessandra Lisi a , Lorenzo D. Botto b , Elisabeth Robert-Gnansia c , Eduardo E. Castilla d,e , Marian K. Bakker f , Sebastiano Bianca g , Guido Cocchi h , Caterine de Vigan i , Maria da Grac¸a Dutra e , Jiri Horacek j , Paul Merlob k , Anna Pierini l , Gioacchino Scarano m,n , Antonin Sipek o , Michiko Yamanaka p , Pierpaolo Mastroiacovo a,∗ a

Centre of the International Clearinghouse for Birth Defects Surveillance and Research - ICBDSR, Via Carlo Mirabello, 19, 00195 Rome, Italy Division of Medical Genetics, Department of Pediatrics, University of Utah, School of Medicine, Salt Lake City, UT, United States c REMERA: REgistre des Malformations En Rhône-Alpes, Faculté de Médecine Laennec, Lyon, France d CEMIC, Buenos Aires, Argentina e ECLAMC-FIOCRUZ, Rio de Janeiro, Brazil f EUROCAT Northern Netherlands, Department of Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands g ISMAC Registry, Genetica Medica, ARNAS Garibaldi Nesima, Catania, Italy h IMER, Institute of Neonatology and Preventive Pediatric Health Care, Bologna University, Bologna, Italy i INSERM, Epidemiological Research Unit on Perinatal and Women’s Health, Villejuif, France j National Registry of Congenital Anomalies in the Czech Republic, Postgraduate Medical Institute, Medical Genetics, Prague, Czech Republic k Department of Neonatology, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel l Institute of Clinical Physiology, Unit of Epidemiology, CNR Area di Ricerca di San Cataldo, Pisa, Italy m Campania Birth Defects Register, Division of Medical Genetics, General Hospital “G.Rummo” Benevento, Italy n Regional Epidemiologic Observatory, Health Council, Benevento, Italy o National Registry of Congenital Anomalies in the Czech Republic, Department of Medical Genetics, Thomayer’s University Hospital, Prague, Czech Republic p Kanawaga Children’s Medical Center, Division of Obstetrics and Gynecology, Yokohama City, Japan b

a r t i c l e

i n f o

Article history: Received 4 November 2009 Received in revised form 3 March 2010 Accepted 21 March 2010 Available online 27 March 2010 This paper is dedicated to Alessandra Lisi (1976–2006). In her work as a birth defect epidemiologist she has made major contributions to the implementation of SAFE-Med and to the findings reported here. Keywords: Teratogen Drug Medication Post-marketing surveillance Birth defect Preconception

a b s t r a c t To evaluate whether the routinely collected data in birth defect registries could be used to assess association between medications and risk for congenital anomalies an “exposed case-only” design was performed. Twelve registries provided 18,131 cases exposed to a medication during the first trimester of pregnancy and with at least one major malformation. Odds ratios for malformations associated with maternal use of selected medications were computed. Among seven most commonly used medications very few significant associations with malformations were identified. Among fourteen potentially teratogenic medications several strong associations were found, including valproic acid with spina bifida, and insulin (as proxy for diabetes) with several types of cardiac defects. Finding known associations provides assurance on the validity of this approach, whereas identifying new associations provides a signal to be followed by confirmatory studies. Through this activity, international networks of birth defect registries can contribute with limited resources to post-marketing surveillance of the teratogenicity of medications. © 2010 Elsevier Inc. All rights reserved.

1. Introduction

∗ Corresponding author. Tel.: +39 06 3701905; fax: +39 06 3701904. E-mail address: [email protected] (P. Mastroiacovo). 0890-6238/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2010.03.005

Birth defects are currently the leading cause of infant death in developed countries, and account for an increasing proportion of infant deaths worldwide [1,2]. For these reasons, preventing birth defects could have a significant impact on child survival and health internationally. Some public health prevention efforts are

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A. Lisi et al. / Reproductive Toxicology 29 (2010) 433–442

