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Pregnancy outcomes after maternal betahistine exposure: A case series
Reproductive Toxicology 79 (2018) 79–83
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Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Pregnancy outcomes after maternal betahistine exposure: A case series a,⁎
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Cuneyt Kemal Buharalioglu , Selin Acar , Hilal Erol-Coskun , Gözde Küçüksolak , Barış Karadasb,c, Tijen Kaya-Temizb,c, Yusuf Cem Kaplanb,c a b c
Izmir Katip Celebi University Faculty of Pharmacy, Department of Pharmacology Izmir, Turkey Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey Izmir Katip Celebi University School of Medicine, Department of Pharmacology Izmir, Turkey
A R T I C LE I N FO
A B S T R A C T
Keywords: Betahistine Pregnancy Congenital abnormalities Birth defects Pregnancy outcomes Antivertigo drug
Objective: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. Methods: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. Results: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. Conclusions: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.
1. Introduction Betahistine is a histamine analog with a postsynaptic H1 receptor partial agonist and presynaptic H3 heteroreceptor antagonist properties. This multifactorial mode of action supposedly make betahistine a vestibular suppressant to restore proper balance and decrease symptoms of vertigo not only in Meniere disease [1,2] but also in vestibular migraine [3]. Although it has been commonly used in European countries since 1966 [4,5], betahistine has not been approved by the U.S. Food and Drug Administration [6]. In Turkey, it is available as a tablet form only with a recommended adult maintenance dose range of 24–48 mg daily. Both vertigo and migraine are common in pregnant women. The Pacific Northwest pregnancy cohort study indicated that approximately one in four pregnant women had migraines and about 60% of pregnant women had experienced dizziness at some point in the first trimester. Among them, the most frequent symptom (35.7%) associated with dizziness was vertigo, while the second most frequent (21.4%) was deviated or unbalanced gait as well as unstable floating head sensation [7]. Probably stemming from the hormonal changes during the first gestational trimester [8], these complaints tend to seriously affect the quality of life and perceived wellbeing of the expectant mothers. Therefore, the possibility that pregnant women are being exposed to
betahistine is not small. Although betahistine has a good safety profile in general population [9,10], possible risks associated with its use during pregnancy are largely unknown. Studies with betahistine in pregnant rabbits failed to show any teratogenic effect [11] and evidence in humans is currently very limited. Betahistine is assigned to the category B in FDA risk categories, which were announced to be replaced by the new pregnancy and lactation labeling rule [12]. In order to expand the limited data and provide additional value to the clinicians assessing the possible teratogenic risks of inadvertent betahistine exposure during pregnancy, we aimed to evaluate and describe the pregnancy outcomes following maternal betahistine exposure by using the data from Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center, Turkey). 2. Methods Terafar records were searched to retrieve pregnant women with a prospective referral for risk assessment regarding betahistine use during pregnancy between 2009 and 2017. The study has been approved by the Izmir Katip Celebi University Non-Interventional Studies Ethics Committee (02.06.2016, #156).
⁎ Corresponding author at: Izmir Katip Celebi University University Faculty of Pharmacy, Department of Pharmacology, Balatçık Mahallesi Havaalanı Şosesi No:33/2 Balatçık 35620 Çiğli Izmir, Turkey. E-mail address: [email protected] (C.K. Buharalioglu).
https://doi.org/10.1016/j.reprotox.2018.06.004 Received 7 March 2018; Received in revised form 30 April 2018; Accepted 11 June 2018 Available online 13 June 2018 0890-6238/ © 2018 Elsevier Inc. All rights reserved.
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All relevant data regarding basic demographics, maternal characteristics, medical, obstetric and family history, medication and other exposures (e.g. drugs of abuse, herbal supplements, etc.) were recorded through face-to-face interviews using a detailed and structured questionnaire. For the timing of gestational exposure, the last menstrual period (LMP) date was determined by early ultrasound (USG) examination or maternal recall at the initial contact. To investigate the pregnancy outcomes, after the birth, a standardized follow-up telephone interview was conducted with the mothers/families, based on a structured questionnaire and oral informed consent was also obtained. This aimed to obtain the following information: Possible complications during pregnancy (e.g. preeclampsia, gestational diabetes etc.), further information in case of pregnancy loss, gestational age at birth, sex, birth weight and length, head circumference and Apgar scores. The survey also aimed to identify whether there had been any major or minor congenital malformations or any other adverse physical effects in the infant discovered either at birth, or during routine family physician visits. In this study, the primary outcomes of interest were the rate and pattern, if present, 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) [13,14] by three study authors (CKB, SA, HE-C) in an unblinded fashion. Any disagreements were resolved by consulting a fourth author (YCK). Miscarriage was defined as the spontaneous loss of a pregnancy < 20th week, elective termination was defined as the voluntary 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 < 2500 g at term. Due to inclusion of twin pregnancies in the study sample, the pregnancy outcome rates were calculated using the total number of exposed fetuses (n = 26) as the denominator.
Fig. 1. Study flow diagram.
