Pregnancy outcomes after maternal use of thiocolchicoside: A case series

Accepted Manuscript Title: Pregnancy outcomes after maternal use of thiocolchicoside: A case series Authors: Yusuf C. Kaplan, Elif Keskin-Arslan, G¨ozde Kuc ¨ ¸ uksolak, ¨ Fatih Akyol, Barıs¸ Karadas, Sacit Nuri G¨orgel, Tijen Kaya-Temiz PII: DOI: Reference:

S0890-6238(17)30483-5 https://doi.org/10.1016/j.reprotox.2018.01.003 RTX 7623

To appear in:

Reproductive Toxicology

Received date: Revised date: Accepted date:

4-7-2017 26-12-2017 23-1-2018

Please cite this article as: Kaplan Yusuf C, Keskin-Arslan Elif, Kuc ¨ ¸ uksolak ¨ G¨ozde, Akyol Fatih, Karadas Barıs¸, G¨orgel Sacit Nuri, Kaya-Temiz Tijen.Pregnancy outcomes after maternal use of thiocolchicoside: A case series.Reproductive Toxicology https://doi.org/10.1016/j.reprotox.2018.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Pregnancy outcomes after maternal use of thiocolchicoside: A case series Running Title: Pregnancy outcomes following thiocolchicoside exposure

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Yusuf C. Kaplan1,2, M.D., Elif Keskin-Arslan1,2, M.D., Gözde Küçüksolak1, S.M.S., Fatih Akyol1, J.M.S., Barış Karadas1,2, M.D., Sacit Nuri Görgel3, M.D., Tijen Kaya-Temiz1,2, Ph.D.

Author initials: YC Kaplan, E Keskin-Arslan, G Kucuksolak, F Akyol, B Karadas, SN Gorgel, T

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Kaya-Temiz

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Author affiliations

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1. Terafar - Izmir Katip Celebi University Teratology Information, Training and Research

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Center, Izmir, Turkey.

2. Izmir Katip Celebi University School of Medicine, Department of Pharmacology Izmir,

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Turkey

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3. Izmir Katip Celebi University School of Medicine, Department of Urology, Izmir, Turkey

Word Count: 2471 (not including abstract, highlights, tables, figures, acknowledgments or

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references)

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Tables: 4

Figures: 1 Appendix: 0

Corresponding Author: Yusuf Cem Kaplan, M.D., Professor of Pharmacology Director, Terafar, Izmir Katip Celebi University Teratology Information, Training and

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Research Center, Izmir, Turkey Address: Izmir Katip Celebi Ataturk Egitim ve Arastirma Hastanesi, Klinik Farmakoloji ve Toksikoloji Birimi, 35360, Karabaglar, Izmir, TURKEY. Telephone: +902322444444 Ext.1798 Fax: +90 232 245 04 38

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Email: [email protected]

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Highlights

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 In 2014, the EMA restricted the use of thiocolchicoside in reproductive-age women

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 Previous and this case series indicate that thiocolchicoside is not a major teratogen.

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 Current restrictions on use should continue.

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 EMA’s report might be increasing the perceived teratogenic risk and needs a revision.

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Abstract

OBJECTIVE: The 2014 report by European Medicines Agency (EMA) restricted the use of

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thiocolchicoside for all reproductive-age women. In this study, we aim to expand the systematically-collected human data and discuss it within the frame provided by this report. METHODS: We identified and evaluated the outcomes of 48 prospectively recorded pregnancies referred to Terafar (Teratology Information Service, Izmir, Turkey).

RESULTS: Of 42 pregnancies with first-trimester exposure and known outcomes, 31 resulted in live births, four in miscarriage and seven ended with elective terminations. There were 26 normal outcomes, two major and three minor congenital malformations among the live births.

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CONCLUSIONS: Despite a number of limitations, our results and previous case series collectively strengthen the view that thiocolchicoside is unlikely to be a major teratogen.