already ongoing, such as fortifying flour with folic acid (to prevent spina bifida) and immunizing children with rubella vaccine (to prevent congenital rubella syndrome). On a more individualized basis, preconception care is increasingly seen as major opportunity for prevention for birth defects as well as many other adverse pregnancy outcomes [3]. Included in preconception care is the promotion of the judicious use of medications before and during pregnancy, to ensure that they are effective in the mother and safe for the fetus [4]. Because medications, unlike many other exposures, are taken voluntarily and often under some form of medical supervision or advice, there are significant opportunities for women and health professionals to prevent medication-related birth defects. For example, valproic acid is an effective seizure medication that is also a known fetal teratogen, and can be often substituted before pregnancy with safer alternatives [5]. Other highly teratogenic medications such as retinoic acid or thalidomide have been placed in many countries within programs aimed at reducing pregnancy exposures, by controlling the distribution of the medication or requiring contraception during their use [6,7]. A prerequisite for such interventions is knowing the fetal safety of medications. However, such information is surprisingly limited, even for many products that have long been on the market. According to one estimate, the teratogenicity of at least 80% of medications is uncertain, including many that have been on the market for 15–20 years [8]. This is probably in part because pre-marketing data on fetal safety are scarce and often limited to few animal studies, and post-marketing surveillance in human populations is rarely, if ever, systematic or timely. Such state of affairs is all the more concerning because many women, and in some countries most women, take medications at some time during pregnancy—more than half, according to studies in the United States [9] and Europe [10]. At such high exposure rates, even a small increase in birth defect risk associated with medication use may translate in many affected children. Conversely, avoiding all medications during pregnancy, or mistakenly labeling a medication as carrying a fetal risk while it does not [11,12] may damage the health of the mother, and possibly of the fetus, by withholding effective treatment of serious conditions. To improve knowledge on the fetal effect of medications, and to counter the limits of pre-marketing testing, several strategies for post-marketing surveillance have been used over the years. These include the voluntary reporting system by the US Food and Drug Administration, medication-specific registries for women exposed for example to anti-retroviral medications, vaccines, and psychotropic medications [13–16], teratogen information services [17–22], ad-hoc research studies [9,23,24] or, rarely, cluster investigations [25,26]. Although these studies continue to be helpful, many are neither systematic nor ongoing. A system of systematic and timely monitoring would be extremely helpful, particularly if it can leverage available resources. Here we describe an approach to post-marketing surveillance of fetal effects of medications that leverages data that is continuously gathered by existing birth defect surveillance programs internationally. Such system was started as the MADRE project [27,28] and has developed into the current Surveillance of Adverse Fetal Effects of Medications (SAFE-Med) program, organized through the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) [29,30], an international network of birth defects surveillance programs. The primary objective of this report is to show the feasibility of using such system to screen incoming data for signals suggestive of teratogenic risks. The report also shows selected examples with a focus on common medications and potentially teratogenic medications, evaluated in a cohort of more than 18,000 babies with birth defects born in Europe, Japan, and South America.

Fig. 1. Format of a basic “exposed case-only” design, evaluating the association between medication X and malformation 1. The odds ratio (ad/bc) assesses the association between medication X and malformation 1. Because it is evaluated among birth defect cases, all of which were exposed to some medication, the association provides an indication of the medications’ differential or specific risk for that malformation compared to other malformations as a group.

2. Materials and methods 2.1. Study design Monitoring is based on a case–control analysis among the cohort of subjects with malformations who also had a reported first trimester exposure to medications. In fact, the case-control analysis is an “exposed case-only” design, because all subjects are affected by some birth defect and exposed to some medication. In its basic design, each pairwise analysis contrasts each type of malformation with each type of medication, as illustrated by the two-by-two table in Fig. 1. In the table, “cases” are those subjects with the specific malformation being tested, and “controls” are those with any other malformation; “exposed” are those subjects with a reported exposure to the medication being tested, and “unexposed” are those exposed to any other medication. This pairwise contrast is repeated for every malformation and medication. Each pairwise contrast, that is, each table, generates an odds ratio and confidence interval that provide an estimation of the strength and direction of association between malformation and medication. If there is no specific association, then the expected odds ratio is 1, within the confines of random variation. Otherwise, increased odds ratios, particularly if the absolute value is high, the confidence interval is tight, and number of exposed cases is clinically relevant, constitute a signal to further evaluate a particular malformation-medication association. This analytic approach was conceived and initially implemented by professor Bengt Källén at the University of Lund, Sweden [28]. 2.2. Setting The study is conducted in the setting of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR or Clearinghouse). The Clearinghouse is an international network of registries that conduct joint monitoring of major birth defects, including multiple congenital anomalies, chromosomal conditions, and teratogen-associated phenotypes [29,30]. 2.3. Participants The study population consists of liveborn infants, stillbirths, or terminations of pregnancy with a major birth defect with a reported exposure to a medication during the first trimester, and ascertained by one of the participating surveillance programs. 2.4. Data sources Twelve surveillance programs participated to SAFE-Med at different times from 1990 to 2004, the study period reported here. The coverage, structure, methods, and sources of ascertainment vary by program and are summarized in Table 1. Further details on these programs have been published [29,31–41]. The upper limit of time of ascertainment varies from the neonatal period through two or more years of life. Exposure to medication is most commonly ascertained retrospectively by maternal interview, with a minority of programs relying on pharmacy records or prenatal records completed prospectively (Table 1). 2.5. Bias Several potential sources of bias and confounding should be considered, including a retrospective ascertainment of medication use (leading to recall bias if mothers of babies with birth defects report exposures differently than mothers of controls), the fact that the illness for which a medication is used could itself be teratogenic (leading to bias by indication), and potential confounding by other risk factors for birth defects such as smoking or lack of folic acid use. The study design attempts

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Table 1 Main characteristics of surveillance programs participating to the SAFE-Med project of the International Clearinghouse for Birth Defects Surveillance and Research. Program

Coveragea

Births per year

Information on 1st trimester maternal medication use b

Years covered by this study

Main reference with program’s methods

Czech Republic France-Central East

RP PP1

90,000 100,000

1996–2004 1990–2004

Sipek et al. [31] Robert-Gnansia et al. [32]