The infant with the only major congenital malformation, which was an intestinal malrotation, died at the 11th day, postnatally (Case 10, Table 4). The two minor congenital malformations were a patent foramen ovale (PFO) in two female infants (Case 6 and Case 9, Table 4). In terms of perinatal complications, one term infant (Case 6, Table 4) was diagnosed with both hypothyroidism and bronchitis 10 days after birth. One infant was reported to have cardiopulmonary arrest at birth. Following the recussitation she stayed in incubator for 9 days and survived. In line with the FDA Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment [15], a detailed descriptive analysis of the infants with congenital malformations including the high number of concomitant medication exposures is presented in Table 4.
3. Results 27 cases with an exposure to betahistine during pregnancy were identified in the period between 2009– 2017. The malformation rate calculations were restricted to first trimester exposures that resulted only in live births, due to the unavailability of data regarding major congenital malformations from the pathological examinations of miscarriages and elective terminations. After excluding the cases lost to follow-up (n = 3), 24 betahistine exposures with known outcomes were included, including one live birth without available malformation data (Fig. 1). The median maternal gestational age at admission was 8 weeks (range: 4–25 weeks). Detailed maternal characteristics are presented in Table 1. Pregnant women with more than one chronic disease were considered in each disease category. The patterns of exposure are presented in Table 2. The median daily dose of betahistine was 24 mg/day and the duration of exposure varied between 1 and 71 days of pregnancy with the oral route of administration in all of the pregnancies. Child characteristics are presented in Table 3. In 24 pregnancies, two were twin pregnancies (one twin was missed abortus and the mother reported to have one umbilical artery in detailed USG). Therefore, for the calculation of percentages 26 exposed fetuses is used as the denominator. Of 26 fetuses with known outcomes, 21 (80.8%) were live births, two (8.3%) were miscarriages, and three (11.5%) were elective terminations. The median age of the children at the time of the followup was 23 months (range: 4–63 months). One infant was reported to have a low birth weight for gestational age, and seven other were reported to be born preterm. Among 20 live births with in utero exposure to betahistine during the first trimester, there were 17 (85%) normal outcomes, 1 major (5%) and 2 minor (10%) congenital malformations.
4. Discussion To the best of our knowledge, this is the first detailed case series investigating the outcomes of pregnant women exposed to betahistine during pregnancy. In 24 recorded pregnancies with betahistine exposure, the rates of major [our study with confidence intervals vs. background estimate: 5% (0.1–24.9) vs. 1–8% [16],] and minor malformations [10% (1.2–31.7) vs. 4% [17],] and low birth weight [5.3% (0.1–26) vs. 8.4% [18],] were comparable with the general population rates. However, elective termination [11.5% (2.4–30.2) vs. 4.7% [19],] and preterm birth rates [33.3% (14.6–57) vs. 12% [20],] were considerably higher. However, it should be highlighted that small sample size and data sampling limitations associated with Teratology Information Center surveillance methods discussed elsewhere [21] might have limited the precision of those estimates, therefore they should be cautiously interpreted. The only major malformation, in this study, was intestinal malrotation while the minor malformations were patent 80
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Table 1 Maternal characteristics and obstetric history.
Table 3 Pregnancy outcomes and children characteristics. Number (%) or Median (range)
Age (n = 24) < 35 years ≥35 years Gestational age at admission (n = 24) Maternal education (n = 18) None Primary school Secondary school High school University Chronic disease (n = 28)* Yes Meniere Disease/Vertigo Depression Hypothyroidism Behçet’s Disease Mitral Valve prolapse Panic Attack Asthma No Unknown Alcohol (n = 24) No Yes Smoking (n = 24) No ≤5 cigarettes/day > 5 cigarettes/day Drugs of abuse (n = 24) No Radiation exposure (n = 24) No Yes X-ray CT MR Previous pregnancies (n = 23) 0 1 ≥2 Previous parities (n = 24) 0 1 ≥2 Previous miscarriages (n = 21) 0 1 ≥2 Previous elective terminations (n = 21) 0 1 ≥2
32 (20-45) 15 (62.5%) 9 (37.5%) 8 weeks (4-25) 1 5 5 6 1
Outcomes (n = 26)a Live birth Miscarriageb Elective termination Stillbirth Mode of delivery (n = 20) Normal Birth C/S Gestational age at birth (n = 21) Preterm Term Sex (n = 19) Female Male Children’s age at follow-up (months) (n = 17) Birth weight (n = 19) < 2500 g 2500-4000 g Length (n = 14) Outcomes of live births (n = 20)d Healthy Total congenital malformations Major Minor
(5.5%) (27.8%) (27.8%) (33.4%) (5.5%)
15 (53.6%) 6 (40%) 3 (20%) 2 (13.4%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 12 (42.9%) 1 (3.5%) 22 (91.7%) 2 (8.3%) 16 (66.6%) 4 (16.7%) 4 (16.7%)
% (95% Confidence Interval) or Median (range)
21 2 3 –
80.8 (60.1-93.4) 8.3 (1-27) 11.5 (2.4-30.2) –
8 12 38 weeks 7 14
40 (19.1-63.9) 60 (36.1-80.9) (33-40) 33.3 (14.6-57) 66.7 (43-85.4)
9 10 23
47.4 52.6 (4-63)
3500 g 2c 17 50 cm
(2300-3750) 10.5 (1.3-33.1) 89.5 (66.9-98.7) (47-56)
17 3 1 2
85 (62.1-96.8) 15 (3.2-37.9) 5 (0.1-24.9) 10 (1.2-31.7)
a