EMA’s 2014 report should be revised to reflect this finding, while current restrictions on use

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should continue until more detailed safety information is available.

Keywords: Thiocolchicoside; pregnancy; congenital abnormalities; birth defects; pregnancy

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outcomes; muscle relaxants

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Introduction

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Thiocolchicoside is a semi-synthetic derivative of the naturally occurring glycoside, colchicoside, used as muscle-relaxant by per oral, intramuscular and topical routes, with authorization in

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countries including European Union Member States such as France, Italy, Spain and Portugal (1–3). Although initially thought to be a GABAA receptor agonist (4), later studies challenged this finding

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by demonstrating its GABAA receptor antagonistic (5,6) and convulsant effect in animals (6,7) and humans (8). Other in vitro and in vivo studies showed its strychnine-sensitive glycine receptor

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agonistic (9), analgesic and anti-inflammatory (10), anti-vasospastic (11), anti-osteoclastogenic actions (12). Although some studies supported its efficacy in the treatment of acute low-back pain (13, 14), its efficacy over placebo is controversial (15). The chemical structure of thiocolchicoside is closely related to colchicine which predicts a similar adverse effect profile (15).

Although used for decades, data regarding thiocolchicoside use in pregnancy is surprisingly scarce. The issue was further complicated by the report of European Medicines Agency’s Committee on Human Medicinal Products (EMA-CHMP) in 2013, later updated in 2014 (2). This report, initially triggered by a referral by Italian Medicines Regulatory Agency (AIFA), suggested that, after taking

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therapeutic doses of thiocolchicoside by mouth, thiocolchicoside metabolite M2 (or SL59.0955) levels may reach the threshold for the occurrence of aneuploidy, a risk factor for adverse fetal

development, reduced fertility and cancer. In addition, the review of the anecdotal post-marketing data in two global databases revealed nine cases of malformed infants after mothers’ exposure to thiocolchicoside during pregnancy. Based on these experimental and clinical findings, EMA-CHMP

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decided to restrict the maximum dose and duration permitted for thiocolchicoside treatment via

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the peroral and intramuscular route. Moreover, the use of thiocolchicoside was contraindicated in

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children, pregnant and lactating women, and even in reproductive age women not using

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contraception.

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The restriction imposed by EMA-CHMP was undoubtedly pertinent; however, there remains the

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issue of how to counsel pregnant women who are inadvertently exposed to thiocolchicoside. To date, the systematically collected human data regarding thiocolchicoside exposure during

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pregnancy are limited to three case series (16-18), which investigated the outcomes of 133 pregnant women in total, and reported a rate of congenital malformations no different than the

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background rate of 3%.

Given that both unplanned pregnancy and acute-low back pain are frequent in the general

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population (19–21), the possibility that pregnant women are being exposed to thiocolchicoside is not small. To expand the limited human data and advance the discussion relating to the current framework provided by EMA-CHMP’s 2014 report, we aimed to evaluate the outcome of exposed pregnancies referred to Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center, Turkey).

Methods This study received ethical approval from Izmir Katip Celebi University Non-Interventional Studies Ethics Committee (26.05.2016, #124). In our study, we included all women exposed to

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thiocolchicoside during pregnancy who were referred for a risk assessment to Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center, Turkey) between 2009 and 2014.

All relevant data regarding maternal characteristics, medical, obstetric and family history,

medication and other exposures (e.g., drugs of abuse, herbal supplements, etc.) were recorded

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through face-to-face interviews using a structured questionnaire at the time of the referral, before

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any outcome was known, therefore most of the data can be regarded as prospective. However, for

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the pregnant women enrolled later during the 2nd trimester, the term “prospective” might have

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limitations since the patient probably have had an USG at that time and her medication history would carry retrospective features in case the exposure had happened in the first trimester.

