Reproductive Toxicology 27 (2009) 196–198
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Pregnancy outcome of women inadvertently exposed to ribostamycin during early pregnancy: A prospective cohort study Si Won Lee a,b , Jung Yeol Han a,b,∗ , June Seek Choi a,b , Jin Hoon Chung b , Moon Young Kim b , Jae Hyug Yang b , Mi Kyoung Koong b , Alejandro A. Nava-Ocampo c,d,e , Gideon Koren c a
The Korean Motherisk Program, Cheil General Hospital & Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea Department of Obstetrics and Gynecology, Cheil General Hospital & Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea c The Motherisk Program, Hospital for Sick Children, Toronto, Canada d Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada e PharmaReasons, Toronto, Canada b
a r t i c l e
i n f o
Article history: Received 28 August 2008 Received in revised form 22 November 2008 Accepted 15 December 2008 Available online 31 December 2008 Keywords: Aminoglycosides Maternal exposure Transplacental exposure
a b s t r a c t No information is currently available on the safety of the aminoglycoside ribostamycin in pregnancy. We aimed to study the pregnancy outcome of women inadvertently exposed to ribostamycin during the ﬁrst trimester of pregnancy. In a prospective cohort study, 102 women inadvertently exposed to ribostamycin during the ﬁrst trimester of pregnancy and an age- and gravidity-matched control group, were enrolled. Study outcomes were gestational age at birth, major and minor malformations, and birth weight. Fetal outcomes were evaluated in 85 women inadvertently exposed to ribostamycin during the ﬁrst-trimester of pregnancy and in 170 control subjects. Newborns were clinically examined at birth by a neonatologist and by imaging studies if any suspicious abnormalities were noted. There were 4/85 (4.9%) babies born with major malformations in the exposed group and 3/170 (1.8%) in the control group (P = 0.7). Gestational age at delivery, rate of minor anomalies, rate of preterm births, and birth weight were not different between groups. In conclusion, similar to what is reported for other aminoglycoside, exposure to ribostamycin during the ﬁrst-trimester of pregnancy does not appear to increase the risk of adverse fetal outcomes. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Ribostamycin is an aminoglycoside antibiotic originally derived from Streptomyces ribosidiﬁcus and currently prepared synthetically . This antimicrobial agent is effective for treating infections caused by gram-negative organisms such as Neisseria gonorrhoeae, Escherichia coli, Klebsiella spp., Proteus spp., and Groups A and B streptococci, but it is less active against anaerobes. It has similar efﬁcacy and reduced ototoxicity when compared to other major aminoglycosides . It is primarily used to treat infections such as pelvic inﬂammatory disease (PID), cystitis, and severe upper respiratory tract infections (URTI), administered intramuscularly once a day, at doses of 500–1000 mg .
∗ Corresponding author at: The Korean Motherisk Program, Cheil General Hospital & Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea. Tel.: +82 2000 7125; fax: +82 2000 7796. E-mail address: [email protected]
(J.Y. Han). 0890-6238/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2008.12.008
Only limited studies on the teratogenicity of aminoglycosides in human pregnancy have been reported. Reprotox (Reproductive Toxicology Center, Bethesda MD, United States) advises caution regarding the use of the aminoglycoside antibiotics streptomycin, gentamicin, kanamycin and neomycin during pregnancy . The major concern appears to be related to the potential ototoxicity secondary to in utero exposure to aminoglycosides [5–7]. However, a recent study in 40 infants who were exposed to gentamicin in utero documented no case of hearing loss . Furthermore, Czeizel et al. did not ﬁnd any increased rate of congenital malformations in a large teratological study on aminoglycoside antibiotics . No information is yet available on fetal outcomes following maternal exposure to ribostamycin during pregnancy in humans or in experimental animal models. The information is limited to the pharmacokinetics of ribostamycin in adults and pediatric patients [1,10–13]. Infectious diseases such as PID, cystitis, and URTI are common among women of reproductive age, and ribostamycin is frequently used in Korea to treat these infections. This situation is aggravated by the fact that approximately half of the pregnancies in Korea are unplanned . This study was therefore conducted in
S.W. Lee et al. / Reproductive Toxicology 27 (2009) 196–198
Table 1 Characteristics of the participants. Exposed (n = 85)
Control (n = 170)
Age (years) Gravity (n) No. of medications
30.6 ± 3.0 2.1 ± 1.1 8.9 ± 6.0
31.0 ± 3.2 2.0 ± 1.2 7.8 ± 5.7
0.4 0.5 0.2
Exposure during pregnancy to Alcohol Cigarette smoking X-rays
34 (40.0%) 8 (9.4%) 10 (11.8%)
84 (49.4%) 18 (10.6%) 47 (27.6%)
0.1 0.8 0.004
Gestational age at exposure (week) Dose of ribostamycin (mg/day) Duration of exposure (days)
3.9 ± 1.5 (range: 0.5–8.0) 250–1000 2.4 ± 2.6
– – –
– – –
Data were summarized either as mean ± S.D. or as n (%). Table 2 Pregnancy outcomes of women who were inadvertently exposed to ribostamycin in the ﬁrst trimester of pregnancy.