Fetal outcomes presented due to the presence of twin pregnancies. One twin pregnancy resulted in a live birth and a missed abortus. Denominator was 24 with regard to the definition of miscarriage (< 20 weeks). c One infant was preterm. d Birth information of one infant was available, however we could not reach his information regarding malformations. b
24 (100%) 16 (66.7%) 8 (33.3%) 1 1 6
foramen ovale in two cases. The mother of the infant with intestinal malrotation was exposed to betahistine at 10th week of pregnancy for 3 days (Case 10, Table 4). This coincides with the sensitive period for the development of the gut, since the final 90˚ rotation of the duodenum and 180˚ rotation of the cecum occurs in 10th and 12th weeks of the gestation [22]. The mother also had concomitant medication exposures, namely pantoprazole, antacid combinations, piracetam and trimebutine. However, none of these medications have previously been associated with intestinal malrotation. It has been reported that male infants are more frequently affected than female infants [23], which is consistent with our case. The infant died in 11th day after the birth which can be due to the anomalous intestinal mesenteric fixation as reported by Marseglia et al. [24] or volvulus [25]. The mother had retained placenta, which was needed to be removed after birth and she stayed in hospital for 3 days. Interestingly, parity of the mother was 2 which was suggested to be a reduced risk factor for the intestinal malrotation [26]. Any suggestion of an association between betahistine and congenital malrotation would be speculative due to the relatively frequent prevalence of this malformation (1:500–1:3500) [27,22]. Of note, patent foramen ovale were reported in two infants (Case 6 and Case 9, Table 4). Betahistine exposure in Case 9 occurred in the 13th weeks of pregnancy (LMP), before the sensitive period for the development of major septa of the heart (4–5 weeks postconception) [28]; thus any possible association is excluded. Considering Case 6, betahistine exposure (0-9th weeks of pregnancy) overlaps with organogenesis of the heart. However, potential confounding factors might be the mother’s psychiatric condition and related life style factors and/or concomitant paroxetine exposure [29]. Furthermore, the relatively frequent prevalence (1 in 100 living births; regardless of exposure [30]) and proposed genetic background of this minor malformation [31] makes any association between patent foramen ovale and betahistine unlikely. The infant (Case 6, Table 4) was also diagnosed with
0 (0 %) 8 (34.8%) 15 (65.2%) 2 (8.3%) 9 (37.5%) 13 (54.2%) 18 (85.7%) 1 (4.8%) 2 (9.5%) 16 (76.2%) 3 (14.3%) 2 (9.5%)
* Values do not sum to total because some patients had multiple chronic diseases. Table 2 Patterns of betahistine exposure. Number (%) or Median (range) Route of administration (n = 24) Oral Daily dose of betahistine (n = 17) Time of exposure (n = 20) Preconception and 1st trimester 1st trimester Duration of exposure (n = 19) Indication for betahistine (n = 10) Meniere (Vertigo) Co-exposure (n = 24) Yes No
Number
24 (100%) 24 mg (16-48) 8 (40%) 12 (60%) 14 days (1 -71) 10 (100%) 23 (95.8%) 1 (4.2%)
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Table 4 Descriptive analysis of the children with major and minor congenital malformations after in utero exposure to betahistine with regard to the FDA Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment [FDA].
The clinical and laboratory manifestations and course of the event
Demographic characteristics of patients with events (e.g., age, gender, race) Exposure duration Time from initiation of product exposure to the adverse event
Case 6 - Minor congenital malformation
Case 9 - Minor congenital malformation
Case 10 - Major congenital malformation
Patent foramen ovale (2 mm) at birth and unspecified valvular defect. Current status of child’s clinical condition is not known due to incomplete pediatric examination. Thyroid glands was not functional and bronchitis 10 days after birth was developed and follow up continues. 34-year-old Caucasian mother. The girl infant was born via C/S at term.
Patent foramen ovale at birth which was closed at one year of age. Mild jaundice was also reported.
Intestinal malrotation
20-year-old Caucasian mother. The girl infant was born via spontaneous birth at the 39th week of gestation. 15 day, between the 1sth and 3th weeks of pregnancy First trimester exposure, however do not coincide with the sensitive period.
36-year-old Caucasian mother. The male infant was born via spontaneous birth at term.
71 days, between the 0 and 9th weeks of pregnancy First trimester exposure, and coincides with the sensitive period for the development of interatrial septum (4-5 weeks postconception)
Doses used in cases, including labeled doses, greater than labeled doses, and overdoses Use of concomitant medication
Peroral, 48 mg/day for 71 days. The dose is compliant with the maximum peroral recommended dose. Propranolol, levothyroxine, hydroxyzine, paroxetine and amitriptyline.
Peroral, 24 mg/day. The dose is compliant with the maximum peroral recommended dose. Ibuprofen and vitamin B complex.
The presence of co-morbid conditions, particularly those known to cause the adverse event
The mother had hypothyroidism and did not use folic acid. Smoking (< 5 cigarettes/day).
The mother had no history of chronic disease and used folic acid between gestational weeks 8 and 12. No history of smoking, alcohol or drug use.