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To investigate the pregnancy outcomes, a subsequent telephone interview was conducted with the

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mothers after the birth, based on a structured follow-up questionnaire. This aimed to obtain the following information: Possible complications during pregnancy (e.g., preeclampsia, gestational

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diabetes, etc.), further information in case of pregnancy loss, gestational age at birth, sex, birth

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weight and length, head circumference and Apgar scores. The survey also aimed to identify whether there had been any major and minor congenital malformations or adverse physical and

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neurodevelopmental effects in the infant discovered either at birth or during routine family physician visits. The gestational week at the initial contact was calculated with regard to the ultrasound (USG) or, if unavailable, the last menstrual period (LMP). In this study, the primary outcomes of interest were the rate and pattern of major congenital malformations. The secondary outcomes were the rate of

miscarriage, elective termination, stillbirth, preterm birth and low birth weight. Major and minor congenital malformations were classified using the Malformation Coding Guides of European Surveillance of Congenital Anomalies (EUROCAT) (22, 23). Miscarriage was defined as the spontaneous loss of a pregnancy <20th week, elective termination was defined as the voluntary

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abortion for non-medical intent, stillbirth was defined as the birth with no signs of life >20th week, preterm birth was defined as the birth <37th week and low birth weight was defined as the birth weight <2500g. Results

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Over the five-year period between 2009 – 2014, 48 prospective cases with exposure to

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thiocolchicoside during pregnancy were identified. The malformation rate calculations were

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restricted to first trimester exposures that resulted in live births, due to the unavailability of data

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regarding major congenital malformations from the pathological examinations of miscarriages and elective terminations.

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After excluding the cases lost to follow-up (n=5) and exposures occurred during the second or third

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trimester (n=1), 42 first trimester exposures with known outcomes were included (Figure 1). The median maternal gestational age at admission was 7 (range: 5-14) weeks. The median start time of

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exposures were three weeks after LMP (gestational age was determined by USG in 82% of the

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patients with a definite exposure period) (range: 0-9 weeks) and median duration of 6 (range: 149) days. Detailed maternal characteristics are presented in Table 1 and patterns of exposure are

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presented in Table 2. A high number of exposed co-medications were identified and presented in Table 4. Of the 42 pregnancies with known outcomes, 31 (73.8%) were live births, 4 (9.5%) were miscarriages, and 7 (16.7%) were elective terminations. The median age of the children at the time of the follow-up was 21 months (range: 13-41 months). One infant was reported to have a low birth

weight for gestational age, and another was reported to be born preterm. Child characteristics are presented in Table 3. Among 31 live births with in utero exposure to thiocolchicoside during the first trimester, there were 26 (83.8%) normal outcomes, two major (6.5%) and three minor (9.7%) congenital malformations. The two major congenital malformations identified were: a cleft lip with

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palate in a male infant (Case 21, Table 4), and a bilateral hip dislocation in a female (Case 42, Table 4). The three minor congenital malformations were a bilateral vesicoureteral reflux (VUR) (Case 38, Table 4) in a female with intrauterine growth retardation (IUGR), a preauricular skin tag in a male (Case 16, Table 4) and a patent foramen ovale (PFO) in a female (Case 19, Table 4) respectively . A detailed descriptive analysis of the infants with congenital malformations with regard to the FDA

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Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (24) is

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presented in Table 4.

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Discussion

We evaluated 42 prospectively recorded pregnancies with thiocolchicoside exposure. While the

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rates of major and minor malformations, stillbirth, preterm birth and low birth weight were not

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higher than the general population rates (25, 26, 27, 28), there was a considerably higher rate of elective termination (29, 30). Although the miscarriage rate in our case series was similar to the

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population rate, it should be highlighted that computing and comparing the risk estimate of miscarriage with patients being enrolled at different times during pregnancy might be inaccurate.

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The two major malformations in our case series were cleft lip with the palate and bilateral hip dysplasia while the three minor malformations were VUR, preauricular skin tag and patent foramen

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ovale.