France-Paris

PP1

38,500

1992–2004

De Vigan et al. [33]

Italy-IPIMC Italy-IMER Italy-Tuscany

H H PP2

130,000 28,000 25,000

Maternal interview Medical record review (majority), maternal interview (minority) Medical record review (majority), maternal interview (minority) Maternal Interview Maternal Interview Maternal Interview

1992–1994 1990–2003 1992–2003

Italy-BDRCam Italy-ISMAC Israel-IBDMS Japan-JAOG

H H H H

60,000 19,000 20,000 89,000

Maternal Interview Maternal Interview Maternal Interview Maternal Interview

1991–2003 1991–2001 1990–2004 1990–2004

Northern Netherlands

RP

20,000

1990–2004

Latin America-ECLAMC

H

150,000

Pharmacy data and Maternal Interview Maternal Interview

Mastroiacovo et al. [34] Calzolari et al. [35] Italy-Tuscany website [36] Scarano [37] Bianca et al. [38] Merlob et al. [39] ICBDSR Annual Report 2003 [29] Reefhuis et al. [40]

1990–1996

Castilla and Orioli [41]

a

RP: resident population, including only births to resident mothers (even if delivered outside of covered geographic area) and excluding births to non-resident mothers who delivered in the area. PP1: present population, including all births delivered in the area covered by the program, regardless of maternal residence. PP2: present population, excluding births to non-resident mothers delivering in the covered geographic area, and not including births to resident mothers delivering outside of covered area. H: hospital based, typically including a variable, sometimes high proportion of births delivered in the covered geographic area. b Maternal interviews are done soon after delivery and constitute a retrospective report of pregnancy exposures. Prospectively ascertained exposures through review of pregnancy-related medical records or pharmacy records were collected in the surveillance programs from France-Central East, France-Paris, and Northern Netherlands.

to directly address recall bias by including only subjects with birth defects. Bias by indication is difficult to control or identify, as underlying illnesses were not reported to the central database used for this study. Stratifying all analyses by reporting registry may in part control for indication as well as region-specific variation in the use of specific medications. Potential confounding by concurrent risk factors is also difficult to eliminate, unless detailed information on these factors is collected. In this phase of the study it was decided to minimize the quantity of variables and information requested from programs to avoid work overload and increase the number of participating programs. One of the features of this project was precisely to use the information already available within a registry, which could be provided with very limited, if any, additional resources or cost.

and the Nordic Council on Medicines, and is used internationally. In the ATC, medications are typically grouped by organ system on which they act, and by chemical, pharmacological and therapeutic properties. The ATC system specifies medications using a code with up to seven digits. Such codes are hierarchical, such that the coding can be used to aggregate medications based on shared properties. This system provides a uniform approach to analyzing associations between malformations and either specific medications (i.e., by unique chemical) or increasingly larger groups of medications. Typically, five levels are identified from the seven digit ATC codes. The 1st level defines the main anatomical group (1st digit); the 2nd level, the therapeutic subgroup (3 digits); the 3rd level, the pharmacological subgroup (4 digits); the 4th level, the chemical subgroup (5 digits); and the 5th level, the chemical substance (7 digits).

2.6. Study size 2.8. Statistical methods The study is ongoing and is prospective, with no specific target number of cases. All surveillance programs that could provide the data were included in the study. 2.7. Variables The case-information is collected and reviewed by a team of the International Clearinghouse composed by clinicians and epidemiologists, and the malformation(s) and medication(s) are coded and classified using a standardized approach, described below. Information on malformation were provided as verbatim description by Italy IPIMC, Italy BDRCAM, Israel IBDMS and Japan JAOG; as ICD-9 or ICD-10 codes by France Central East, France Paris, Italy Tuscany, and Czech Republic; and by both verbatim description and codes by Italy IMER, Italy ISMAC, Northern Netherlands, and South America ECLAMC. For the classification of malformations, cases are reviewed by a clinician with expertise in genetic and dysmorphology to separate cases of isolated major malformations from cases of multiple congenital anomalies. Syndromic cases are included. Isolated major malformations are defined as cases with one major malformation or a major sequence (e.g.: spina bifida plus hydocephalus, gastroschisis plus intestinal malrotation, holoprosencephaly with cleft lip) with or without minor malformations (e.g.: low set ears, clinodactyly). Multiple malformations are defined as two or more major unrelated malformations without a diagnosis of a syndrome. VATER association and oculo-auricolar-vertebral association (Goldhenar syndrome) are classified as multiple malformations. Malformations are coded using the BPA (British Paediatric Association) modification of the World Health Organization’s ICD-9 (International Classification of Diseases) system (BPA, 1979). Malformations were analyzed by defect group, and, within each group, separately for isolated malformations and multiple congenital anomalies. With the exception of Italy-Tuscany, which provided directly coded data on medications, all other programs submitted original medication information that was coded centrally using the ATC (Anatomical Therapeutic Chemical) system by a single investigator (ERG). The ATC was developed jointly by the World Health Organization

Associations between medications and malformation were assessed using odds ratios, 99% confidence intervals, and p values. Analyses were stratified by surveillance program and year. Heterogeneity across strata was evaluated with the Breslow-Day test. For associations without significant heterogeneity among strata, a Mantel-Haenzel pooled estimate (together with its 99% CI p value) was obtained. Each malformation group was analyzed also separately for isolated cases and multimalformed cases separately. The analyses were done using SAS version 9.1 and STATA. Each malformation group was analyzed first in isolated cases and in multimalformed cases, then in all cases. The first step aims to identify possible association with a specific phenotype, the second step aims to increase the sample size.