3 days, within the 10th week of pregnancy First trimester exposure which coincides with the sensitive period for the formation of the alimentary tract which starts at the 4th and completed by 8-10th gestational week. Peroral, 48 mg/day for 3 days at 10th week. The dose is compliant with the maximum peroral recommended dose. Pantoprazole, antiacid (calcium carbonate, magnesium carbonate, sodium alginate), piracetam, trimebutine, The mother had no history of chronic disease and not used folic acid. No history of smoking, alcohol or drug use.
relationship with the medications were excluded and an inherited mitochondriopathy was suspected. A female infant with a partial bilateral syndactyly of the second and third toe with the maternal betahistine exposure of the third month of the pregnancy, for whom maternal alcohol consumption was considered as a risk factor. Another infant presented with the complex syndrome of radial limb defects and scoliosis after intrauterine exposure to betahistine, which was diagnosed as VACTERL-association. Authors concluded that identified exposed cases are not comprehensive enough to assess possible teratogenic effects of betahistine therapy during pregnancy and these malformations had no identifiable pattern. There is also a difference between the reported cases in the database and our case series in terms of the types of malformations. Additionally, it is critical to highlight the lack of important details regarding medical and obstetric history of the mother and the exposure in these reports due to the unsystematic nature of the collection of data. With the lack of a critical assessment and interpretation from a teratological point of view, they are susceptible to confounding (such as family and obstetric history and lack of genetic analysis) and misinterpretation. Moreover, retrospective reports such as these databases with adverse pregnancy outcomes are shown to be overrepresented [37].
congenital hypothyroidism which is probably associated with maternal iodine deficiency indicated by the discontinuation of levothyroxine, which was reported by the mother, at 9th gestational week for the fear that medication may be harmful for the fetus. The rate of elective terminations and preterm birth rates in our study group was much higher than for the Turkish population Higher elective termination rates can be explained by overestimation of the potential teratogenic risks of medications as shown by several studies [32,33]. Therefore, the pregnant women included in this case series and their physicians might have had high teratogenic risk perception regarding betahistine exposure during pregnancy. The higher preterm birth rate in our study may be associated with the presence of the risk factors in the mothers, such as preeclampsia and arrhythmia, or perinatal complications (bleeding from previous caesarean sections), and older age (≥37 in two pregnancies). Betahistine have been reported to be contraindicated in pregnancy [34]. While it is prudent to avoid use of a medication lacking rigorous data in pregnancy, this advice does not appear to be well substantiated and supported by evidence. In a recent case series, published as an abstract, Kadıoğlu et al. [35] described 15 cases with first trimester betahistine exposure with no congenital malformation. They reported 12 healthy live births, two spontaneous abortions, and one elective termination (concomitant paroxetine exposure). Authors have concluded that betahistine was unlikely to have a substantial embryotoxic effect. To our knowledge, there are only two post-marketing studies concerning betahistine usage during pregnancy. In a multicenter, openlabel post-marketing surveillance study of betahistine in patients with tinnitus, one pregnant with 18 days betahistine exposure (48 mg/day) present with normal outcome and no adverse drug reactions was reported, however investigators did not mention the exposure time window [36]. Three congenital abnormalities were reported in betahistine global safety database, which covers the past 35 years in a total 554 individual adverse drug reactions report out of 2032 subject [10]. A female infant, presented with microcephalus, hyperlactataemia and calcification of basal ganglia, died at the age of 3 years. Although mother had used betahistine for 10 days (with the concomitant use of caffeine and dihydroergotamine) during early pregnancy, a causal
4.1. Limitations It is well known that case series have major methodological drawbacks. Therefore, it is important to note the limitations of our study. First and the most important, the limited sample size and lack of comparison cohort does not permit us to rule out moderate increases in risk of major or other organ specific malformations. Second, the dose of betahistine widely differed among the pregnant women included. Third, we were not able to evaluate the outcomes of four pregnancies among 27 cases. Although this is an acceptable loss to follow-up rate (14.8%), it is possible that some malformations were missed. Fourth, because the majority of our cases were first trimester exposures, possible fetal adverse effects of betahistine exposure during later trimesters could not be evaluated. Finally, there was no opportunity either to investigate the miscarriages and elective terminations with regard to 82
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possible malformations, or to conduct genetic tests for the infants with malformations to elucidate chromosomal defects.
[13]
5. Conclusion [14]
Our study, combined with the previously reported a case series [35] and post-marketing data [10,36] do not suggest an increased rate of major congenital malformations following betahistine exposure. However, the small sample size and data collection methods of our study calls for caution in the interpretation of results. Nevertheless, this information still may offer some value in assessing the possible teratogenic risks of pregnant women with inadvertent betahistine exposure. Larger prospective series or cohorts are needed before more definite conclusions can be drawn. In addition, because there are also concerns regarding its effectiveness in Meniere’s disease [38,39], it would be wise to avoid betahistine during pregnancy.
[15]
[16]
[17]
[18] [19]
Funding/support
[20]
This research did not receive any specific grant from funding agencies. [21]
Conflict of interest statement
[22]
All authors have completed the Unified Competing Interest Form (available on request from the corresponding author) and declare no support from 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 relationships or activities that could appear to have influenced the submitted work.
[23] [24]
[25] [26]
Acknowledgements Preliminary findings of this study was presented as a poster at the 27 Annual ENTIS Conference 2016 in Berlin and an abstract was published in Reproductive Toxicology (2016; 60:177).