The mother of the infant with cleft lip with palate was exposed to thiocolchicoside between 3rd and 4th weeks of pregnancy (Case 21, Table 4). Depending on the route of administration, thiocolchicoside and its metabolites are known to be completely eliminated from the body in

approximately two days (31). Therefore, it is not possible to link this malformation to the exposure, as lip and palate development takes place between weeks 5 and 12 (32), with the critical period from 6 to 9 weeks. Similarly, any possible association between thiocolchicoside and the hip dislocation was deemed as unlikely, since the sensitive period for the embryologic development of

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the hip joint begins at the 7th week of the pregnancy, which did not concur with the time of

exposure (33). Regarding the infant with VUR, thiocolchicoside exposure of the mother (Case 38, Table 4) coincides with the sensitive period for the formation of the kidney and ureter, which

begins at the 35th day of gestation (34). Nevertheless, any suggestion of an association would be purely speculative due to the relatively frequent prevalence and proposed genetic background of

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this minor malformation (34, 35). This infant was also diagnosed with IUGR; however, the mother

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reported that the physical developmental milestones were reached, and the VUR was ameliorating

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at a second follow-up (at 25th month). It is important to note that in the consecutive pregnancy, his

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sibling was also diagnosed with IUGR. A preauricular skin tag is accepted as a minor malformation (Case 16, Table 4); however, associations with other craniofacial malformations, renal anomalies,

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and hearing impairment have also been described (36, 37). Exposure to thiocolchicoside in this

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case (8th week) concurs with the sensitive period for the development of the ear, between 5th and 20th week of gestation (38). However, it may be similarly unwise to conclude any association with

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thiocolchicoside exposure, since preauricular skin tag is also relatively common among newborns

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(36). The mother reported no additional malformations. However, the infant had diagnosed with bronchitis at 12 months and nephrolithiasis at the 17 months of age. His renal USG at the 19 and 21

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months of age reported a minimal distension in the pelvicalyceal structures, and the anterioposterior (AP) diameter of the right renal pelvis was measured as 4.5 mm and 3 mm, respectively. The pelvicalyceal structures of the right and left kidney were minimally pronounced at the 33 months, and normal findings were reported in renal USG at the 37 months of age. Patent foramen ovale is a common minor malformation (Case 16, Table 4) which occurs in 25% of the

population (39). Thiocolchicoside exposure in this case, occurred in the 2nd week of pregnancy (LMP), before the start of the organogenesis and sensitive period for the development of interatrial septum (4-5 weeks postconception); thus any possible association is excluded (40).

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The rate of elective terminations in our study group (16.7%) was reported to be much higher than for the Turkish (4.7%) population (29). One possible reason is the high teratogenic risk perception of the pregnant women and their physicians regarding thiocolchicoside exposure during pregnancy, as numerous studies have shown that potential teratogenic risks of medications are frequently overestimated (41-45).

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Human data regarding thiocolchicoside exposure during pregnancy has been systematically

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collected in only three previous studies (16–18) two of which were published by different

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teratology information centers in Turkey (16, 17). In the first study, published as an abstract, the

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authors assessed the data from 51 exposures to thicolchicoside during pregnancy, of which 41 cases had known outcomes (16). Of these, 35 were healthy live births, three pregnancies were

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electively terminated, and two ended in miscarriage. One infant, whose mother had a

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preconceptional exposure to thiocolchicoside, was diagnosed with short bowel syndrome and died on the 7th day after birth (16). The second study consisted of an assessment of the outcome of 18

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exposures to thiocolchicoside during pregnancy in the first trimester (17). It reported 16 healthy live births, one miscarriage and one elective termination, and no major congenital malformations.

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The third case series, which was published as an abstract, was the result of a collaborative effort by French regional centers of pharmacovigilance (18). The study identified a single minor

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malformation (hip luxation), but no major congenital malformation, among 57 live births from 74 pregnancies with known outcomes. While it is important to acknowledge the limitations of these studies (16-18), all suggested that thiocolchicoside was unlikely to have a substantial embryotoxic effect.