3. Results The study included 18,131 cases of malformed infants with first trimester medication exposures identified by 12 programs among approximately 7.5 million monitored births. Assuming a 1.5% rate of clinically significant, major birth defects diagnosed in the newborn period, it can be estimated that approximately 112,500 babies were born with major birth defects in that birth population. From these figures, the estimated frequency of reported medication use during the first trimester of pregnancy in the case population is approximately 16% (81,131/112,500). Nearly 90% of cases were contributed by programs in Italy (31%), France (24%), Northern Netherlands (17%), and Latin America (16%). Table 2 summarizes the frequency of the main malformation groups among the cases. Table 3 describes the specificity of medication

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Table 2 Number of malformations registered in the SAFE-Med Database 1990-2004. International Clearinghouse for Birth Defects Surveillance and Research. Malformation

All

Isolated

Multimalformed cases

Ventricular septal defects Hypospadias Cleft lip with or without palate Club foot Polydactyly Hydronephrosis Cardiac outflow tract defect Hip dislocation Cleft palate (included Pierre Robin) Limb reduction defect Spina bifida Hydrocephaly Syndactyly Cardiac left ventricle obstructive defects Cardiac right ventricle obstructive defects Anorectal atresia/stenosis Cystic kidney Oesophageal atresia/stenosis Anencephaly Axial skeleton malformation Atrial septal defects Diaphragmatic defect Unilateral kidney a/dysgenesis Intersexual organs, ambiguous Microcephaly Omphalocele Patent ductus arteriousus Gastroschisis Severe ear malformation Craniostenosis Cardiac endocardial cushion defects Encephalocele Bilateral kidney a/dysgenesis Intestinal atresia/stenosis Ureter stenosis/atresia Duodenal atresia Facial dysmorphisms Holoprosencephaly Choanal atresia Urethral atresia/stenosis sequence Multiple malposition/contractures Cardiac common ventricle Situs anomalies Bladder exstrophy Ebstein’s anomaly Anophthalmia Cardiac total anomalous pulmonary venous return Situs inversus ± dextrocardia Prune Belly sequence Epispadias Levo transposition of great arteries Exstrophy of cloaca

1476 1302 967 947 885 827 736 609 551 542 517 455 410 374 324 314 300 289 287 279 273 250 214 210 172 154 152 114 111 110 100 99 93 79 75 74 73 59 58 56 51 47 37 35 27 25 25 25 24 24 14 8

1304 1124 826 946 745 706 637 608 395 382 446 307 306 309 291 155 207 160 242 91 216 177 152 107 84 89 116 88 72 80 74 70 46 67 55 48 73 27 39 41 37 41 35 20 22 9 19 16 13 16 13 1

172 178 141 0 140 121 99 0 156 160 71 148 104 65 33 159 93 129 45 188 57 73 62 103 88 65 36 26 39 30 26 29 47 12 20 26 0 32 19 15 14 6 2 15 5 16 6 9 11 8 1 7

Table 3 Number of medication exposures reported among 18,131 cases with malformations, by program and number of digits of ATC code, SAFE-Med database 1990-2004. International Clearinghouse for Birth Defects Surveillance and Research. Registry

Number of cases

Classification levela 1

France-Central East France-Paris Italy-IPIMC Italy-IMER Italy-Tuscany Italy-BDRCam Italy-ISMAC Israel-IBDMS Northern Netherlands Czech Republic South America-ECLAMC Japan-JAOG Total a

2455 1857 1573 981 1213 1391 517 232 3007 1117 2836 952 18,131

2 4 1

3

4 66

341 257 70 81 65 10 1 14 87

20

453 7

251 11

460 317 1278 148 326 1909 556 61 537 160 521 139

321

1731

1188

6412

169

127

46 25 78 130 908 14

4

Number of exposures to medications

5 3208 2035 821 1014

222 4366 1345 2950 1271

4059 2635 2247 1373 1468 1933 557 301 5183 1505 4195 1428

17,232

26,884

1st level: anatomical main group (1 digit), 2nd level: therapeutic subgroup (3 digits), 3rd level: pharmacological subgroup (4 digits) 4th level: chemical subgroup (5 digits), 5th level: chemical substance (7 digits).