[27]
th
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Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Pregnancy outcomes after maternal betahistine exposure: A case series a,⁎
b,c
b,c
T
b
Cuneyt Kemal Buharalioglu , Selin Acar , Hilal Erol-Coskun , Gözde Küçüksolak , Barış Karadasb,c, Tijen Kaya-Temizb,c, Yusuf Cem Kaplanb,c a b c
Izmir Katip Celebi University Faculty of Pharmacy, Department of Pharmacology Izmir, Turkey Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey Izmir Katip Celebi University School of Medicine, Department of Pharmacology Izmir, Turkey
A R T I C LE I N FO
A B S T R A C T
Keywords: Betahistine Pregnancy Congenital abnormalities Birth defects Pregnancy outcomes Antivertigo drug
Objective: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. Methods: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. Results: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. Conclusions: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.
1. Introduction Betahistine is a histamine analog with a postsynaptic H1 receptor partial agonist and presynaptic H3 heteroreceptor antagonist properties. This multifactorial mode of action supposedly make betahistine a vestibular suppressant to restore proper balance and decrease symptoms of vertigo not only in Meniere disease [1,2] but also in vestibular migraine [3]. Although it has been commonly used in European countries since 1966 [4,5], betahistine has not been approved by the U.S. Food and Drug Administration [6]. In Turkey, it is available as a tablet form only with a recommended adult maintenance dose range of 24–48 mg daily. Both vertigo and migraine are common in pregnant women. The Pacific Northwest pregnancy cohort study indicated that approximately one in four pregnant women had migraines and about 60% of pregnant women had experienced dizziness at some point in the first trimester. Among them, the most frequent symptom (35.7%) associated with dizziness was vertigo, while the second most frequent (21.4%) was deviated or unbalanced gait as well as unstable floating head sensation [7]. Probably stemming from the hormonal changes during the first gestational trimester [8], these complaints tend to seriously affect the quality of life and perceived wellbeing of the expectant mothers. Therefore, the possibility that pregnant women are being exposed to
betahistine is not small. Although betahistine has a good safety profile in general population [9,10], possible risks associated with its use during pregnancy are largely unknown. Studies with betahistine in pregnant rabbits failed to show any teratogenic effect [11] and evidence in humans is currently very limited. Betahistine is assigned to the category B in FDA risk categories, which were announced to be replaced by the new pregnancy and lactation labeling rule [12]. In order to expand the limited data and provide additional value to the clinicians assessing the possible teratogenic risks of inadvertent betahistine exposure during pregnancy, we aimed to evaluate and describe the pregnancy outcomes following maternal betahistine exposure by using the data from Terafar (Izmir Katip Celebi University Teratology Information, Training and Research Center, Turkey). 2. Methods Terafar records were searched to retrieve pregnant women with a prospective referral for risk assessment regarding betahistine use during pregnancy between 2009 and 2017. The study has been approved by the Izmir Katip Celebi University Non-Interventional Studies Ethics Committee (02.06.2016, #156).
⁎ Corresponding author at: Izmir Katip Celebi University University Faculty of Pharmacy, Department of Pharmacology, Balatçık Mahallesi Havaalanı Şosesi No:33/2 Balatçık 35620 Çiğli Izmir, Turkey. E-mail address: [email protected] (C.K. Buharalioglu).
https://doi.org/10.1016/j.reprotox.2018.06.004 Received 7 March 2018; Received in revised form 30 April 2018; Accepted 11 June 2018 Available online 13 June 2018 0890-6238/ © 2018 Elsevier Inc. All rights reserved.
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All relevant data regarding basic demographics, maternal characteristics, medical, obstetric and family history, medication and other exposures (e.g. drugs of abuse, herbal supplements, etc.) were recorded through face-to-face interviews using a detailed and structured questionnaire. For the timing of gestational exposure, the last menstrual period (LMP) date was determined by early ultrasound (USG) examination or maternal recall at the initial contact. To investigate the pregnancy outcomes, after the birth, a standardized follow-up telephone interview was conducted with the mothers/families, based on a structured questionnaire and oral informed consent was also obtained. This aimed to obtain the following information: Possible complications during pregnancy (e.g. preeclampsia, gestational diabetes etc.), further information in case of pregnancy loss, gestational age at birth, sex, birth weight and length, head circumference and Apgar scores. The survey also aimed to identify whether there had been any major or minor congenital malformations or any other adverse physical effects in the infant discovered either at birth, or during routine family physician visits. In this study, the primary outcomes of interest were the rate and pattern, if present, 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) [13,14] by three study authors (CKB, SA, HE-C) in an unblinded fashion. Any disagreements were resolved by consulting a fourth author (YCK). Miscarriage was defined as the spontaneous loss of a pregnancy < 20th week, elective termination was defined as the voluntary 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 < 2500 g at term. Due to inclusion of twin pregnancies in the study sample, the pregnancy outcome rates were calculated using the total number of exposed fetuses (n = 26) as the denominator.
Fig. 1. Study flow diagram.