Gestational age at delivery (week) Birth weight (g) Low birth weight (<2500 g) Preterm births before 37 weeks Major malformationsa Minor malformations
Exposed (n = 85)
Controls (n = 170)
38.7 ± 3.1 3271 ± 473 4 (4.9) 7 (8.2) 4 (4.9) 2 (2.4)
38.9 ± 2.5 3224 ± 485 7 (4.1) 7 (4.1) 3 (1.8) 3 (1.8)
0.3 0.4 0.7 0.2 0.2 0.8
Data were summarized either as mean ± S.D. or as n (%). a In the exposed group, a baby was born with agenesis of corpus callosum, another baby with right hydronephrosis due to ureteropelvic junction obstruction, the third case had congenital megacolon, and the last case had club foot. In the control group, a baby was born with tetralogy of Fallot with CATCH 22 syndrome (cardiac defects, abnormal facial features, thymic hypoplasia, cleft palate, and hypocalcemia), another baby with hydrocephalus with contractures of upper extremities, and the third case in this group was born with left inguinal hernia.
order to investigate whether such exposure is associated with and increased risk of adverse fetal outcomes. 2. Materials and methods The protocol was approved by the Institutional Review Board at Cheil General Hospital and Women’s Healthcare Center, Seoul, Korea; the study was performed between January 1999 and February 2008 at the Korean Motherisk Program, a teratogen information service that provides evidence-based information on the safety and risk of exposure to therapeutic and illicit drugs, smoking, chemicals and radiation during pregnancy and lactation. During the initial interview, pregnant women who were inadvertently exposed to ribostamycin were invited to participate into the study. There were 102 women who enrolled. Pregnancy was conﬁrmed by transvaginal ultrasound examination performed immediately before the teratogenic risk counseling. In all cases, gestational age was estimated according to the somatometric results of the transvaginal ultrasound examination, and the time of exposure time to ribostamycin was calculated accordingly. Demographic information, medical and obstetric history, and details of any additional exposure were recorded at the beginning of the study by means of a standardized questionnaire. Details of any exposure to medications including gestational age at exposure, duration, dose, frequency and indication, were also collected. Participants underwent a high-resolution ultrasound examination between the 20th and the 24th weeks of gestation to rule out visualized malformations. The ﬁndings of the ultrasound examinations were provided to the participants. In addition, a large group of pregnant women who were not exposed to any aminoglycoside or to any known or potential human teratogen were followed-up prospectively as potential controls. From this group, two consenting controls were enrolled for each case, after matching for age (±2 years that of the control) and gravidity. At birth, the newborns were clinically examined by a neonatologist and in the presence of any potential abnormality, the babies underwent further evaluation by imaging studies. Normal, healthy babies were discharged from the hospital 1 day after birth. Babies with malformations underwent further medical and surgical evaluations as needed. All babies were followed-up by telephone for 3–84 months after birth and, if required, additional information was obtained from the patients’ charts.