The EMA-CHMP report is based on spontaneous pregnancy reports to the Marketing Authorisation Holders’ databases (46). In the first database, 11 exposed cases with six malformations were identified none of which suggested an identifiable pattern. There was also a major difference between the first database and our case series regarding the rates of malformations among the

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cases reported. Almost the half the cases in the former had major malformations, whereas in our case series, the risk was lower with two among 31 first trimester exposures with the imputability of thiocolchicoside considered unlikely. The second database described 23 cases, and in 20, the

exposure occurred in the embryonic period. Of these 20, there were 11 known outcomes, two of which presented with malformations. The remaining three cases consisted two cases of

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malformations. However, it is critical to highlight the lack of important details regarding the

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medical and obstetric history of the mother and the exposure in these reports, due to the

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unsystematic nature of the collection of data. In addition, with the lack of a critical assessment and

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interpretation from a teratological point of view, they are open to confounding and misinterpretation. As with other postmarketing databases, retrospective reports with adverse

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pregnancy outcomes are overrepresented (47). Therefore, these data do not allow correct

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calculation of malformation rates.

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It is important to note the limitations of our case series. First, because this and previous case series are of limited sample size and lack comparison cohorts, even moderate increases in risk of major or

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other organ-specific malformations cannot be ruled out. Second, we were not able to evaluate the outcomes of five of the 48 cases. Although this is an acceptable loss to follow-up rate (10.4%), it is

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possible that some malformations were missed. Finally, it should be noted that there was no opportunity either to investigate the miscarriages and elective terminations with regard to possible malformations or to conduct genetic tests for the infants with malformations. Conclusion

Our results, combined with the previously reported case series (16–18) suggest that thiocolchicoside is unlikely to be a major human teratogen, as in the cases of thalidomide or isotretinoin. Although these results may be of interest to clinicians for counseling pregnant women with inadvertent thiocolchicoside exposure, the small number of cases and lack of a control group

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preclude more definite conclusions. Nevertheless, it is important that revisions should be

considered to the 2014 EMA-CHMP report in the light of pertinent human data, to avoid the

overestimation of teratogenic risk posed by thiocolchicoside exposure during pregnancy, both by

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patients and physicians.

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Acknowledgements: Preliminary findings of this study was presented orally by Fatih Akyol

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who received ENTIS (European Network of Teratology Information Services) Presentation

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Award at the 27th Annual ENTIS Conference 2016 in Berlin and an abstract was published in Reproductive Toxicology (2016; 60:174-175.).

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Funding/Support: None reported.

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Conflict of Interest Statement: All authors have completed the Unified Competing Interest Form (available on request from the corresponding author) and declare no support from

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any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other

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relationships or activities that could appear to have influenced the submitted work.

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Jeremiah C. Tracy , Arnold S. Lee , Andrew R. Scott , and Collin S. Karmody M.A. Embryology and Anomalies of the External Ear. In: Advanced Cosmetic Otoplasty, First Edition, eds Shiffman MA, Verlag Berlin Heidelberg: Springer, 2013: 3-13. Asrress KN, Marciniak M, Marciniak A, Rajani R, Clapp B. Patent foramen ovale: the current state of play. Heart 2015; 101(23): 1916-25.

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Calvert PA, Rana BS, Kydd AC, Shapiro LM. Patent foramen ovale: anatomy, outcomes, and closure. Nat Rev Cardiol 2011; 8(3): 148-60.

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Koren G. The way women perceive teratogenic risk. Can J Clin Pharmacol 2007;

42.

SC RI PT

14(1): 10-6. Sanz E, Gómez-López T, Martínez-Quintas MJ. Perception of teratogenic risk of common medicines. Eur J Obstet Gynecol Reprod Biol 2001; 95(1): 127-31. 43.

Damase-Michel C, Pichereau J, Pathak A, Lacroix I, Montastruc JL. Perception of

area. Pharm Pract (Granada) 2008; 6(1): 15-9.