The infant with the only major congenital malformation, which was an intestinal malrotation, died at the 11th day, postnatally (Case 10, Table 4). The two minor congenital malformations were a patent foramen ovale (PFO) in two female infants (Case 6 and Case 9, Table 4). In terms of perinatal complications, one term infant (Case 6, Table 4) was diagnosed with both hypothyroidism and bronchitis 10 days after birth. One infant was reported to have cardiopulmonary arrest at birth. Following the recussitation she stayed in incubator for 9 days and survived. In line with the FDA Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment [15], a detailed descriptive analysis of the infants with congenital malformations including the high number of concomitant medication exposures is presented in Table 4.
3. Results 27 cases with an exposure to betahistine during pregnancy were identified in the period between 2009– 2017. The malformation rate calculations were restricted to first trimester exposures that resulted only in live births, due to the unavailability of data regarding major congenital malformations from the pathological examinations of miscarriages and elective terminations. After excluding the cases lost to follow-up (n = 3), 24 betahistine exposures with known outcomes were included, including one live birth without available malformation data (Fig. 1). The median maternal gestational age at admission was 8 weeks (range: 4–25 weeks). Detailed maternal characteristics are presented in Table 1. Pregnant women with more than one chronic disease were considered in each disease category. The patterns of exposure are presented in Table 2. The median daily dose of betahistine was 24 mg/day and the duration of exposure varied between 1 and 71 days of pregnancy with the oral route of administration in all of the pregnancies. Child characteristics are presented in Table 3. In 24 pregnancies, two were twin pregnancies (one twin was missed abortus and the mother reported to have one umbilical artery in detailed USG). Therefore, for the calculation of percentages 26 exposed fetuses is used as the denominator. Of 26 fetuses with known outcomes, 21 (80.8%) were live births, two (8.3%) were miscarriages, and three (11.5%) were elective terminations. The median age of the children at the time of the followup was 23 months (range: 4–63 months). One infant was reported to have a low birth weight for gestational age, and seven other were reported to be born preterm. Among 20 live births with in utero exposure to betahistine during the first trimester, there were 17 (85%) normal outcomes, 1 major (5%) and 2 minor (10%) congenital malformations.
4. Discussion To the best of our knowledge, this is the first detailed case series investigating the outcomes of pregnant women exposed to betahistine during pregnancy. In 24 recorded pregnancies with betahistine exposure, the rates of major [our study with confidence intervals vs. background estimate: 5% (0.1–24.9) vs. 1–8% [16],] and minor malformations [10% (1.2–31.7) vs. 4% [17],] and low birth weight [5.3% (0.1–26) vs. 8.4% [18],] were comparable with the general population rates. However, elective termination [11.5% (2.4–30.2) vs. 4.7% [19],] and preterm birth rates [33.3% (14.6–57) vs. 12% [20],] were considerably higher. However, it should be highlighted that small sample size and data sampling limitations associated with Teratology Information Center surveillance methods discussed elsewhere [21] might have limited the precision of those estimates, therefore they should be cautiously interpreted. The only major malformation, in this study, was intestinal malrotation while the minor malformations were patent 80
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Table 1 Maternal characteristics and obstetric history.
Table 3 Pregnancy outcomes and children characteristics. Number (%) or Median (range)
Age (n = 24) < 35 years ≥35 years Gestational age at admission (n = 24) Maternal education (n = 18) None Primary school Secondary school High school University Chronic disease (n = 28)* Yes Meniere Disease/Vertigo Depression Hypothyroidism Behçet’s Disease Mitral Valve prolapse Panic Attack Asthma No Unknown Alcohol (n = 24) No Yes Smoking (n = 24) No ≤5 cigarettes/day > 5 cigarettes/day Drugs of abuse (n = 24) No Radiation exposure (n = 24) No Yes X-ray CT MR Previous pregnancies (n = 23) 0 1 ≥2 Previous parities (n = 24) 0 1 ≥2 Previous miscarriages (n = 21) 0 1 ≥2 Previous elective terminations (n = 21) 0 1 ≥2
32 (20-45) 15 (62.5%) 9 (37.5%) 8 weeks (4-25) 1 5 5 6 1
Outcomes (n = 26)a Live birth Miscarriageb Elective termination Stillbirth Mode of delivery (n = 20) Normal Birth C/S Gestational age at birth (n = 21) Preterm Term Sex (n = 19) Female Male Children’s age at follow-up (months) (n = 17) Birth weight (n = 19) < 2500 g 2500-4000 g Length (n = 14) Outcomes of live births (n = 20)d Healthy Total congenital malformations Major Minor
(5.5%) (27.8%) (27.8%) (33.4%) (5.5%)
15 (53.6%) 6 (40%) 3 (20%) 2 (13.4%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 12 (42.9%) 1 (3.5%) 22 (91.7%) 2 (8.3%) 16 (66.6%) 4 (16.7%) 4 (16.7%)
% (95% Confidence Interval) or Median (range)
21 2 3 –
80.8 (60.1-93.4) 8.3 (1-27) 11.5 (2.4-30.2) –
8 12 38 weeks 7 14
40 (19.1-63.9) 60 (36.1-80.9) (33-40) 33.3 (14.6-57) 66.7 (43-85.4)
9 10 23
47.4 52.6 (4-63)
3500 g 2c 17 50 cm
(2300-3750) 10.5 (1.3-33.1) 89.5 (66.9-98.7) (47-56)
17 3 1 2
85 (62.1-96.8) 15 (3.2-37.9) 5 (0.1-24.9) 10 (1.2-31.7)
a