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Table 4 Number of medication exposures reported among 18,131 cases with malformations, by type of case: isolated or associated defects. SAFE-Med database 1990–2004. International Clearinghouse for Birth Defects Surveillance and Research. Number of medications used in the first trimester

Total

1

2

3

≥4

All cases

12.144 67.0%

4.032 22.2%

1.385 7.6%

570 3.1%

18.131 100.0%

Isolated cases

11.036 67.4%

3.600 22.0%

1.234 7.5%

502 3.1%

16.372 100.0%

Multimalformed cases

1.108 63.0%

432 24.6%

151 8.6%

68 3.9%

1.759 100.0%

codes available in the data set. Of the 18,131 cases, 85% had been exposed to medications coded to the 4th and 5th level of the ATC system. Of these 18,131 there were 1246 syndromic cases (6.9%) (chromosomal or genetic conditions such as trisomies or ostechondrodysplasias). These were always included in the ‘affected control’ group. Table 4 describes the number of medication exposures in the first trimester of pregnancy by type of cases. Almost two-third of cases were exposed to a single medication. No difference was found among isolated and multimalformed cases. The results of the analysis presented here serve as examples of how the system works and the type of findings that can be generated. The first set of findings focuses on the commonest medications. The type and frequency of the seven most commonly reported medications are shown in Table 5. For some of these medications, reported use varied by geographic area. For example, reports of use of pregnen derivatives, which are used to reduce the risk of miscarriage, was considerably higher in Italy (15–30% of reported cases) than elsewhere (6–9%). The second set of findings focuses on 14 medications selected because of known or potential teratogenicity (insulin was included as an indicator of underlying diabetes rather than as a potential teratogen). As summarized in Table 6, in this group of 14 medications

the frequency of use for fatty acid derivates, used as antiepileptics (valproic acid and valproate) was reported more frequently by surveillance programs in France (8–14%) than in other countries (0.3–4%). Tables 7 and 8 summarize the statistically significant associations between specific medications and malformations (at least 3 cases exposed). No significant associations were identified with acetaminophen (paracetamol), salycilic acid, vitamin K antagonists, lithium, triazole derivatives, and retinoids. The following significant associations in Table 7 were based on at least ten exposed cases: (a) pregnen derivatives (mainly progesterone) with isolated hypospadias; (b) amino-phenylethanol derivatives (mainly isoxsuprine) with isolated hypospadias and isolated anorectal atresia; (c) thyroid hormones (mainly levothyroxine) with isolated unilateral kidney agenesis. Among the significant associations summarized in Table 8 the following associations are noteworthy and based on at least 10 exposed cases: (a) antiepileptics—fatty acid derivatives (mainly valproic acid) with spina bifida (isolated and multiples), hypospadias (isolated and multiples), and polydactyly (multiple congenital anomaly only); (b) carboxamide derivatives (mainly carbamazepine) with isolated cleft palate and isolated spina bifida; (c) barbiturates with isolated cleft

Table 5 Most common medications and number of exposed pregnancies among 18,131 cases of malformations, SAFE-Med Database 1990-2004. International Clearinghouse for Birth Defects Surveillance and Research. Medication

ATC code

Number exposed

Percent exposed

Pregnen-4 derivatives (e.g.: progesterone) 2-amino-1-phenylethanol derivatives (e.g.: isoxsuprine) Penicillins with extended spectrum (e.g.: ampicillin) Paracetamol (Acetaminophen) Thyroid hormones (e.g.: levothyroxine) Salicylic acid and derivatives (e.g.: acetylsalicylic acid) Sympathomimetics, labour repressants (e.g.: ritodrine)

G03DA C04AA J01CA N02BE01 H03AA N02BA G02CA

1448 1143 1018 751 707 699 635

7.99 6.30 5.61 4.14 3.90 3.86 3.50

Table 6 Frequency of medications with known or suspected teratogenic potential among 18,131 subjects with malformations exposed to medications, SAFE-Med database 1990-2004. International Clearinghouse for Birth Defects Surveillance and Research. Medication

ATC code

Total exposures

Percent exposed

Benzodiazepines and derivatives Insulins and analogues Fatty acid derivativesa Barbiturates, derivatives and plain Carboxamide derivatives Sulfur-containing imidazole derivatives Hydantoin derivatives Oral blood glucose lowering drugs Other antiepileptics Prostaglandins Vitamin K antagonists Lithium Triazole derivatives Retinoidsb

N03AE-N05BA-N05CD A10A N03AG N03AA-N05CA N03AF H03BB N03AB A10B N03AC-N03AD-N03AX A02BB B01AA N05AN J02AC D10BA-D05BB

472 445 335 179 179 80 69 46 43 32 15 14 7 4

2.60 2.45 1.85 0.99 0.99 0.44 0.38 0.25 0.24 0.18 0.08 0.08 0.04 0.02

a b

Includes antiepileptics such as valproate. For treatment of acne or psoriasis.