Nordeng H, Ystrøm E, Einarson A. Perception of risk regarding the use of medications

N

44.

U

teratogenic and foetotoxic risk by health professionals : a survey in Midi-Pyrenees

45.

M

A

and other exposures during pregnancy. Eur J Clin Pharmacol 2010; 66(2): 207–14. Csajka C, Jaquet A, Winterfeld U, Meyer Y, Einarson A, Panchaud A. Risk perception by

D

healthcare professionals related to drug use during pregnancy: a Swiss survey. Swiss

46.

TE

Med Wkly 2014; 144: w13936.

European Medicines Agency. Annex II-Scientific conclusions and grounds for

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variation to the terms of the marketing authorisations [homepage on the Internet].

CC

c2014 [cited 2016 Sep 21]. Available from http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Th

A

iocolchicoside-containing_medicines/WC500162335.pdf.

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Etwel F, Koren G. Bias Against the Null Hypothesis in Retrospective Registries of Gestational Drug Exposure. J Obstet Gynaecol Can 2016; 38(12): 1120-23.

48.

Hundt M De, Vlemmix F, Bais JM, Hutton EK, Groot CJ De, Mol BW, Kok M. Risk factors for developmental dysplasia of the hip: a meta-analysis. Eur J Obstet Gynecol Reprod

Biol 2012; 165(1): 8-17. 49.

Ortiz-Neira CL, Paolucci EO, Donnon T. A meta-analysis of common risk factors associated with the diagnosis of developmental dysplasia of the hip in newborns. Eur

A

CC

EP

TE

D

M

A

N

U

SC RI PT

J Radiol 2012; 81(3): e344-51.

Figure Legends

SC RI PT

Figure 1. Study flow diagram

U

Pregnancies with thiocolchicoside exposure between years 2009 and 2014 (n=48)

TE

D

M

A

N

Pregnancies lost to followup (n=5)

EP

Pregnancies with first trimester exposures which are included in the study (n=42)

A

CC

Figure 1. Study flow diagram

Pregnancies with second or third trimester exposure (n=1)

Table Legends

Table 2. Patterns of thiocolchicoside exposure Table 3. Pregnancy outcomes and children characteristics

SC RI PT

Table 1. Maternal characteristics and obstetric history

Table 4. Descriptive analysis of the children with major and minor congenital malformations after in utero exposure to thiocolchicoside with regard to the FDA Guidance on Good Pharmacovigilance

A

CC

EP

TE

D

M

A

N

U

Practices and Pharmacoepidemiologic Assessment

N U SC RI PT

Table 1. Maternal characteristics

Number (%) or Median (range) 31 (20-42) 33 (78.6%) 9 (21.4%)

Gestational age at admission (n=42)

7 weeks (5-14)

M

ED

Maternal education (n=27) None Primary school Secondary school High school University

4 (14.9%) 9 (33.3%) 5 (18.5%) 3 (11.1%) 6 (22.2%) 10 (23.8%) 5 (50%) 3 (30%) 1 (10%) 1 (10%) 1 (10%) 1 (10%) 1 (10%)

No Unknown

19 (45.2%) 13 (31%)

PT

Chronic disease (n=42) Yes Diabetes mellitus Hypertension Hepatitis B carrier Hypothyroidism Depression Arrythmia Migraine

CC E A

A

Age (n=42) <35 years ≥35 years

Alcohol (n=40) No Yes

39 (97.5%) 1 (2.5%)

N U SC RI PT

28 (70%) 7 (17.5%) 5 (12.5%)

Drugs of abuse (n=40) No

40 (100%)

22 (59.5%) 15 (40.5%) 12 1 5

M

ED

Radiation exposure (n=37) No Yes* X-ray CT MR

A

Smoking (n=40) No ≤5 cigarettes/day >5 cigarettes/day

10 (24.4%) 17 (41.5%) 14 (34.1%)