Fetal outcomes presented due to the presence of twin pregnancies. One twin pregnancy resulted in a live birth and a missed abortus. Denominator was 24 with regard to the definition of miscarriage (< 20 weeks). c One infant was preterm. d Birth information of one infant was available, however we could not reach his information regarding malformations. b
24 (100%) 16 (66.7%) 8 (33.3%) 1 1 6
foramen ovale in two cases. The mother of the infant with intestinal malrotation was exposed to betahistine at 10th week of pregnancy for 3 days (Case 10, Table 4). This coincides with the sensitive period for the development of the gut, since the final 90˚ rotation of the duodenum and 180˚ rotation of the cecum occurs in 10th and 12th weeks of the gestation [22]. The mother also had concomitant medication exposures, namely pantoprazole, antacid combinations, piracetam and trimebutine. However, none of these medications have previously been associated with intestinal malrotation. It has been reported that male infants are more frequently affected than female infants [23], which is consistent with our case. The infant died in 11th day after the birth which can be due to the anomalous intestinal mesenteric fixation as reported by Marseglia et al. [24] or volvulus [25]. The mother had retained placenta, which was needed to be removed after birth and she stayed in hospital for 3 days. Interestingly, parity of the mother was 2 which was suggested to be a reduced risk factor for the intestinal malrotation [26]. Any suggestion of an association between betahistine and congenital malrotation would be speculative due to the relatively frequent prevalence of this malformation (1:500–1:3500) [27,22]. Of note, patent foramen ovale were reported in two infants (Case 6 and Case 9, Table 4). Betahistine exposure in Case 9 occurred in the 13th weeks of pregnancy (LMP), before the sensitive period for the development of major septa of the heart (4–5 weeks postconception) [28]; thus any possible association is excluded. Considering Case 6, betahistine exposure (0-9th weeks of pregnancy) overlaps with organogenesis of the heart. However, potential confounding factors might be the mother’s psychiatric condition and related life style factors and/or concomitant paroxetine exposure [29]. Furthermore, the relatively frequent prevalence (1 in 100 living births; regardless of exposure [30]) and proposed genetic background of this minor malformation [31] makes any association between patent foramen ovale and betahistine unlikely. The infant (Case 6, Table 4) was also diagnosed with
0 (0 %) 8 (34.8%) 15 (65.2%) 2 (8.3%) 9 (37.5%) 13 (54.2%) 18 (85.7%) 1 (4.8%) 2 (9.5%) 16 (76.2%) 3 (14.3%) 2 (9.5%)
* Values do not sum to total because some patients had multiple chronic diseases. Table 2 Patterns of betahistine exposure. Number (%) or Median (range) Route of administration (n = 24) Oral Daily dose of betahistine (n = 17) Time of exposure (n = 20) Preconception and 1st trimester 1st trimester Duration of exposure (n = 19) Indication for betahistine (n = 10) Meniere (Vertigo) Co-exposure (n = 24) Yes No
Number
24 (100%) 24 mg (16-48) 8 (40%) 12 (60%) 14 days (1 -71) 10 (100%) 23 (95.8%) 1 (4.2%)
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Table 4 Descriptive analysis of the children with major and minor congenital malformations after in utero exposure to betahistine with regard to the FDA Guidance on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment [FDA].
The clinical and laboratory manifestations and course of the event
Demographic characteristics of patients with events (e.g., age, gender, race) Exposure duration Time from initiation of product exposure to the adverse event
Case 6 - Minor congenital malformation
Case 9 - Minor congenital malformation
Case 10 - Major congenital malformation
Patent foramen ovale (2 mm) at birth and unspecified valvular defect. Current status of child’s clinical condition is not known due to incomplete pediatric examination. Thyroid glands was not functional and bronchitis 10 days after birth was developed and follow up continues. 34-year-old Caucasian mother. The girl infant was born via C/S at term.
Patent foramen ovale at birth which was closed at one year of age. Mild jaundice was also reported.
Intestinal malrotation
20-year-old Caucasian mother. The girl infant was born via spontaneous birth at the 39th week of gestation. 15 day, between the 1sth and 3th weeks of pregnancy First trimester exposure, however do not coincide with the sensitive period.
36-year-old Caucasian mother. The male infant was born via spontaneous birth at term.
71 days, between the 0 and 9th weeks of pregnancy First trimester exposure, and coincides with the sensitive period for the development of interatrial septum (4-5 weeks postconception)
Doses used in cases, including labeled doses, greater than labeled doses, and overdoses Use of concomitant medication
Peroral, 48 mg/day for 71 days. The dose is compliant with the maximum peroral recommended dose. Propranolol, levothyroxine, hydroxyzine, paroxetine and amitriptyline.
Peroral, 24 mg/day. The dose is compliant with the maximum peroral recommended dose. Ibuprofen and vitamin B complex.
The presence of co-morbid conditions, particularly those known to cause the adverse event
The mother had hypothyroidism and did not use folic acid. Smoking (< 5 cigarettes/day).
The mother had no history of chronic disease and used folic acid between gestational weeks 8 and 12. No history of smoking, alcohol or drug use.