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Table 7 Associations between commonly used medications and malformations (p < 0.01 and more than 3 exposed cases) SAFE-Med database 1990–2004. International Clearinghouse for Birth Defects Surveillance and Research. Malformations

ATC code Total number of exposed cases Hypospadias

Cases exposed to common medications Pregnen-4derivatives (e.g.: progesterone)

2-Amino-1phenylethanol (e.g.: isoxsuprine)

Penicillins (e.g.: ampicillin)

Thyroid hormones (e.g.: levothyroxine)

Sympaticomimetics (e.g.: ritodrine)

G03DA 1448 Isolated cases (133) 1.56 (1.18–2.06)****

C04AA 1143 Isolated cases (134) 1.43 (1.07–1.92)*

J01CA 1018

H03AA 707

G02CA 635

Unilateral kidney a/dysgenesis Anorectal atresia

Isolated cases (16) 2.06 (1.02–4.15)* Isolated cases (25) 2.00 (1.101–3.94)*

Axial skeleton malformations

Endocardial cushion defect

Multimalformed cases (6) 5.40 (1.27–22.97)** Isolated cases (9) 2.94 (1.15–7.58)*

Urethra atresia Prune belly sequence

All cases (6) 3.69 (1.01–13.49)* Isolated cases (4) 8.47 (1.35–46.98)**

*p < 0.01; **p < 0.001; ***p < 0.0001; ****p < 0.00001. () brackets = number of exposed cases.

lip/palate; (c) insulins with isolated VSD, cardiac outflow tract defects and secundum atrial septal defect; left ventricle obstructive defects (all cases); isolated and multiples axial skeleton defects, (d) benzodiazepines with isolated cleft lip/palate. Several additional associations reached statistical significance with fewer than 10 cases, typically with an odds ratio of at least 3 and often with p < 0.001. 4. Discussion This study shows the feasibility of using networks of existing birth defect surveillance programs as a tool to screen for possible teratogenic effects of medications. Specifically, the SAFE-Med activity of the International Clearinghouse can be viewed as a significant opportunity for post-marketing surveillance of the fetal effects of medications. Although it has limitations, this activity has the advantage of being ongoing and systematic, and because it builds upon existing surveillance programs, it can be implemented in many areas with limited additional resources. In this report, we show how the SAFE-Med approach detected several well known associations between malformations and medications. These include associations between valproic acid and spina bifida, hypospadias, and craniosynostosis [42–48], as well as between phenobarbital and oral clefts [5]. Additional findings included the association between certain thyroid medications (sulfur imidazole derivatives such as carbimazole and thiamazole/methimazole) and choanal atresia, which is less well established and more recently reported [49]. It was also reassuring to find strong associations between several major malformations and the use of insulin, as an indicator of clinically significant diabetes. The odds ratios were quite strong for several conditions of likely early embryonic origin, including holoprosencephaly (odds ratio—OR 28.2 isolated, p < 0.00001; 5.63 in multiples, p = 0.00098), l-transposition of the great arteries (OR 10.7; p < 0.00001), total anomalous pulmonary return (OR 8.2, p = 0.00038), and common ventricle (OR 7.0, p < 0.00001). Scanning a set of commonly used medications also provided instructive findings. Monitoring fetal effects of common medications is important because at such high rate of exposure even small increases in teratogenic risk could lead to many affected pregnan-

cies. Among the few “signals” observed in the seven most frequently used medications, one might be considered for follow-up studies, namely, the association between thyroid medication (H03AA) and urinary tract anomalies (with isolated unilateral kidney agenesis and all type of urethra atresia), also in light of experimental data in rats suggesting that pharmacologically induced hypothyroidism during a critical window might affect renal development [50,51]. Although it is difficult to know for sure, the remaining “signals” among common medications are likely associations due to chance (e.g.: isolated prune belly sequence and penicillins, and axial skeleton defects and sympaticomimetics). Alternatively, some may be due to the underlying maternal conditions that led to the use of medications. For example, the analysis identified an association between (a) hypospadias and the use of isoxsuprine and other 2-amino-1-phenylethano derivatives or of progestins (pregnen-4 derivatives), which are typically used in some countries in women with previous miscarriages or with threatened abortion in the index pregnancy, and (b) cleft lip/palate and benzodiazepines which are often used in women with epilepsy. Interpreting the findings of the SAFE-Med approach require understanding what this analysis can provide, as well as its limitations and strengths. The analysis provides odds ratios, but because all subjects in the analysis, have malformations and all have been exposed to some medication (by design), their interpretation is somewhat different from that of standard case–control studies. The odds ratios estimate not so much the relative risk of disease among those exposed (as in a classic case–control design), but rather the how strongly a medication is associated with a specific malformation, compared to the overall association of all other medications with all other malformations. In other words, the odds ratios reflect how much a given association stands out among the underlying association patterns among all birth defects and medications. Limitations of the current system include the potential for missed signals or false negatives, as well as for spurious signals or false positives. Missing true associations (less than perfect sensitivity) can stem from several factors, including the rarity of the exposure and misclassification (typically non-differential) of exposures, outcomes, or both. For example, the association between retinoids and severe ear anomalies (OR 110.9, p < 0.00001) did not trigger a signal because the system was set to ignore associations

Table 8 Associations between medications with known or suspected teratogenic potential and selected malformations (p < 0.01 and more that 3 exposed cases). SAFE-Med Database 1990–2004. International Clearinghouse for Birth Defects Surveillance and Research. Malformations