Previous parities (n=41) 0 1 ≥2

10 (24.4%) 21 (51.2%) 10 (24.4%)

Previous miscarriages (n=38) 0 1 ≥2

35 (92.1%) 2 (5.3%) 1 (2.6%)

Previous elective terminations (n=38) 0 1

35 (92.1%) 1 (2.6%)

A

CC E

PT

Previous pregnancies (n=41) 0 1 ≥2

N U SC RI PT

≥2

2 (5.3%)

A

CC E

PT

ED

M

A

* Some patients had multiple exposures

N U SC RI PT

Table 2. Patterns of thiocolchicoside exposure

Number (%) or Median (range)

A

ED

Daily dose of thiocolchicoside (n=35)

PT

Time of exposure (n=42) Preconception and 1st trimester 1st trimester

CC E

Duration of exposure (n=39)

28 (66.7%) 10 (23.8%) 4 (9.5%)

M

Route of administration (n=42) Oral Intramuscular Unknown

8 mg (4-24)

2 (4.8%) 40 (95.2%) 6 days (1-49)

3 (37.5%) 1 (12.5%) 2 (25%) 1 (12.5%) 1 (12.5%)

Co-exposure (n=48) Yes

48 (100%)

A

Indication for thicolchicoside (n=8) Spinal disc herniation Lumbalgia Knee pain Overdose Urinary tract infection

N U SC RI PT

Table 3. Pregnancy outcomes and children characteristics

Number (%) or Median (range)

A

ED

Mode of delivery (n=31) Normal Birth C/S

31 (73.8%) 4 (9.5%) 7 (16.7%)

M

Outcomes (n=42) Live birth Miscarriage Elective termination

10 (32.3%) 21 (67.7%) 39 weeks (36-41) 1 (3.3%) 29 (96.7%)

Sex (n=28) Female Male Children’s age at follow-up (months) (n=28)

14 (50%) 14 (50%) 21 (13-41)

Birth weight (n=28) <2500 g 2500-4000 g >4000 g Length (n=17)

3275 g (2000-4670) 1 (3.6%) 25 (89.3%) 2 (7.1%) 50 cm (42-54)

A

CC E

PT

Gestational age at birth (n=30) Preterm Term

N U SC RI PT

26 (83.8%) 5 (16.2%) 2 (6.5%) 3 (9.7%)

A

CC E

PT

ED

M

A

Outcomes of live births (n=31) Healthy Total congenital malformations Major Minor

N U SC RI PT

Table 4. Descriptive analysis of the children with major and minor congenital malformations after in utero exposure to thiocolchicoside with regard to the FDA Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (24). Case 38 - Minor congenital malformation Vesicoureteral reflux (VUR) in both kidneys (Grade 1-2). The infant was reported to reach the physical developmental milestones and his VUR was ameliorating at a second follow-up (at 25th month).

20-year-old Caucasian mother. The female infant was born via spontaneous birth at the 37th week of gestation.

23-year-old Caucasian mother. The female infant was born via C/S at the 40th week of gestation.

M

A

Case 42 - Major congenital malformation Bilateral hip dislocation. The child has been receiving orthopedic treatment.

CC E

PT

ED

The clinical and laboratory manifestations and course of the event

Case 21 - Major congenital malformation Cleft lip with palate. The child has been operated during infancy and currently in good health as described by the mother.

A

Demographic characteristics of patients with events (e.g., age, gender, race)

21-year-old Caucasian mother. The male infant was born via spontaneous birth at the 39th week of gestation.

Case 16 – Minor congenital malformation Left preauricular skin tag. The infant was hospitalized for bronchitis around 12 months of age. Nephrolithiasis was detected at 17 months of age in renal USG. Renal USG at the 19, 21 nd 33 months of age reported a minimal distension in the pelvicalyceal structures. Normal findings were reported in renal USG at the 37 months of age. 28-year-old Caucasian mother. The male infant was born via C/S at the 40th week of gestation.