3 days, within the 10th week of pregnancy First trimester exposure which coincides with the sensitive period for the formation of the alimentary tract which starts at the 4th and completed by 8-10th gestational week. Peroral, 48 mg/day for 3 days at 10th week. The dose is compliant with the maximum peroral recommended dose. Pantoprazole, antiacid (calcium carbonate, magnesium carbonate, sodium alginate), piracetam, trimebutine, The mother had no history of chronic disease and not used folic acid. No history of smoking, alcohol or drug use.
relationship with the medications were excluded and an inherited mitochondriopathy was suspected. A female infant with a partial bilateral syndactyly of the second and third toe with the maternal betahistine exposure of the third month of the pregnancy, for whom maternal alcohol consumption was considered as a risk factor. Another infant presented with the complex syndrome of radial limb defects and scoliosis after intrauterine exposure to betahistine, which was diagnosed as VACTERL-association. Authors concluded that identified exposed cases are not comprehensive enough to assess possible teratogenic effects of betahistine therapy during pregnancy and these malformations had no identifiable pattern. There is also a difference between the reported cases in the database and our case series in terms of the types of malformations. Additionally, it is critical to highlight the lack of important details regarding medical and obstetric history of the mother and the exposure in these reports due to the unsystematic nature of the collection of data. With the lack of a critical assessment and interpretation from a teratological point of view, they are susceptible to confounding (such as family and obstetric history and lack of genetic analysis) and misinterpretation. Moreover, retrospective reports such as these databases with adverse pregnancy outcomes are shown to be overrepresented [37].
congenital hypothyroidism which is probably associated with maternal iodine deficiency indicated by the discontinuation of levothyroxine, which was reported by the mother, at 9th gestational week for the fear that medication may be harmful for the fetus. The rate of elective terminations and preterm birth rates in our study group was much higher than for the Turkish population Higher elective termination rates can be explained by overestimation of the potential teratogenic risks of medications as shown by several studies [32,33]. Therefore, the pregnant women included in this case series and their physicians might have had high teratogenic risk perception regarding betahistine exposure during pregnancy. The higher preterm birth rate in our study may be associated with the presence of the risk factors in the mothers, such as preeclampsia and arrhythmia, or perinatal complications (bleeding from previous caesarean sections), and older age (≥37 in two pregnancies). Betahistine have been reported to be contraindicated in pregnancy [34]. While it is prudent to avoid use of a medication lacking rigorous data in pregnancy, this advice does not appear to be well substantiated and supported by evidence. In a recent case series, published as an abstract, Kadıoğlu et al. [35] described 15 cases with first trimester betahistine exposure with no congenital malformation. They reported 12 healthy live births, two spontaneous abortions, and one elective termination (concomitant paroxetine exposure). Authors have concluded that betahistine was unlikely to have a substantial embryotoxic effect. To our knowledge, there are only two post-marketing studies concerning betahistine usage during pregnancy. In a multicenter, openlabel post-marketing surveillance study of betahistine in patients with tinnitus, one pregnant with 18 days betahistine exposure (48 mg/day) present with normal outcome and no adverse drug reactions was reported, however investigators did not mention the exposure time window [36]. Three congenital abnormalities were reported in betahistine global safety database, which covers the past 35 years in a total 554 individual adverse drug reactions report out of 2032 subject [10]. A female infant, presented with microcephalus, hyperlactataemia and calcification of basal ganglia, died at the age of 3 years. Although mother had used betahistine for 10 days (with the concomitant use of caffeine and dihydroergotamine) during early pregnancy, a causal
4.1. Limitations It is well known that case series have major methodological drawbacks. Therefore, it is important to note the limitations of our study. First and the most important, the limited sample size and lack of comparison cohort does not permit us to rule out moderate increases in risk of major or other organ specific malformations. Second, the dose of betahistine widely differed among the pregnant women included. Third, we were not able to evaluate the outcomes of four pregnancies among 27 cases. Although this is an acceptable loss to follow-up rate (14.8%), it is possible that some malformations were missed. Fourth, because the majority of our cases were first trimester exposures, possible fetal adverse effects of betahistine exposure during later trimesters could not be evaluated. Finally, there was no opportunity either to investigate the miscarriages and elective terminations with regard to 82
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possible malformations, or to conduct genetic tests for the infants with malformations to elucidate chromosomal defects.
[13]
5. Conclusion [14]
Our study, combined with the previously reported a case series [35] and post-marketing data [10,36] do not suggest an increased rate of major congenital malformations following betahistine exposure. However, the small sample size and data collection methods of our study calls for caution in the interpretation of results. Nevertheless, this information still may offer some value in assessing the possible teratogenic risks of pregnant women with inadvertent betahistine exposure. Larger prospective series or cohorts are needed before more definite conclusions can be drawn. In addition, because there are also concerns regarding its effectiveness in Meniere’s disease [38,39], it would be wise to avoid betahistine during pregnancy.
[15]
[16]
[17]
[18] [19]
Funding/support
[20]
This research did not receive any specific grant from funding agencies. [21]
Conflict of interest statement
[22]
All authors have completed the Unified Competing Interest Form (available on request from the corresponding author) and declare no support from 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 relationships or activities that could appear to have influenced the submitted work.
[23] [24]
[25] [26]
Acknowledgements Preliminary findings of this study was presented as a poster at the 27 Annual ENTIS Conference 2016 in Berlin and an abstract was published in Reproductive Toxicology (2016; 60:177).
[27]
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