2.1. Study outcomes We considered a major malformation any structural abnormality that was either lethal or required treatment (surgical or medical) due to cosmetic effect or interference with health or quality of life.
2.2. Statistical analysis Continuous variables including gestational age at birth (weeks) and birth weight (grams) were compared between groups by a Student’s t-test. Categorical variables including rate of minor and major malformations, were compared between groups by means of a Fisher’s exact test. A P < 0.05 was considered as statistically signiﬁcant.
3. Results We recruited 102 pregnant women who were inadvertently exposed to ribostamycin. Ribostamycin was prescribed for treatment of one or more of the following affections: complicated common cold (n = 45), cystitis (n = 21), vaginitis (n = 18), conjunctivitis (n = 3), otitis media (n = 3), skin laceration (n = 4), and dermatitis (n = 6) as well as for post-surgical antimicrobial prophylaxis (n = 2). Pregnancy outcomes of cases included 85 births (83.3%), 6 spontaneous abortions (5.9%), 8 voluntary abortions (7.8%), 1 ongoing pregnancy (1.0%) and 2 cases were lost to follow-up (2.0%). Fetal outcomes were evaluated in 85 women inadvertently exposed to ribostamycin during the ﬁrst-trimester of pregnancy and in an age- and gravidity-matched 170 control subjects. In ribostamycin-exposed cases women were inadvertently exposed to ribostamycin at the 3.9 ± 1.5 (mean ± S.D.) weeks of gestation (median: 4.1 weeks) at a dose ranging from 250 mg to 1 g per day (mean duration of exposure: 2.4 days) (Table 1). No statistical differences were observed in the age, gravity, number of medications used, alcohol exposure and cigarette smoking between the exposed and control groups, although there were more women exposed to radiation in the control group (Table 1). The mean gestational age at delivery, babies’ birth weight and the rate of preterm births were not different between the exposed and the control groups (Table 2). In addition, there were no signiﬁcant differences in the rate of major malformations between groups (P = 0.7). The rate of minor congenital anomalies included a case of bilateral choroid plexus cysts and one baby with unilateral renal pelvis dilatation in the exposed group, and a baby born with single umbilical artery, a case of unilateral renal pelvis dilatation (n = 1),
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and another case of internal rotation of unilateral foot (n = 1) in the control group. 4. Discussion This appears to be the ﬁrst prospective cohort study to examine the outcome of infants exposed to ribostamycin in early pregnancy. The rate of major malformations, neonatal ototoxicity, minor anomalies, preterm delivery, gestational age at birth and birth weight of the infants were not different between the exposed women and their matched controls. Although in our study the sample size had a power of <20% to detect signiﬁcant differences in major malformations between groups (only an excess of more than ﬁve times of malformations in the exposed group would be signiﬁcantly detected), our results support previous studies with larger sample size showing that exposure to other aminoglycosides during pregnancy is not associated with adverse maternal or fetal outcomes [8,9]. Ribostamycin inhibits bacterial protein synthesis by binding to 30S ribosomal subunits and 50S ribosomal subunits, and appears to have relatively higher efﬁcacy and lower toxicity in comparison to other aminoglycosides when used for treating URTIs, urinary tract infections, and other minor infections [1–2,10–13]. When administered by intramuscular injection, ribostamycin has a similar pharmacokinetic proﬁle to kanamycin . In adults, a dose of 500 mg ribostamycin yields peak serum concentration (Cmax ) of 32.6 g/ml at approximately 30 min. The elimination half-life (t1/2 ) is approximately 100 min, but it may be longer in patients with impaired hepatic or renal function and in children . Ribostamycin is mainly eliminated by glomerular ﬁltration and approximately 70% of this drug can be found in urine