Case 19 - Minor congenital malformation Patent foramen ovale at birth which was closed at one year of age. Minimal asymmetric septal hypertrophy was detected in the follow-up echocardiographies at 2, 3 and 4 years of age.

30-year-old Caucasian mother. The female infant was born via spontaneous birth at the 40th week of gestation.

N U SC RI PT

1 day, between the 0th and 4th weeks of pregnancy

1 day, within the 5th week of pregnancy

1 or 2 days, during the 8th week of pregnancy

3 days, during 2nd week of pregnancy

First trimester exposure, however do not coincide with the sensitive period for hip development (begins at the 7th week of pregnancy).

First trimester exposure which coincides with the sensitive period for the formation of the kidney and ureter which starts at the 35th day of gestation.

First trimester exposure. The exposure occured at the 8th week which concurs with the sensitive period for the ear development (5th to 20th week of gestation).

First trimester exposure before the start of the organogenesis and the sensitive period for the developent of interatrial septum (4-5 weeks postconception).

Peroral, 24 mg/day (acute overdose with suicidal intention). The dose is higher than the maximum peroral recommended dose (8 mg every 12 hours, 16 mg/day).

Jntramuscular 4 mg/day for once. The dose and duration of the treatment are compliant with the maximum intramucular recommended dose (4 mg every 12 hours, 8 mg/day, for up to 5 days).

Peroral, 4 or 8 g/day for 1 or 2 days. The dose and duration of the treatment are compliant with the recommendations (8 mg every 12 hours, 16 mg/day 7 consecutive days).

Intramuscular 4 mg/day for 3 days. The dose and duration of the treatment are compliant with the maximum intramucular recommended dose (4 mg every 12 hours, 8 mg/day, for up to 5 days).

Esomeprazole, desloratadine

Diclofenac

Pantoprazole, paracetamol,

Diclofenac, desloratadine

PT

ED

M

Time from initiation of product exposure to the adverse event

11 days, between the 3rd and 4th weeks of pregnancy First trimester exposure, however do not coincide with the sensitive period for lip and palate development (between the 5th and 12th weeks, with the critical period from weeks 6 to 9). Peroral, 16 mg/day for 11 days. The dose is compliant with the maximum peroral recommended dose (8 mg every 12 hours, 16 mg/day). However the duration of the treatment is longer than suggested (11 vs 7 consecutive days). Rabeprazole, dexketoprofen,

A

Exposure duration

A

CC E

Doses used in cases, including labeled doses, greater than labeled doses, and overdoses

Use of concomitant medication

M

PT CC E A

paracetamol, chlorpheniramine, fenylpropanolamin, flurbiprofen, montelukast, levocetirizine and oxerutin The mother had no history of chronic disease and used folic acid between gestational weeks 8 and 12. The mother had vaginal bleeding and threat of premature birth. The infant was the first born child and female which are previously reported risk factors (48, 49) for hip dislocation. No history of smoking, alcohol or drug use.

A

The chronic disease status of the mother was unknown. She had started to use folic acid at the 6th weeks of gestation, however duration of use is unknown.No history of smoking, alcohol or drug use.

ED

The presence of comorbid conditions, particularly those known to cause the adverse event

N U SC RI PT

etodolac and nimesulide.

chlorpheniramine and pseudoephedrine, caffeine, acetyl salicylic acid, dextromethorphan

The mother had no history of chronic disease and used folic acid between weeks 6 and 40 The infant was also diagnosed with IUGR. Her sibling was also diagnosed with IUGR, in the consecutive pregnancy, Smoking + (≤5 cigarettes/day), no history of alcohol or drug use.

The mother had no history of chronic disease and used folic acid between weeks 8 and 12. No history of smoking, alcohol or drug use.

The chronic disease status of mother was unknown. She had used folic acid after week 5, however duration of use is unknown. Smoking + (>5 cigarettes/day), no history of alcohol or drug use.