Medications (short name) with ATC code Medications used mainly in epilepsy

Medications for diabetes

Other suspected or proven teratogens

Fatty acid

Carboxamide

Hydantoin

Barbiturates

Other AED

Insulins

Oral glucose lowering

Benzodiazepines

Imidazole derivatives

Prostaglandines (e.g.: misoprostol)

ATC code

N03AG

N03AF

N03AB

N03AA N05CA

N03AC N03AD N03AX

A10A

A10B

H03BB

A02BB

Number of exposed cases Ventricular septal defect

335

179

69

179

43

445

46

N03AE N05BA NO5CD 472

80

32

Hypospadias

Isolated cases (27) 1.80 (1.04–3.11)* Multimalformed cases (16) 5.76 (2.72–12.21)****

Isolated cases (50) 1.60 (1.0–2.43)*

Polydactyly

Cardiac Outflow tract defect Cleft palate

Limb deficiency

Spina bifida

Multimalformed cases (10) 4.16 (1.63–10.58)*** Multimalformed cases (8) 3.74 (1.35–10.35)*** Multimalformed cases (9) 2.98 (1.15–7.68)** Multimalformed cases (8) 2.81 (1.08–7.37)** Isolated cases (43) 5.97 (3.68–9.67)**** Multimalformed cases (6) 5.30 (1.51–18.61)****

Isolated cases (31) 3.59 (2.06–6.23)****

Multimalformed cases (3) 14.08(2.59–76.66)****

Multimalformed cases (4) 5.34 (1.35–21.19)***

Multimalformed cases (3) 9.98 (1.96–56.63)***

Isolated cases (38) 1.73 (1.10–2.73)*

Isolated cases (31) 2.14 (1.30–3.57)***

Isolated cases (14) 2.33 (1.12–4.84)** Isolated cases (4) 6.22 (1.51–25.68)** Isolated cases (10) 2.44 (1.04–5.74)*

Isolated cases (5) 5.48 (1.30–21.65)**

Hydrocephaly

Multimalformed cases (5) 10.62 (2.82–40.01)****

Unilateral kidney a/dysgenesis Left ventricle outflow obstructive defects Axial skeleton malformations

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Cleft lip ± palate

Multimalformed cases (3) 23.78(3.80–148.82)**** All cases (20) 2.11 (1.13–3.93)*

Multimalformed cases (4) 9.16 (2.18–38.52)****

439

Isolated cases (10) 4.35 (1.68–11.28)*** Multimalformed cases (19) 3.88 (1.95–7.73)****

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Table 8 (Continued ) Malformations

Medications (short name) with ATC code Medications used mainly in epilepsy Fatty acid

Carboxamide

Hydantoin

Atrial septal defect, secundum Microcephaly

Isolated cases (5) 4.33 (1.06–17.80)*

All cases (3) 5.36 (1.02–28.24)*

Barbiturates Multimalformed cases (4) 9.77 (2.45–39.06)**** Isolated cases (6) 7.20 (2.20–3.57)****

Other AED

Medications for diabetes

Other suspected or proven teratogens

Insulins

Benzodiazepines

Oral glucose lowering

Prostaglandines (e.g.: misoprostol)

Isolated cases (11) 2.28 (1.00–5.19)*

Omphalocele

Isolated cases (4) 12.67 (2.69–59.70)**** Isolated cases (9) 3.34 (1.29–8.61)**

Gastroschisis

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Patent ductus arteriosous

Craniosynostosis

Imidazole derivatives

Isolated cases (8) 3.95 (1.44–10.80)** Isolated cases (7) 14.16 (3.62–55.33)****

Bilateral kidney agenesis

Multimalformed cases (4) 4.55 (1.15–17.98)* Isolated cases (6) 3.88 (1.22–12.33)**** Multimalformed cases (3) 16.66 (2.45–113.04)****

Intestinal atresia

Holoprosencephaly

Choanal atresia

Single ventricle (cardiac) Total anomalous pulmonary venous return L-transposition of the great arteries *p < 0.01; **p < 0.001; ***p < 0.0001; ****p < 0.00001. () brackets = number of exposed cases.

Isolated cases (4) 10.06(2.40–49.18)**** Multimalformed cases (4) 5.63 (1.23–25.85)** Isolated cases (5) 4.87 (1.17–20.28)* Isolated cases (8) 7.03 (2.48–19.90)**** Isolated cases (3) 8.24 (1.32–51.38)** Isolated cases (4) 10.66 (2.13–53.38)****