within 6 h after injection. According to previous reports , aminoglycoside induced ototoxicity leads to permanent bilaterally severe, high-frequency sensorineural hearing loss and temporary vestibular hypofunction which are accompanied by degeneration of hair cells and neurons in the cochlea of the internal ear. The onset of development of otic placode occurs on 24th day of fetal development (38th gestational age, or 5th gestational week). However, the onset of otic invagination occurs on the 30th day of fetal development, while the onset of development of otic vesicle is on the 34th day of gestation age . The target of amninoglycosyde toxicity is the hair cells of cochlea which starts to develop after the 34th day of organogenesis, i.e. after the 48th gestational day (at the end of 6th gestational week). In our study, the mean gestational age at exposure was 3.9 gestational weeks, thus we cannot evaluate the possible ototoxic effect of ribostamycin because there was no overlapping between the time of exposure and the critical period of congenital anomaly studied. In conclusion, similar to what is reported for other amino-
glycoside, exposure to ribostamycin during the ﬁrst-trimester of pregnancy does not appear to increase the risk of adverse fetal outcomes. Studies with a sample size sufﬁcient to conﬁrm these results are required. In addition, the risk of ototoxicity cannot yet be ruled out. Therefore, if therapy with aminoglycosides is required during pregnancy, the use of other drugs with proven safety should be preferred. Conﬂict of interest statement The authors declare that there are no conﬂicts of interests. The study was supported by grant No. 08152KFDA417 from the Korea Food & Drug Administration. The study was not supported in any form by any pharmaceutical company. References  Zhou SL, Shen G, Zhong HF. Pharmacokinetics of ribostamycin in paediatric patients. Clin Pharmacokinet 1992;22:144–51.  Kitasato I, Yokota M, Inouye S, Igarashi M. Comparative ototoxicity of ribostamycin, dactimicin, dibekacin, kanamycin, amikacin, tobramycin, gentamicin, sisomicin and netilmicinin the inner ear of guinea pigs. Chemotherapy 1990;36:155–68.  Dodson MG. Antibiotic regimens for treating acute pelvic inﬂammatory disease. An evaluation. J Reprod Med 1994;39:285–96.  Micromedex Healthcare Series: Thomson Micromedex, Greenwood Village, CO [accessed March 2008].  Conway M, Birt BD. Streptomycin in pregnancy: effect on the foetal ear. Br Med J 1965;2:260–3.  Canadian Adverse Drug Reaction Monitoring Program. Summary of reported adverse reactions. Suspected drug: gentamicin—SOC: fetal disorders; all reports received from January 1, 1965 to June 30, 2008. Available at: http://www.hcsc.gc.ca/dhp-mps/medeff/databasdon/index-eng.php [accessed August 4, 2008]. ˜ RC, Moro SM. Relationship between a case  Sánchez S-TC, Gutiérrez FR, Ibánez of severe hearing loss and use of gentamycin in the pregnant mother. An Esp Pediatr 1998;49:397–8 [in Spanish].  Kirkwood A, Harris C, Timar N, Koren G. Is gentamicin ototoxic to the fetus? J Obstet Gynaecol Can 2007;29:140–5.  Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis 2000;32:309–13.  Di Nola F, Eandi M, Soranzo ML. Kinetic and clinical research into a new aminoglycosidic antibiotic: ribostamycin. Drugs Under Exp Clin Res 1980;6:77–90.  Yamasaku F, Suzuki Y, Umemura K. Pharmacokinetics of ribostamycin in healthy volunteers and patients with impaired renal function. Jpn J Antibiot 1983;33:1318–31.  Zhang M, Gu Y. Studies on the clinical pharmacology of ribostamycin. New Drugs Clin Rem 1985;4:199–201.  Murata S, Kadosawa H, Shomura T, Umemura K. Studies on absorption, distribution, metabolism and excretion of drugs. Distribution, metabolism and excretion of ribostamycin. Yakuzaigaku 1971;31:1–7.  Han JY, Nava-Ocampo AA, Koren G. Unintended pregnancies and exposure to potential human teratogens. Birth Defects Res A Clin Mol Teratol 2005;73:245–8.  Guthrie OW. Aminoglycoside induced ototoxicity. Toxicology 2008;249:91–6.  Sadler TW. Langman’s medical embryology. 9th ed. Baltimore: Lippincott Williams and Wilkins; 2004. p. 403–14.