Isolated cases (4) 36.96 (6.60–207.09)****

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with less than three exposed cases, even when statistically significant, and this specific association had only one exposed case in the study. Misreporting or misclassifying exposures or outcomes is also a major concern in such activity. In an international collaboration there is heterogeneity among program in the collection and reporting of malformations and medications. This may have been a factor in the variability of the exposures reported by program, even within the same country (see Italian programs in Table 3). The high rate of exposures reported in some programs, such as in the Netherlands may be due to better reporting due also to access to pharmacy data. If such misreporting is non-differential, associations may be diluted and true teratogenic signals may be missed (false negative finding). To reduce the potential for spurious findings, several measures are taken. Medications and malformations are reviewed and coded centrally. Also, the analysis is stratified by program, and greater consideration is given to associations that hold across multiple programs and countries. Finally, associations that could be missed, because of the analytic design, are those in which a teratogen causes in equal measure all types of malformations. In our view, this is not a major limitation, as most known teratogens cause one or few specific types of malformations, but not all. A second concern is that of false positive associations. These also can be due to several reasons. In case–control studies, a basic concern is differential recall between mothers of affected babies and mothers of unaffected babies (controls). In SAFE-Med, this is less of a concern because of the case-only design, in which the ‘control’-mothers in any given analytic contrast also had affected babies. Misreporting may still generate false associations (false positives) if, for example, information on use of certain medications (e.g.: valproate) is elicited with greater intensity by the interviewer among women of pregnancies with certain malformations (e.g.: spina bifida) compared to other malformations. False positive association can be also due to multiple testing alone. To decrease this problem, the SAFE-Med activity has been set to use fairly stringent parameters, including a minimum number of exposed cases, small p values (less than 0.01), and replication in at least two programs. Evidence for biologic plausibility can also be helpful. Information on medication dose, timing, or indication are also available in this study but in a very limited number of cases. This is mainly a consequence of an approach based on available data from registries collected as part of ongoing surveillance. The SAFE-Med approach also has specific strengths. First, because it uses available information, it is relatively inexpensive. By using currently active birth defect programs, it may provide systematic, ongoing surveillance in places where no such system was in place. However, to be eligible to contribute, a program should demonstrate its ability to provide systematically information on first trimester medication exposure, collected through medical records, prenatal notes, or maternal interviews. Second, as previously noted, the approach does not rely on unaffected controls, which are difficult if not impossible to incorporate in many public health programs without resorting to research studies. Using affected subjects only could in fact decrease recall or reporting biases that are though to occur to some degree in traditional case–control studies, particularly when using selfreported exposures. As also noted previously, one strength of SAFE-Med its systematic and centralized approach to reviewing and classifying both malformations and medications. This allows for examples also to analyze associations by isolated versus multiple congenital anomaly cases. Finally, the international contribution to the surveillance effort allows testing of the associations in different populations, and this provides not only access to a larger base population (and greater statistical power) but also offers an internal test of consistency across systems and populations.

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The SAFE-Med approach can be improved. The protocol is currently being revised to include additional information on the precise timing of exposure (gestational weeks instead of just first trimester), on the indication for the medication (to try and assess the relation between the effects of medication and underlying illness), and on potential confounders or effect modifiers (e.g.: consumption of vitamin or folic acid supplements, smoking, alcohol use). An important issue is how best to use the data generated by programs such as SAFE-Med. Experience has shown that premarketing testing does not exclude teratogenic risks and cannot ensure the fetal safety of medications in humans. Whereas it does not substitute other approaches such as the voluntary notification of adverse effects, SAFE-Med provides systematic and ongoing post-marketing surveillance of many medications used in pregnancy. In addition, SAFE-Med by using the accumulating database can be used to quickly replicate putative associations suggested by single case-reports or small case-series, with the additional advantage of using a large, international sample. An ongoing challenge remains the sensitivity of the system, which is largely driven by the frequency of the exposure, the associated odds ratio of disease, and the reporting characteristics of the contributing program. By using the infrastructure of existing birth defect surveillance programs, approaches such as SAFE-Med can likely be implemented and expanded rapidly and with limited amount of funding. Finally, it is important to note that many times pregnant women take medications on the advice of medical professionals or influenced by marketing by pharmaceutical companies. In our view, this fact provides a strong argument to the health and business communities for continued and expanded support of post-marketing surveillance of medications, both as an ethical obligation and practical necessity. Conflict of interest statement All authors declare that there are no conflicts of interest. Ethics review The report is based on the analysis of pooled, de-identified data from participating birth defect programs, for which ethics review or patient consent data were not necessary. The primary data are collected by each birth defect program, who maintain and are responsible for the ethics review process at each site. Acknowledgements We acknowledge the support for this project to the Centre of the ICBDSR from the US Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Cooperative Agreement Number U50/CCU207141 and Grant Number 1U50DD000524-01. The France-Paris Registry received financial support from INSERM (Institut National de la Santé et de la Recherche Médicale), DGS (Direction Générale de la Santé) and InVS (Institut de Veille Sanitaire). The ECLAMC had Grant sponsor: CNPq/MS/DECIT: 40.3444/ 2004-7; 40.1467/2004-0; CNPq, Brazil: 472086/2004–9; CNPq, Brazil: 30.8885/2006-6; FAPERJ, Brazil: E-26/152.831/2006; Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), Argentina: PICTO-CRUP 2005 # 31101; CONICET: Argentina. References [1] Christianson A, Howson C, Modell B. March of dimes global report on birth defects: the hidden toll of dying and disabled children. White Plains (NY): March of Dimes Birth Defects Foundation; 2006.

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